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The following article examines both the cultural and bi-cultural complexities of self-sacrifice as a major familial and communal demand experienced by African American1 professional women at mid-life. As a prelude to this clinical discussion, an examination of the sociological, cultural and inter-cultural dimensions of self-sacrifice are provided. To support clinical intervention and self help, a series of conceptual models, and problem solving and assessment tools are presented to aid practitioners in delivering culturally competent, personally relevant self-empowerment, relational management, and self care strategies for this client group. [ABSTRACT FROM AUTHOR]

In general, the photonic crystal (PC) is a periodical optical structure, but there are some studies considering aperiodic structures. If we insert a defect layer into a one-dimensional periodic PC to break its translational symmetry order (TSO), some peaks, called defect modes, appear in the transmittance spectrum. The defect layer thickness governs the frequencies of these defect modes but almost does not affect the other part of the spectrum. The discovery of quasi-crystals tells us that not only the TSO but also other orders can produce Bragg diffraction. It is well known that triadic Cantor set (TCS) PCs, which lack TSO but have a self-similar symmetry order (SSO), still exhibit narrow transmission peaks. In this work, we try to break the SSO in TCS PCs and find the resulting optical phenomena, where single-negative materials and dielectrics are chosen as the constituents of PCs. The study method is the transfer matrix method, and the calculation results show that the background intensity of the transmittance spectrum rather than the frequency of peaks obviously periodically changes with the break of SSO. It follows that the SSO does have physical meaning, and not only the transmission peaks but also the background should be treated as a significant optical property.

Down syndrome is the most common chromosomal disorder in the United States, occurring in about 14.14/10,000 births. It is associated with multiple medical anomalies, including cardiac, gastrointestinal, musculoskeletal, and genitourinary abnormalities, which increases the burden of morbidity for this patient population. Management is typically directed toward optimizing health and function throughout childhood and into adulthood; however, consensus regarding their management in adulthood is controversial. The burden of congenital cardiac diseases in children with trisomy 21 is well established, seen in more than 40% of cases. Although screening echocardiography is performed routinely within 1 month of birth, current consensus advocates for diagnostic echocardiography only in symptomatic adults with Down syndrome. Here, we advocate that screening echocardiography should be performed routinely in this patient population at all ages, particularly in late adolescence and early adulthood, because of a high percentage of residual cardiac defects and an increased risk of developing valvular and structural cardiac disease.

Introduction: The IMMray PanCan-d test combines an 8-plex biomarker signature with CA19-9 in a proprietary algorithm to detect pancreatic ductal adenocarcinoma (PDAC) in serum samples. This study aimed to validate the clinical performance of the IMMray PanCan-d test and to better understand test performance in Lewis-null (le/le) individuals who cannot express CA19-9., Methods: Serum samples from 586 individuals were analyzed with the IMMray PanCan-d biomarker signature and CA19-9 assay, including 167 PDAC samples, 203 individuals at high risk of familial/hereditary PDAC, and 216 healthy controls. Samples were collected at 11 sites in the United States and Europe. The study was performed by Immunovia, Inc (Marlborough, MA), and sample identity was blinded throughout the study. Test results were automatically generated using validated custom software with a locked algorithm and predefined decision value cutoffs for sample classification., Results: The IMMray PanCan-d test distinguished PDAC stages I and II (n = 56) vs high-risk individuals with 98% specificity and 85% sensitivity and distinguished PDAC stages I-IV vs high-risk individuals with 98% specificity and 87% sensitivity. We identified samples with a CA19-9 value of 2.5 U/mL or less as probable Lewis-null (le/le) individuals. Excluding these 55 samples from the analysis increased the IMMray PanCan-d test sensitivity to 92% for PDAC stages I-IV (n = 157) vs controls (n = 379) while maintaining specificity at 99%; test sensitivity for PDAC stages I and II increased from 85% to 89%., Discussion: These results demonstrate the IMMray PanCan-d blood test can detect PDAC with high specificity (99%) and sensitivity (92%)., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Chronic lymphocytic leukemia (CLL) is the most commonly encountered leukemia in the clinical laboratory. Cytoskeletal defects in CLL lymphocytes can result in the formation of up to 75% smudge cells (SCs) during blood film preparation. Failure to account for these damaged lymphocytes in the white blood cell (WBC) differential diminishes the accuracy and reproducibility of the results. Lacking clear practice standards on handling SCs in CLL, different laboratories may employ different methods to mitigate SC-induced errors. This review explores the pathophysiology of SCs, their effect on WBC differentials in CLL, and how these results can impact clinical decisions. The pros and cons of various SC corrective methods are described to assist laboratories in developing an optimized protocol to reduce errors and inconsistencies in WBC differentials. Finally, the potential utility of SC enumeration as an indicator of CLL prognosis is discussed in terms of laboratories with differing access to technology., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The idea of artificial intelligence for social good (henceforth AI4SG) is gaining traction within information societies in general and the AI community in particular. It has the potential to tackle social problems through the development of AI-based solutions. Yet, to date, there is only limited understanding of what makes AI socially good in theory, what counts as AI4SG in practice, and how to reproduce its initial successes in terms of policies. This article addresses this gap by identifying seven ethical factors that are essential for future AI4SG initiatives. The analysis is supported by 27 case examples of AI4SG projects. Some of these factors are almost entirely novel to AI, while the significance of other factors is heightened by the use of AI. From each of these factors, corresponding best practices are formulated which, subject to context and balance, may serve as preliminary guidelines to ensure that well-designed AI is more likely to serve the social good.

Artificial intelligence (AI) research and regulation seek to balance the benefits of innovation against any potential harms and disruption. However, one unintended consequence of the recent surge in AI research is the potential re-orientation of AI technologies to facilitate criminal acts, term in this article AI-Crime (AIC). AIC is theoretically feasible thanks to published experiments in automating fraud targeted at social media users, as well as demonstrations of AI-driven manipulation of simulated markets. However, because AIC is still a relatively young and inherently interdisciplinary area-spanning socio-legal studies to formal science-there is little certainty of what an AIC future might look like. This article offers the first systematic, interdisciplinary literature analysis of the foreseeable threats of AIC, providing ethicists, policy-makers, and law enforcement organisations with a synthesis of the current problems, and a possible solution space.

We theoretically study the one-way absorption in two 1D defective asymmetric photonic crystals, air/(DB) N A(BD) M /air and air/(DB) N A(BD) M A(DB) N A(BD) M /air, where A and B are dielectrics, D is the semiconductor, n-InSb, and N, M are stack numbers with N≠M. It is revealed that their absorption spectra exhibit one-way properties. We also find that the number of one-way absorption peaks depends on the symmetry and number of defect layers, which are similar to the defect modes in the transmittance spectra of the usual symmetry photonic crystals. Additionally, effects of the incident angles for both TE and TM waves on the one-way feature are also presented. At a large incident angle, the TE wave is almost reflected, whereas the TM wave can have a partial absorption.

We theoretically study wave properties for one-dimensional defective asymmetric photonic crystals, air/(AB) M G(BA) N /air, air/(AQ) M G(QA) N /air, and air/(BQ) M G(QB) N /air, where A is a lossy epsilon-negative material, B is a lossy mu-negative material, G and Q are dielectrics with different refractive indexes, and M and N are stack numbers with M≠N. Special attention has been paid to their absorption spectra. It is found that at certain frequencies the absorption can exhibit unidirectional properties. Our calculated results show two kinds of unidirectional absorption peaks. One is a single absorption peak whose frequency depends on the thickness of defect layer G. For the other peaks, its frequency does not change when the defect layer's thickness changes. In addition, in the second kind of peaks, the peak numbers for forward and backward propagation are different, that is, there are (M-1) absorption peaks for forward propagation, while there are (N-1) absorption peaks for backward propagation. When the two kinds of unidirectional absorption peaks are merged, some new peaks appear, and both forward and backward propagation will have (M+N-1) absorption peaks.

The ferroelectric material KTaO 3 (KTO) has a very high refractive index, which is advantageous to the photonic crystal (PC) design. KTO polycrystalline crystal has a high extinction coefficient. In this work, we perform a theoretical study of the transmission properties of a PC bandpass filter made of polycrystalline KTO at terahertz (THz) frequencies. Our results show that the defect modes of usual PC narrowband filters no longer exist because of the existence of the high loss. We provide a new PC structure for the high-extinction materials and show that it has defect modes in its transmittance spectra, providing a possible bandpass filter design in the THz region.

In this work, we propose a filter structure using a one-dimensional ferroelectric-dielectric periodic multilayer, air/[(ABA) N s C] Np (ABA) N s /air, where N s and N p are the two numbers of periods. Here, B is a dielectric material of SiO 2 , C is the same as B with a different thickness, and A is taken to be a ferroelectric material Ba 55 Sr 45 TiO 3 +30%Mg 2 SiO 4 , whose dielectric constant is very high (ϵ=439 at 10 GHz). The results show that the transmittance spectra have N s -channel groups at microwave frequencies and these groups can be classified into two types. The first type has only one channel group with N p narrower channels. The other has N s -1 groups, each of which has N p +1 broader channels. In this filter structure the group number and channel number of each group can be determined simply by changing N s and N p .

An 82-year-old Japanese nonsmoking man presented with persistent dry cough and small left apical pneumothorax. High resolution CT scan of the chest demonstrated bilateral upper lobe pleuroparenchymal thickening and architectural distortion. Serial imaging revealed mild progression and development of small bilateral pneumothoraces, and pneumomediastinum. A surgical lung biopsy was required to confirm the diagnosis., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

The novel heterometallic polyoxotitanate cage [Ti18MnO30(OEt)20(MnPhen)3] (1), obtained by solvothermal reaction of Ti(OEt)4 with Mn(AcO)3·(H2O)2 and 1,10-phenanthroline (Phen) in EtOH, has a C3 symmetric core structure containing an interstitial tetrahedral Mn(II) ion and is surrounded by three Mn(II)(Phen) fragments. The molecular structure is retained in thin film electrodes of 1 deposited by solution drop-casting onto fluorinated tin oxide (FTO). Both solid state and solution phase electrochemical measurements show dual redox couples, consistent with the two distinct Mn coordination environments in the cage structure. Sintering of 1 in air at 600 °C produces a black crystalline solid which consists of Mn-doped TiO2 (mainly in the rutile phase) together with α-Mn2O3. Such a composite semiconductor has an optical band gap of ca. 1.80 eV, similar to that of α-Mn2O3.

In this work, the photonic band gap (PBG) structure in a one-dimensional ferroelectric photonic crystal (PC) is theoretically investigated. We consider a PC, air/(AB) N /air, in which layer A is a dielectric of MgO and layer B is taken to be a ferroelectric of Ba 0.55 Sr 0.45 TiO 3 (BSTO). With an extremely high value in the dielectric constant in BSTO, the calculated photonic band structure at microwave frequencies exhibits some interesting features that are significantly different from those in a usual dielectric-dielectric PC. First, the photonic transmission band consists of multiple and nearly discrete transmission peaks. Second, the calculated bandwidth of the PBG is nearly unchanged as the angle of incidence varies in the TE wave. The bandwidth will slightly reduce for the TM mode. Thus, a wide omnidirectional PBG can be obtained. Additionally, the effect of the thickness of the ferroelectric layer on the PBG is much more pronounced compared to the dielectric layer thickness. That is, the increase of ferroelectric thickness can significantly decrease the PBG bandwidth.

Rationale: Interferon-γ release assays have significant advantages over tuberculin skin testing in many clinical situations. However, recent studies have called into question their reliability in serial testing of healthcare workers because of reportedly high rates of positivity and high conversion/reversion rates on retesting., Objectives: To define the performance characteristics of the T-SPOT.TB test, an interferon-γ release assay, during serial screening programs of healthcare workers at 19 U.S. hospitals., Methods: A total of 42,155 T-SPOT.TB test results from healthcare workers at 19 geographically diverse hospitals obtained for routine tuberculosis screening programs were analyzed to determine the rates of positivity, reversion, and conversion in serial testing data., Measurements and Main Results: In 19,630 evaluable serial pairs from 16,076 healthcare workers, the mean test positivity rate was 2.3% (range, 0.0-27.4%). The mean conversion rate was 0.8% (range, 0.0-2.5%), and the mean reversion rate was 17.6%. Positivity and conversion rates correlated with known tuberculosis risk factors including age and sex. The observed specificity of the T-SPOT.TB test was at least 98.6%., Conclusions: The high concordance and test completion rates in this study suggest that the T-SPOT.TB test is a reliable tool for healthcare worker serial screening. As expected, the observed positivity rates were lower compared with the tuberculin skin test, likely reflecting the higher specificity of this test. Furthermore, the observed rates of conversion were low and significantly correlated with the geographic incidence of tuberculosis. Our findings suggest that the T-SPOT.TB test is an accurate and reliable way to screen healthcare workers.

Previous theoretical studies of C3B have suggested that boron-doped graphite is a promising H2- and Li-storage material, with large maximum capacities. These characteristics could lead to exciting applications as a lightweight H2-storage material for automotive engines and as an anode in a new generation of batteries. However, for these applications to be realized a synthetic route to bulk C3B must be developed. Here we show the thermolysis of a single-source precursor (1,3-(BBr2)2C6H4) to produce graphitic C3B, thus allowing the characteristics of this elusive material to be tested for the first time. C3B was found to be compositionally uniform but turbostratically disordered. Contrary to theoretical expectations, the H2- and Li-storage capacities are lower than anticipated, results that can partially be explained by the disordered nature of the material. This work suggests that to model the properties of graphitic materials more realistically, the possibility of disorder must be considered., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Metal-doped polyoxotitanium cages (M-POTs) of the type [TixOy(OR)zMnXm] (M = a main group, transition metal or lanthanide; X = an anion such as a halide) can be regarded as molecular fragments of metal-doped TiO2. As such M-POTs can be used as structural models for the inclusion of metal ions into the TiO2 lattice and the ways in which well-defined microstructural changes affect photo-induced hole-electron separation. They are also potential organically-soluble redox-catalysts for a range of organic transformations and have been shown to be useful single-source precursors for the deposition of metal-doped TiO2. The applications of M-POTs as molecular precursors to metal-doped TiO2 offers a high degree of atomic control in the low temperature fabrication of photocatalytic thin films, which have applications in pollution control and water splitting. This perspective highlights the structural trends in M-POTs, their electronic behaviour and their applications as single-source precursors, looking at current and future trends in the development of inorganic precursors for device applications.

A fractal multilayer structure made of two dielectric materials can exhibit photonic bandgap (PBG). In this work, with the use of this PBG, we study the transmission properties of periodic triadic Cantor set structures. The results indicate that the structure can be used to design multichannel filters with channel number equal to N-1 for a given number of periods, N. In addition, the channel frequencies can be designed at will. The considered structure provides another new type of design for a tunable multichannel filter.

To what extent the presence of transition metal ions can affect the optical properties of structurally well-defined, metal-doped polyoxotitanium (POT) cages is a key question in respect to how closely these species model technologically important metal-doped TiO2. This also has direct implications to the potential applications of these organically-soluble inorganic cages as photocatalytic redox systems in chemical transformations. Measurement of the band gaps of the series of closely related polyoxotitanium cages [MnTi14(OEt)28O14(OH)2] (1), [FeTi14(OEt)28O14(OH)2] (2) and [GaTi14(OEt)28O15(OH)] (3), containing interstitial Mn(II), Fe(II) and Ga(III) dopant ions, shows that transition metal doping alone does not lower the band gaps below that of TiO2 or the corresponding metal-doped TiO2. Instead, the band gaps of these cages are within the range of values found previously for transition metal-doped TiO2 nanoparticles. The low band gaps previously reported for 1 and for a recently reported related Mn-doped POT cage appear to be the result of low band gap impurities (most likely amorphous Mn-doped TiO2).

Photoactive in one step! A nanocomposite water-oxidation photocatalyst was assembled by a straightforward and one-step spin-coating procedure of a Ti- and Ni-containing molecule on nanostructured WO3. The photoanode oxidizes water to O2 with good activity and stability in alkaline solution, and thereby features light absorption, charge separation and water-oxidation catalysis (see scheme)., (© 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.)

Cobalt-containing polyoxotitanates (TiCo) are excellent precursors for the simple and scalable preparation of Nocera-type CoOx water-oxidation electrocatalysts. The TiCo cages serve as a reservoir for cobalt ions in a titania matrix on fluoride-doped tin oxide electrodes, and form, in situ, the active CoOx catalyst for O2 evolution with high stability in phosphate buffer in pH neutral water.

The solvothermal reactions of Ti(OEt)(4) with LnCl(3) (Ln = La, Ce) produced new Ti(28) Ln cages, in which the Ln(3+) ions are coordinated within a metallocrown arrangement, which represents the highest nuclearity cages of this type (see figure)., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Over-expression of the multifunctional zinc-finger transcription factor Yin Yang 1 (YY1) has been associated with cellular proliferation and resistance to apoptotic stimuli. In this study, we report that YY1 was uniformly highly over-expressed in a wide range of human cancer cell lines and in human colon cancer tissue samples. The examination of YY1-specific mRNA expression demonstrated at least six mRNA isoforms ubiquitously expressed in normal human adult and fetal tissues. Substantial over-expression of two specific mRNA isoforms of 7.5 and 2.9 kb size, respectively, was detected in gastrointestinal and other cancer cells in vitro, whereby mRNA stability differed significantly between various cell lines. YY1 protein expression levels were similar in different colon cancer cell lines. Using FISH analysis of several colorectal cancer cell lines, the human YY1 locus was expectedly identified on chromosome 14q32 and no evidence of gene amplification and chromosomal translocation was observed. However, varying degree of aneuploidy was noted in vitro. YY1 immunoreactivity in human colon tumor samples was found more intense in poorly differentiated tumors than in moderately and well differentiated colon cancers and lower expression levels tended to be associated with shorter survival. In conclusion, YY1 was over-expressed in colon cancer in the absence of gene amplification and chromosomal translocation. YY1 mRNA and protein stability are important regulatory mechanisms of YY1 expression in colon cancer.

The aryl hydrocarbon receptor nuclear translocator (ARNT) is a basic helix-loop-helix-PAS heterodimeric transcription factor that dimerizes with other basic helix-loop-helix-PAS proteins to mediate biological responses. The function of ARNT2 is poorly understood. Here we provide an initial characterization of the zebrafish arnt2 null (arnt2(-/-)) mutant to identify functions of Arnt2 during development. Arnt2(-/-) mutant zebrafish develop normally until 120 hours postfertilization (hpf ) when morphological changes and functional deficits occur. The C-start escape response initiated by either touch or startle stimuli is absent in the mutants. Brain ventricle size is markedly increased at 120 hpf. Heart ventricles are enlarged, with decreased ventricle wall thickness. A cardiac arrhythmia, characterized by missing beats, is also observed in the mutants. This is associated with bradycardia in arnt2(-/-) larvae. Dilated liver sinusoids merge abnormally to form an extensive, labyrinth-like network of vascular channels. External appearance of arnt2(-/-) larvae at 120 hpf is indistinguishable from wild type except that the swim bladder is not inflated. The arnt2(-/-) mutants are not debilitated when phenotypic effects are first detected at 120 hpf that culminate in mortality, 4 days later around 216 hpf. Gross morphological assessment of the development of forebrain, midbrain, and hindbrain regions, neuromasts and Mauthner neurons, inner ear semicircular canals and otoliths, primary motor neurons, trigeminal ganglia, and trunk skeletal muscles, before or when the arnt2(-/-) phenotype was observed, failed to demonstrate a difference from wild type. The only effect in arnt2(-/-) larvae that occurred before 120 hpf was a decrease in expression of sim1, an Arnt2 dimerization partner, in the hypothalamus and ventral thalamus at 72 hpf. Further research is needed to determine if the primary functions of Arnt2 occur during the larval stage, when the phenotype is observed, or earlier in development.

Introduction: We investigated clinical and pathologic features of breast cancers (BC) in an unselected series of patients diagnosed in a tertiary care hospital serving a diverse population. We focused on triple-negative (Tneg) tumours (oestrogen receptor (ER), progesterone receptor (PR) and HER2 negative), which are associated with poor prognosis., Methods: We identified female patients with invasive BC diagnosed between 1998 and 2006, with data available on tumor grade, stage, ER, PR and HER2 status, and patient age, body mass index (BMI) and self-identified racial/ethnic group. We determined associations between patient and tumour characteristics using contingency tables and multivariate logistic regression., Results: 415 cases were identified. Patients were racially and ethnically diverse (born in 44 countries, 36% white, 43% black, 10% Hispanic and 11% other). 47% were obese (BMI > 30 kg/m2). 72% of tumours were ER+ and/or PR+, 20% were Tneg and 13% were HER2+. The odds of having a Tneg tumour were 3-fold higher (95% CI 1.6, 5.5; p = 0.0001) in black compared with white women. Tneg tumours were equally common in black women diagnosed before and after age 50 (31% vs 29%; p = NS), and who were obese and non-obese (29% vs 31%; p = NS). Considering all patients, as BMI increased, the proportion of Tneg tumours decreased (p = 0.08)., Conclusions: Black women of diverse background have 3-fold more Tneg tumours than non-black women, regardless of age and BMI. Other factors must determine tumour subtype. The higher prevalence of Tneg tumours in black women in all age and weight categories likely contributes to black women's unfavorable breast cancer prognosis.

TCDD is a reproductive toxicant and endocrine disruptor, yet the mechanisms by which it causes these reproductive alterations are not fully understood. In order to provide additional insight into the molecular mechanisms that underlie TCDD's reproductive toxicity, we assessed TCDD-induced transcriptional changes in the ovary as they relate to previously described impacts on serum estradiol concentrations and altered follicular development in zebrafish. In silico computational approaches were used to correlate candidate regulatory motifs with observed changes in gene expression. Our data suggest that TCDD inhibits follicle maturation via attenuated gonadotropin responsiveness and/or depressed estradiol biosynthesis, and that interference of estrogen-regulated signal transduction may also contribute to TCDD's impacts on follicular development. TCDD may also alter ovarian function by disrupting various signaling pathways such as glucose and lipid metabolism, and regulation of transcription. Furthermore, events downstream from initial TCDD molecular-targets likely contribute to ovarian toxicity following chronic exposure to TCDD. Data presented here provide further insight into the mechanisms by which TCDD disrupts follicular development and reproduction in fish, and can be used to formulate new hypotheses regarding previously documented ovarian toxicity.

Biological molecules and intracellular structures operate at the nanoscale; therefore, development of nanomedicines shows great promise for the treatment of disease by using targeted drug delivery and gene therapies. PAMAM dendrimers, which are highly branched polymers with low polydispersity and high functionality, provide an ideal architecture for construction of effective drug carriers, gene transfer devices and imaging of biological systems. For example, dendrimers bioconjugated with selective ligands such as Arg-Gly-Asp (RGD) would theoretically target cells that contain integrin receptors and show potential for use as drug delivery devices. While RGD-conjugated dendrimers are generally considered not to be cytotoxic, there currently exists little information on the risks that such materials pose to human health. In an effort to compliment and extend the knowledge gleaned from cell culture assays, we have used the zebrafish embryo as a rapid, medium throughput, cost-effective whole-animal model to provide a more comprehensive and predictive developmental toxicity screen for nanomaterials such as PAMAM dendrimers. Using the zebrafish embryo, we have assessed the developmental toxicity of low generation (G3.5 and G4) PAMAM dendrimers, as well as RGD-conjugated forms for comparison. Our results demonstrate that G4 dendrimers, which have amino functional groups, are toxic and attenuate growth and development of zebrafish embryos at sublethal concentrations; however, G3.5 dendrimers, with carboxylic acid terminal functional groups, are not toxic to zebrafish embryos. Furthermore, RGD-conjugated G4 dendrimers are less potent in causing embryo toxicity than G4 dendrimers. RGD-conjugated G3.5 dendrimers do not elicit toxicity at the highest concentrations tested and warrant further study for use as a drug delivery device.

In the viviparous bonnethead shark, Sphyrna tiburo, a fluid-filled, acellular egg capsule surrounds fertilized eggs and developing embryos throughout gestation. Like other placental shark species, the capsule remains intact even at the placental implantation site. Although its intervention between the uterine and embryonic tissues of the placenta has long been thought to mediate physiological exchange, little information is available concerning even its basic structure or permeability to solutes. The 1 mum thick capsule wall consists of an inner layer of gelatinous material and an outer layer consisting of at least three laminae of orthogonally arranged fibrous material. These fibers are irregular and often branched. Permeability experiments showed that solutes less than 1,355 Da diffuse across the egg capsule whereas those greater than 6,000 Da do not pass through the membrane. Solute movement across the capsule is a concentration-dependent phenomenon indicating diffusion rather than active transport. Experimental data also suggest that there is an increase in the permeability of the egg capsule to low molecular weight materials during mid- and late gestation. These observations are discussed in relation to the function of the egg capsule as a mediator of maternal-embryonic interactions in matrotrophic sharks.

Novel systemic treatments are needed in pancreatic cancer. The authors sought to establish the frequency of overexpression of the HER-2/neu oncogene in patients with pancreatic adenocarcinoma to determine the potential role of trastuzumab (Herceptin) as a therapeutic agent in this disease. Tumor specimens from patients with pancreatic adenocarcinoma were analyzed by staining for p185HER2 protein using the DAKO immunohistochemical assay. Patients with and without HER-2/neu overexpression by immunohistochemistry were compared with respect to clinical and pathologic characteristics. HER-2/neu gene amplification was also evaluated by fluorescence in situ hybridization (FISH). Thirty-two of 154 patients (21%) had pancreatic adenocarcinoma that demonstrated HER-2/neu overexpression by immunohistochemistry. At initial diagnosis, 16% of resectable cancers, 17% of locally advanced cancers, and 26% of metastatic cancers were determined to have HER-2/neu overexpression. Three of 11 (27%) patients with HER-2/neu overexpression by immunohistochemistry had gene amplification by FISH. HER-2/neu overexpression occurs in a subset of pancreatic cancer. Evaluation of the efficacy of trastuzumab for patients with pancreatic cancer who overexpress HER-2/neu appears indicated.

Background: In vitro data and animal studies suggest that paclitaxel may have a unique ability to activate tumor cell apoptosis in the absence of wild-type p53 function. The authors previously demonstrated that response to paclitaxel and concurrent radiation was not affected by p53 mutations in nonsmall cell lung carcinoma (NSCLC). We sought to determine whether p53 mutations affect response to paclitaxel alone in patients with metastatic NSCLC., Methods: Twenty-five patients with metastatic NSCLC who participated in Brown University Oncology Group protocols utilizing single-agent weekly paclitaxel had tumor tissue that was adequate for p53 analysis. Tumor tissue was evaluated for p53 gene mutations in exons 5 through 8 by single-strand conformation polymorphism analysis. Mutations were confirmed by direct sequencing of altered mobility polymerase chain reaction products., Results: Mutations in p53 were found in 8 of 25 patients (32%). The response rates of 75% for patients with tumors with p53 mutations and 47% for patients with wild-type p53 do not differ significantly (P = 0.12). The 1-year survival rates for patients with and without p53 mutation after treatment with weekly paclitaxel were 63% (95% confidence interval [CI], 31-100%) and 53% (95% CI, 33-86%), respectively., Conclusions: p53 mutations do not adversely affect response to paclitaxel as a single agent in metastatic NSCLC. These results provide clinical support for in vitro observations that paclitaxel can bypass mutant p53 and lead to tumor cell death by alternate pathway(s). Paclitaxel should be considered as a component of treatment for patients with metastatic NSCLC with tumors that have p53 mutations., (Copyright 2000 American Cancer Society.)

Normal mature quiescent human B lymphocytes, isolated as a function of buoyant density, require activation for up-regulation of IL-13R constituents. Cell activation through a combination of surface Ig and CD40 receptor ligation leads to the most substantial message production for IL-13Ralpha1. Functional consequences of this receptor variation, in initially quiescent cells, includes demonstrable effects on cellular proliferation in response to ligand exposure. Variations in the method of surface activation, with particular emphasis on the CD40 receptor, reveals that immobilized CD40 ligand may be sufficient, in and of itself, to up-regulate IL-13Ralpha1, which may bear significance for B-lymphocyte bystander proliferation. Regulation of the IL-13Ralpha1 protein and message also differs as a function of cellular phenotype. Although values are greater in memory than naive B cells, as they are initially isolated from extirpated tonsils, variations in the magnitude of message and protein, as a function of surface stimulation, are more substantial in the naive subset. The magnitude of variation in message production in naive cells is associated with a more vigorous proliferative response to IL-13 than seen in memory lymphocytes. The cellular response to IL-13, as a function of activation and phenotype, is the converse of that demonstrated for IL-2. Evaluation of proliferation, receptor message, ligand binding protein production, and the response to putatively synergistic cytokines reveals that IL-2 is the predominant lymphokine utilized by memory cells. This is in contradistinction to IL-13, which along with IL-4, are the predominant moieties for naive lymphocytes.

GABP is a heteromeric transcription factor complex which consists of the ets related protein, GABPalpha, and the Notch-related protein, GABPbeta. We isolated a human genomic DNA fragment which is highly homologous and colinear with human GABPalpha cDNA, but which lacks introns. This processed pseudogene, psihGABPalpha, is expressed as RNA in U937 human myeloid cells, but a mutation at the site that corresponds to the ATG start methionine codon prevents its translation into protein. The pseudogene was localized to chromosome 7 using a somatic cell hybrid mapping panel and it is not syntenic with authentic GABPalpha, which was localized to chromosome 21. We have identified psihGABPalpha, a novel, GABPalpha-related processed pseudogene which is expressed as a RNA transcript in human myeloid cells.

Molecular genetic alterations that disturb cell cycle regulation in tumor cells can affect their response to chemotherapeutic agents and radiation. Many genes that regulate the critical cell cycle checkpoint at G1S are altered in human tumors. These genetic changes can result in uncontrolled cellular proliferation, genetic instability, and altered response to radiation and chemotherapy. The p53 tumor suppressor gene serves a critical role at the G1S transition, where it can either block entry into S phase or activate programmed cell death (apoptosis) in response to DNA damage. p53 Gene mutations are common in human tumors and interfere with the activation of apoptosis in response to most chemotherapeutic agents. Paclitaxel is a potent chemotherapeutic agent that interferes with mitotic spindle function to block cells at G2M, the most radiosensitive phase of the cell cycle. Utilization of paclitaxel as a radiation sensitizer in vivo to treat aggressive, locally advanced neoplasms has resulted in high response rates and acceptable toxicity in protocols for non-small cell lung carcinoma, upper gastrointestinal tract carcinoma, and other malignancies. Recent evidence suggests that paclitaxel is unique in its ability to activate apoptosis in tumor cells with p53 mutations in vitro and in vivo. The p16(INK4a) (MTS-1, CDKN2) gene product acts in the same pathway as p53 to inhibit cell cycle progression at G1/S. p16(INK4a) is deleted and/or mutated in a significant fraction of human tumors, including pancreatic carcinoma. The effects of p16(INK4a) alterations in response to paclitaxel/radiation and the risk of systemic relapse are currently being evaluated. Information about molecular genetic alterations in individual tumors ultimately may be a critical factor in choosing between therapeutic options.

PCR amplification and product analysis for the detection of chromosomal translocations such as bcl-1/JH have traditionally been performed as a two-step process with separate amplification and product detection. PCR product detection has generally entailed gel electrophoresis, hybridization, or sequencing for confirmation of assay specificity. By using a microvolume fluorimeter integrated with a thermal cycler and the PCR compatible double-stranded DNA (dsDNA) binding dye SYBR Green I, we simultaneously amplified and detected bcl-1/JH translocation products by using rapid cycle PCR and fluorescence melting curve analysis. We analyzed DNA from 25 cases of lymphoproliferative disorders comprising 12 previously documented bcl-1/JH-positive mantle cell lymphomas, and 13 reactive lymphadenopathies. The samples were coded and analyzed in a blind manner for the presence of bcl-1/JH translocations by fluorescence melting curve analysis. The results of fluorescence analysis were compared with those of conventional PCR and gel electrophoresis. All of the 12 cases (100%) previously determined to be bcl-1/JH positive by conventional PCR analysis showed a characteristic sharp decrease in fluorescence at about 86 degrees C by melting curve analysis. For easier visualization of melting temperatures (Tm), fluorescence melting peaks were obtained by plotting the negative derivative of fluorescence over temperature (-dF/dT) versus temperature (T). Dilutional assays revealed that fluorescence melting curve analysis was more sensitive than conventional PCR and agarose gel electrophoresis with ultraviolet transillumination by as much as 40-fold. Our results indicate that nucleic acid amplification integrated with fluorescence melting curve analysis is a simple, reliable, sensitive, and rapid method for the detection of bcl-1/JH translocations. The feasibility of specific PCR product detection without electrophoresis or expensive fluorescently labeled probes makes this methodology attractive for studies in molecular pathology.

Polymerase chain reaction (PCR) amplification and product analysis for the detection of chromosomal translocations, such as the t(14;18), has traditionally been a two-step process. PCR product detection has generally entailed gel electrophoresis and/or hybridization or sequencing for confirmation of assay specificity. Using a microvolume fluorimeter integrated with a thermal cycler and a PCR-compatible double-stranded DNA (dsDNA) binding fluorescent dye (SYBR Green I), we investigated the feasibility of simultaneous thermal amplification and detection of MBR/JH translocation products by fluorescence melting curve analysis. We analyzed DNA from 30 cases of lymphoproliferative disorders comprising 19 cases of previously documented MBR/JH-positive follicle center lymphoma and 11 reactive lymphadenopathies. The samples were coded and analyzed blindly for the presence of MBR/JH translocations by fluorescence melting curve analysis. We also performed dilutional assays using the MBR/JH-positive cell line SUDHL-6. Multiplex PCR for MBR/JH and beta-globin was used to simultaneously assess sample adequacy. All (100%) of the 19 cases previously determined to be MBR/JH positive by conventional PCR analysis showed a characteristic sharp decrease in fluorescence at approximately 90 degrees C by melting curve analysis after amplification. Fluorescence melting peaks obtained by plotting the negative derivative of fluorescence over temperature (-dF/dT) versus temperature (T) showed melting temperatures (Tm) at 88.85+/-1.15 degrees C. In addition, multiplex assays using both MBR/JH and beta-globin primers yielded easily distinguishable fluorescence melting peaks at approximately 90 degrees C and 81.2 degrees C, respectively. Dilutional assays revealed that fluorescence melting curve analysis was more sensitive than conventional PCR and agarose gel electrophoresis with ultraviolet transillumination by as much as 100-fold. Simultaneous amplification and fluorescence melting curve analysis is a simple, reliable, and sensitive method for the detection of MBR/JH translocations. The feasibility of specific PCR product detection without electrophoresis or utilization of expensive fluorescently labeled probes makes this method attractive for routine molecular diagnostics.

Pancreatic adenocarcinoma is a major cause of cancer death in the United States. Most cases are sporadic and are discovered at late stage when they are not curable by surgery. Information about the molecular biology of pancreatic adenocarcinoma has increased significantly in the last five years with the identification of alterations in the K-ras proto-oncogene and the p16INK4a, p53, FHIT, and DPC4 tumor suppressor genes in a high percentage of tumors. Pancreatic adenocarcinoma is not homogeneous genetically, however, and other genes are clearly involved in some sporadic and heritable tumors. This review summarizes recent data relating to the molecular biology of pancreatic adenocarcinoma with emphasis on features which may be of clinical significance for diagnosis and/or therapy. Molecular genetic alterations that disturb cell cycle regulation in tumor cells can affect their response to chemotherapeutic agents and radiation and many of these genes are targeted in pancreatic adenocarcinoma. Knowledge of these genetic alterations in individual tumors may allow selection of optimal therapeutic strategies for individual patients. Furthermore, molecular detection of oncogene and tumor suppressor gene mutations may find application as screening tests for pancreatic adenocarcinoma at least in high risk populations. Biological therapy aimed at specific oncogenes and tumor suppressor gene replacement therapy protocols for pancreatic adenocarcinoma are beginning and may offer promise in the future.

Splenic marginal zone cell lymphomas (SMZCLs) are low-grade B-cell lymphomas that usually present with massive splenomegaly and subtle (subleukemic) peripheral blood involvement. Polymerase chain reaction (PCR) analysis of peripheral blood from a patient with subleukemic SMZCL showed evidence of two clonal immunoglobulin heavy chain (IgH) gene rearrangements. IgH PCR analysis of DNA derived from the patient's splenic neoplasm demonstrated a single clonal IgH rearrangement, which had a different electrophoretic mobility from either of the two PCR products detected in the patient's peripheral blood. Additional characterization of these PCR products by DNA sequencing demonstrated two independent IgH rearrangements in the peripheral blood, one of which used IgH joining region 6c (JH6C) and the other JH4. A different IgH rearrangement was present in the splenic tumor, which used JH4a. No sequences from the splenic neoplasm were detected in the peripheral blood and vice versa. This case illustrates that PCR might reveal monoclonal populations in peripheral blood unrelated to the presence of lymphoma in other anatomic compartments.

Objective: Warthin tumor of the salivary gland is composed of oncocytic epithelium with a prominent follicular lymphoid infiltrate. The purpose of this study was to characterize the clonality of this lymphoid component by means of polymerase chain reaction technology., Study Design: DNA was isolated from paraffin-embedded tissue from 20 cases of typical Warthin tumor of the salivary gland and amplified by polymerase chain reaction to assess B- and T-cell clonality., Results: No dominant clonal populations were identified in any tumor. However, minor clonal expansions of both B and T cells were detected in up to 50% of tumors (immunoglobulin H, 50%; T-cell antigen receptor beta, 10%; T-cell antigen receptor gamma, 5%). No tumors showed evidence of bcl-2 proto-oncogene translocation, whereas 95% contained detectable Epstein-Barr virus DNA., Conclusion: The B- and T-cell components of Warthin tumor are polyclonal with oligoclonal expansion of both T and B cells in some lesions.

Human B cells stimulated through both their immunoglobulin and CD40 receptors up-regulate 745 +/- 51 interleukin (IL)-13 ligand binding sites with an affinity of 0.91 +/- 0.08 nM within 24 h. IL-13 binds primarily to the IL-13Ralpha1 with subsequent sequestration of the IL-4Ralpha into the complex. IL-13Ralpha1 may also be found in those receptors capable of binding IL-4. gamma chain (gammac) participates in receptors capable of binding IL-4 but is not found in association with bound IL-13. Dimeric receptors composed of the IL-4Ralpha complexed with either the IL-13Ralpha1 or gammac occur simultaneously within defined B cell populations. mRNAs for all receptor constituents are increased subsequent to immunoglobulin stimulation alone, while maximal expression of IL-13Ralpha1 is more dependent upon co-stimulation of immunoglobulin and CD40 receptors. mRNA levels for IL-13Ralpha1 vary over a wider range subsequent to surface stimulation than other receptor components. Although gammac is not bound to IL-13 in B cells under the conditions evaluated, it may influence IL-13 binding by competing with IL-13Ralpha1 for association/sequestration with the IL-4Ralpha chain. IL-13Ralpha2 does not participate in the IL-13 receptor that is up-regulated upon activation of quiescent tonsillar B lymphocytes, although mRNA for the protein may be found in the centroblastic fraction of tonsillar cells.