Pancreatic Cancer Susceptibility Loci and Their Role in Survival

Pancreatic cancer has one of the worst mortality rates of all cancers. Little is known about its etiology, particularly regarding inherited risk. The PanScan project, a genome-wide association study, identified several common polymorphisms affecting pancreatic cancer susceptibility. Single nucleotide polymorphisms (SNPs) in ABO, sonic hedgehog (SHH), telomerase reverse transcriptase (TERT), nuclear receptor subfamily 5, group A, member 2 (NR5A2) were found to be associated with pancreatic cancer risk. Moreover the scan identified loci on chromosomes 13q22.1 and 15q14, to which no known genes or other functional elements are mapped. We sought to replicate these observations in two additional, independent populations (from Germany and the UK), and also evaluate the possible impact of these SNPs on patient survival. We genotyped 15 SNPs in 690 cases of pancreatic ductal adenocarcinoma (PDAC) and in 1277 healthy controls. We replicated several associations between SNPs and PDAC risk. Furthermore we found that SNP rs8028529 was weakly associated with a better overall survival (OS) in both populations. We have also found that NR5A2 rs12029406_T allele was associated with a shorter survival in the German population. In conclusion, we found that rs8028529 could be, if these results are replicated, a promising marker for both risk and prognosis for this lethal disease

Increase in perceived case suspiciousness due to local contrast optimisation in digital screening mammography

Item does not contain fulltextOBJECTIVES: To determine the influence of local contrast optimisation on diagnostic accuracy and perceived suspiciousness of digital screening mammograms. METHODS: Data were collected from a screening region in the Netherlands and consisted of 263 digital screening cases (153 recalled,110 normal). Each case was available twice, once processed with a tissue equalisation (TE) algorithm and once with local contrast optimisation (PV). All cases had digitised previous mammograms. For both algorithms, the probability of malignancy of each finding was scored independently by six screening radiologists. Perceived case suspiciousness was defined as the highest probability of malignancy of all findings of a radiologist within a case. Differences in diagnostic accuracy of the processing algorithms were analysed by comparing the areas under the receiver operating characteristic curves (A(z)). Differences in perceived case suspiciousness were analysed using sign tests. RESULTS: There was no significant difference in A(z) (TE: 0.909, PV 0.917, P = 0.46). For all radiologists, perceived case suspiciousness using PV was higher than using TE more often than vice versa (ratio: 1.14-2.12). This was significant (P <0.0083) for four radiologists. CONCLUSIONS: Optimisation of local contrast by image processing may increase perceived case suspiciousness, while diagnostic accuracy may remain similar. KEY POINTS: Variations among different image processing algorithms for digital screening mammography are large. Current algorithms still aim for optimal local contrast with a low dynamic range. Although optimisation of contrast may increase sensitivity, diagnostic accuracy is probably unchanged. Increased local contrast may render both normal and abnormal structures more conspicuous.1 april 201

Mammographic density. Measurement of mammographic density

Mammographic density has been strongly associated with increased risk of breast cancer. Furthermore, density is inversely correlated with the accuracy of mammography and, therefore, a measurement of density conveys information about the difficulty of detecting cancer in a mammogram. Initial methods for assessing mammographic density were entirely subjective and qualitative; however, in the past few years methods have been developed to provide more objective and quantitative density measurements. Research is now underway to create and validate techniques for volumetric measurement of density. It is also possible to measure breast density with other imaging modalities, such as ultrasound and MRI, which do not require the use of ionizing radiation and may, therefore, be more suitable for use in young women or where it is desirable to perform measurements more frequently. In this article, the techniques for measurement of density are reviewed and some consideration is given to their strengths and limitations

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Multiscale modeling of lamellar mesophases

The mesoscale simulation of a lamellar mesophase based on a free energy functional is examined with the objective of determining the relationship between the parameters in the model and molecular parameters. Attention is restricted to a symmetric lamellar phase with equal volumes of hydrophilic and hydrophobic components. Apart from the lamellar spacing, there are two parameters in the free energy functional. One of the parameters, r, determines the sharpness of the interface, and it is shown how this parameter can be obtained from the interface profile in a molecular simulation. The other parameter, A, provides an energy scale. Analytical expressions are derived to relate these parameters to r and A to the bending and compression moduli and the permeation constant in the macroscopic equation to the Onsager coefficient in the concentration diffusion equation. The linear hydrodynamic response predicted by the theory is verified by carrying out a mesoscale simulation using the lattice-Boltzmann technique and verifying that the analytical predictions are in agreement with simulation results. A macroscale model based on the layer thickness field and the layer normal field is proposed, and the relationship between the parameters in the macroscale model from the parameters in the mesoscale free energy functional is obtained

Self-Assembly, Supramolecular Organization, and Phase Behavior of l‑Alanine Alkyl Esters (<i>n</i> = 9–18) and Characterization of Equimolar l‑Alanine Lauryl Ester/Lauryl Sulfate Catanionic Complex

A homologous series of l-alanine alkyl ester hydrochlorides (AEs) bearing 9–18 C atoms in the alkyl chain have been synthesized and characterized with respect to self-assembly, supramolecular structure, and phase transitions. The CMCs of AEs bearing 11–18 C atoms were found to range between 0.1 and 10 mM. Differential scanning calorimetric (DSC) studies showed that the transition temperatures (<i>T</i>_t), enthalpies (Δ<i>H</i>_t) and entropies (Δ<i>S</i>_t) of AEs in the dry state exhibit odd–even alternation, with the odd-chain-length compounds having higher <i>T</i>_t values, but the even-chain-length homologues showing higher values of Δ<i>H</i>_t and Δ<i>S</i>_t. In DSC measurements on hydrated samples, carried out at pH 5.0 and pH 10.0 (where they exist in cationic and neutral forms, respectively), compounds with 13–18 C atoms in the alkyl chain showed sharp gel-to-liquid crystalline phase transitions, and odd–even alternation was not seen in the thermodynamic parameters. The molecular structure, packing properties, and intermolecular interactions of AEs with 9 and 10 C atoms in the alkyl chain were determined by single crystal X-ray diffraction, which showed that the alkyl chains are packed in a tilted interdigitated bilayer format. <i>d</i>-Spacings obtained from powder X-ray diffraction studies exhibited a linear dependence on the alkyl chain length, suggesting that the other AEs also adopt an interdigitated bilayer structure. Turbidimetric, fluorescence spectroscopic, and isothermal titration calorimetric (ITC) studies established that in aqueous dispersions l-alanine lauryl ester hydrochloride (ALE·HCl) and sodium dodecyl sulfate (SDS) form an equimolar complex. Transmission electron microscopic and DSC studies indicate that the complex exists as unilamellar liposomes, which exhibit a sharp phase transition at ∼39 °C. The aggregates were disrupted at high pH, suggesting that the catanionic complex would be useful to develop a base-labile drug delivery system. ITC studies indicated that ALE·HCl forms a strong complex with DNA, suggesting that the AEs may find use in DNA therapeutics as well

Oxidation of Abel's ketone and similar spiroketones with 2,3-dichloro-5,6-dicyano-1,4- benzoquinone (DDQ). Synthesis of novel tropone derivatives

The structure of the novel product obtained from the oxidation of Abel's ketone (1a) and similar spiroketones (1b–d) with 2, 3-dichloro-5, 6-dicyano-1,4-benzoquinone has been determined on basis of spectral data (i.r., n.m.r., and mass