Mapping molecular networks using proteomics: a vision for patient-tailored combination therapy.

Mapping tumor cell protein networks in vivo will be critical for realizing the promise of patient-tailored molecular therapy. Cancer can be defined as a dysregulation or hyperactivity in the network of intracellular and extracellular signaling cascades. These protein signaling circuits are the ultimate targets of molecular therapy. Each patient's tumor may be driven by a distinct series of molecular pathogenic defects. Thus, for any single molecular targeted therapy, only a subset of cancer patients may respond. Individualization of therapy, which tailors a therapeutic regimen to a tumor molecular portrait, may be the solution to this dilemma. Until recently, the field lacked the technology for molecular profiling at the genomic and proteomic level. Emerging proteomic technology, used concomitantly with genomic analysis, promises to meet this need and bring to reality the clinical adoption of molecular stratification. The activation state of kinase-driven signal networks contains important information relative to cancer pathogenesis and therapeutic target selection. Proteomic technology offers a means to quantify the state of kinase pathways, and provides post-translational phosphorylation data not obtainable by gene arrays. Case studies using clinical research specimens are provided to show the feasibility of generating the critical information needed to individualize therapy. Such technology can reveal potential new pathway interconnections, including differences between primary and metastatic lesions. We provide a vision for individualized combinatorial therapy based on proteomic mapping of phosphorylation end points in clinical tissue material.     

Development and evaluation of time‐resolved fluorescent immunochromatographic assay for quantitative detection of SARS‐CoV‐2 spike antigen

BackgroundThe spread of COVID‐19 worldwide caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has necessitated efficient, sensitive diagnostic methods to identify infected people. We report on the development of a rapid 15‐minute time‐resolved fluorescent (TRF) lateral flow immunochromatographic assay for the quantitative detection of the SARS‐CoV‐2 spike protein receptor‐binding domain (S1‐RBD).ObjectivesOur objective was to develop an efficient method of detecting SARS‐CoV‐2 within 15 min of sample collection.MethodsWe constructed and evaluated a portable, disposable lateral flow device, which detected the S1‐RBD protein directly in nasopharyngeal swab samples. The device emits a fluorescent signal in the presence of S1‐RBD, which can be captured by an automated TRF instrument.ResultsThe TRF lateral flow assay signal was linear from 0 to 20 ng/ml and demonstrated high accuracy and reproducibility. When evaluated with clinical nasopharyngeal swabs, the assay was performed at >80% sensitivity, >84% specificity, and > 82% accuracy for detection of the S1‐RBD antigen.ConclusionThe new S1‐RBD antigen test is a rapid (15 min), sensitive, and specific assay that requires minimal sample preparation. Critically, the assay correlated closely with PCR‐based methodology in nasopharyngeal swab samples, showing that the detected S1‐RBD antigen levels correlate with SARS‐CoV‐2 virus load. Therefore, the new TRF lateral flow test for S1‐RBD has potential application in point‐of‐care settings.     

Miscarriage risk for asymptomatic women after a normal first-trimester prenatal visit

OBJECTIVE: To estimate the risk of miscarriage among asymptomatic women after a prenatal visit between 6 and 11 weeks of gestation where proof of fetal viability of a singleton was obtained by office ultrasonography at the same visit. METHODS: This was a prospective cohort study performed over 2 years (March 2004-2006) at an antenatal clinic at a large tertiary hospital in Victoria, Australia. Those recruited were 697 asymptomatic women who attended their first antenatal visit between 6 (+2 days) and 11(+6 days) weeks of gestation, where evidence of fetal cardiac activity of a singleton was obtained by office ultrasonography. The main outcome measure was rates of miscarriage, stratified by gestation at presentation. RESULTS: One case was lost to follow-up. The risk of miscarriage among the entire cohort was 11 of 696 (1.6%). The risk fell rapidly with advancing gestation; 9.4% at 6 (completed) weeks of gestation, 4.2% at 7 weeks, 1.5% at 8 weeks, 0.5% at 9 weeks and 0.7% at 10 weeks (chi(2); test for trend P=.001). Most who miscarried received their ultrasound diagnoses many weeks after their visit; five (45%) were diagnosed in the second trimester, and all but one received their ultrasound diagnoses after 10 weeks of gestation. CONCLUSION: For women without symptoms, the risk of miscarriage after attending a first antenatal visit between 6 and 11 weeks is low (1.6% or less), especially if they present at 8 weeks of gestation and beyond. Our data could be used to reassure such women that the probability of progressing to later than 20 weeks of gestation is very good.     

Antibiotic resistance: a guide for effective prescribing in women's health

Current national and international trends in antibiotic resistance are becoming a public health crisis. Multi-drug resistant organisms are more prevalent in hospital settings and, alarmingly, are now being identified in the community. Over-reliance on broad-spectrum antibiotics, as well as inappropriate prescribing practices, play a significant role in encouraging the emergence of resistant organisms. This article reviews the mechanisms of bacterial resistance, current trends in national and international antibiotic resistance, and examines approaches to combat pathogens while sparing benign microbes.