抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

/pdf/self-assembled-monolayers-of-thiolates-on-metals-as-a-form-1neb0hj3k4.pdf

Self-assembled monolayers of thiolates on metals as a form of nanotechnology.

I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or

Principles of Neural Science

METHODS In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. RESULTS The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin–paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin– paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin–paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin–paclitaxel group. CONCLUSIONS Gefitinib is superior to carboplatin–paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa0810699

Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma

Background Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. Methods To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. Results Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. Conclusions Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.)

http://www.therenegadecell.com/wiki/images/0/0d/NEJM-2012-366%2810%29-883.pdf

Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.

L'invention concerne des methodes de diagnostic ou de pronostic d'un cancer chez un sujet par enrichissement, detection et analyse de cellules rares individuelles, p. ex. de cellules epitheliales, dans un echantillon preleve sur un sujet. L'invention concerne egalement des procedes de marquage de regions de l'ADN genomique dans les cellules individuelles presentes dans ledit echantillon mixte, au moyen de differents marqueurs, chaque marqueur etant specifique de chaque cellule, et de quantification des regions d'ADN genomique marquees de chaque cellule de l'echantillon mixte. Ce procede consiste plus particulierement a detecter la presence de mutations geniques dans les cellules individuelles d'un sous-echantillon.

Analyse de cellules rares par division d'échantillon et utilisation de marqueurs d'adn

Analyse seltener Zellen mittels Probentrennung und DNA-Etiketten


 Cancer-associated alterations in DNA methylation include hypermethylation of focal CpG islands within promoters, as well as hypomethylation of large stretches of gene-poor chromosomal domains, so called Partially Methylated Domains (PMDs). While CpG island hypermethylation is associated with silencing of tumor suppressor genes, the functional consequences of hypomethylation are uncertain. PMDs may be cause or consequence of cancer cell proliferation, and they have been associated with transcriptional de-repression of repetitive sequences, as well as histone modification-triggered silencing of rare protein encoding genes within these domains. In studying Circulating Tumor Cells (CTCs) isolated from blood specimens of patients with prostate cancer, we mapped PMDs at the single cell level, identifying a set of 40 “core PMDs” that are shared across cancer cells, within and across different individuals, as well as in prostate cancer cell lines. By analyzing single nuclei from micro-dissected early-stage prostate tumors, we find that hypomethylation of these core PMDs occurs early during prostate tumorigenesis. Core PMDs are highly enriched for immune-related genes, many of which are co-located within a single chromosomal locus targeted for hypomethylation-associated silencing. Nested between adjacent PMDs, we also identify domains that have retained DNA methylation (Preserved Methylation Islands; PMIs), which have sharply demarcated borders, spanning one or a small number of genes. In contrast to PMDs, PMIs are enriched for cell proliferation-associated genes. Together, these observations suggest that hypomethylation-associated silencing of immune-related genes, with sparing of adjacent proliferation-associated genes, is an early event in prostate cancer development. These large-scale chromosomal modifications are detectable within CTCs and may present diagnostic opportunities.
 Citation Format: Daniel A. Haber, Hongshan Guo, Ben S. Wittner, Joanna A Vuille, Michael S. Lawrence, Chin-Lee Wu, Mehmet Toner, David T. Miyamoto, Shyamala Maheswaran. Hypomethylation of immune-related loci contribute to prostate tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA010.

Abstract IA010: Hypomethylation of immune-related loci contribute to prostate tumorigenesis

Synopsis Objective Objective measurement of antiretrovirals may aid clinical interventions for improving adherence to HIV prevention or treatment regimens. A point-of-care urine test could provide real-time information about recent adherence to regimens containing tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). We developed a lateral flow immunoassay (LFA) and enzyme-linked immunoassay (ELISA) for urinary tenofovir. Methods Intensity of the LFA test line was quantified using an optical reader and visually scored 0 – 5 by two independent people, using a reference card. The sensitivity and specificity of both the ELISA and LFA were determined for two different tenofovir concentration cutoffs for TDF and TAF adherence—1,500 ng/mL and 150 ng/mL, respectively. To validate the assays, we measured 586 urine samples from 28 individuals collected as part of a study of tenofovir pharmacokinetics in adults, which were also measured by mass spectrometry as ground truth. Results Both the LFA signal and ELISA signal were each strongly correlated to drug concentrations (0.91 and 0.92 respectively). The LFA signal and ELISA were highly sensitive and specific at both thresholds (LFA se/sp TDF 89%/96%, TAF 90%/96%; ELISA se/sp TDF 94%/94%, TAF 92%/84%). Visual scoring of the LFA was also highly sensitive and specific at both the TDF and TAF thresholds (se/sp TDF 91%/94%, TAF 87%/90%). Conclusions Our rapid semi-quantitative test can measure TFV concentrations relevant to both TAF or TDF adherence, which may support adherence-promoting interventions across a range of HIV care settings.

Point-of-care semiquantitative test for adherence to tenofovir alafenamide or tenofovir disoproxil fumarate

Cryptosporidium hominis is a serious cause of childhood diarrhea in developing countries. The development of therapeutics is impeded by major technical roadblocks including lack of cryopreservation and simple culturing methods. This impacts the availability of optimized/standardized singular sources of infectious parasite oocysts for research and human challenge studies. The human C. hominis TU502 isolate is currently propagated in gnotobiotic piglets in only one laboratory, which limits access to oocysts. Streamlined cryopreservation could enable creation of a biobank to serve as an oocyst source for research and distribution to other investigators requiring C. hominis. Here, we report cryopreservation of C. hominis TU502 oocysts by vitrification using specially designed specimen containers scaled to 100 μL volume. Thawed oocysts exhibit ~70% viability with robust excystation and 100% infection rate in gnotobiotic piglets. The availability of optimized/standardized sources of oocysts may streamline drug and vaccine evaluation by enabling wider access to biological specimens.

Mehmet Toner

Papers

Analyse de cellules rares par division d'échantillon et utilisation de marqueurs d'adn

Analyse seltener Zellen mittels Probentrennung und DNA-Etiketten

Abstract IA010: Hypomethylation of immune-related loci contribute to prostate tumorigenesis

Point-of-care semiquantitative test for adherence to tenofovir alafenamide or tenofovir disoproxil fumarate

Scalable cryopreservation of infectious Cryptosporidium hominis oocysts by vitrification