Molecular Biomarker Expression in Window of Opportunity Studies for Oestrogen Receptor Positive Breast Cancer-A Systematic Review of the Literature.

Window of opportunity (WoO) trials create the opportunity to demonstrate pharmacodynamic parameters of a drug in vivo and have increasing use in breast cancer research. Most breast cancer tumours are oestrogen receptor-positive (ER+), leading to the development of multiple treatment options tailored towards this particular tumour subtype. The aim of this literature review is to review WoO trials pertaining to the pharmacodynamic activity of drugs available for use in ER+ breast cancer in order to help guide treatment for patients receiving neoadjuvant and primary endocrine therapy. Five databases (EMBASE, Cochrane, MEDLINE, PubMed, Web of Science) were searched for eligible studies. Studies performed in treatment-naïve patients with histologically confirmed ER+ breast cancer were included if they acquired pre- and post-treatment biopsies, compared measurement of a proteomic biomarker between these two biopsies and delivered treatment for a maximum mean duration of 31 days. Fifteen studies were eligible for inclusion and covered six different drug classes: three endocrine therapies (ETs) including aromatase inhibitors (AIs), selective oestrogen receptor modulators (SERMs), selective oestrogen receptor degraders (SERDs) and three non-ETs including mTOR inhibitors, AKT inhibitors and synthetic oestrogens. Ki67 was the most frequently measured marker, appearing in all studies. Progesterone receptor (PR) and ER were the next most frequently measured markers, appearing five and four studies, respectively. All three of these markers were significantly downregulated in both AIs and SERDs; Ki67 alone was downregulated in SERMs. Less commonly assessed markers including pS6, pGSH3B, FSH and IGF1 were downregulated while CD34, pAKT and SHBG were significantly upregulated. There were no significant changes in the other biomarkers measured such as phosphate and tensin homolog (PTEN), Bax and Bcl-2.WoO studies have been widely utilised within the ER+ breast cancer subtype, demonstrating their worth in pharmacodynamic research. However, research remains focused upon routinely measured biomarkers such ER PR and Ki67, with an array of less common markers sporadically used.

Dental erosion as an indicator of gastroesophageal reflux disease.

While evidence shows that dental erosion (DE) is often caused by gastroesophageal reflux disease (GERD), the relationship of DE severity to a patient's symptoms and receipt of appropriate medical treatment for GERD is not clearly understood. The purpose of this study was to evaluate the association between DE and GERD. Eighty participants underwent a Basic Erosive Wear Examination for DE and completed the Patient-Reported Outcomes Measurement Information System (PROMIS) survey on symptoms of gastrointestinal reflux (PROMIS Scale v1.0, Gastrointestinal Gastroesophageal Reflux 13a) in English. Patients with observed erosive patterns were referred for gastroenterologic evaluation. The association between DE and GERD was assessed using multiple regression. The results showed that the extent of DE was positively associated with GERD symptoms (B = 0.585; 95% CI, 0.21-0.96), as measured by the PROMIS survey, in participants without a current diagnosis of GERD. Of the 80 patients in the study, 28 with more severe DE were evaluated in the gastroenterology department. A diagnosis of GERD was established for 27 of the 28, 9 of whom denied a past history of the disease. Twenty patients with GERD underwent upper endoscopy, and esophageal lesions were found in 6 patients (erosive esophagitis in 5 and Barrett esophagus in 1). Patients with clinically identified DE may benefit from medical evaluation and, if necessary, management of GERD. For a subset of patients, DE may be the only clinical indication of untreated or undertreated GERD, which could lead to serious esophageal changes. Dentists should consider referring patients with DE to primary care providers or gastrointestinal specialists to ensure that systemic conditions are identified and managed appropriately.

Evaluating a Causal Relationship between Complement Factor I Protein Level and Advanced Age-Related Macular Degeneration Using Mendelian Randomization.

Importance: Risk of advanced age-related macular degeneration (AAMD) is associated with rare genetic variants in the gene encoding Complement factor I (CFI), which is associated with lower circulating CFI protein levels, but the nature of the relationship is unclear. Objective: Can genetic factors be used to infer whether low circulating CFI is associated with AAMD risk? Design: Two-sample inverse variance weighted Mendelian Randomisation (MR) was used to evaluate evidence for a relationship between CFI levels and AAMD risk, comparing CFI levels from genetically predefined subsets in AAMD and control cohorts. Setting: Published genetic and proteomic data was combined with data from cohorts of Geographic Atrophy (GA) patients in a series of MR analyses. Participants: We derived genetic instruments for systemic CFI level in 3,301 healthy European participants in the INTERVAL study. To evaluate a genetic causal odds ratio (OR) for the effect of CFI levels on AAMD risk, we used results from a genome-wide association study of 12,711 AAMD cases and 14,590 European controls from the International AMD Genomics Consortium (IAMDGC), and CFI levels from patients entered into the research studies SCOPE and SIGHT. Results: We identified one common CFI variant rs7439493 which was strongly associated with low CFI level, explaining 4.8% of phenotypic variance. Using rs7439493 our MR analysis estimated that AAMD odds increased per standard deviation (SD) decrease in CFI level; OR 1.47 (95% confidence interval (CI) 1.30-1.65, P=2.1×10-10). We identified one rare variant (rs141853578 encoding p.Gly119Arg) which was genome-wide significantly associated with CFI levels after imputation; based on this, a 1 SD decrease in CFI leads to increased AAMD odds of 1.79 (95% CI 1.46-2.19, P=1.9×10-8). The rare variant rs141853578 explained a further 1.7% of phenotypic variance. To benchmark the effect of low CFI levels on AAMD odds using a CFI-specific proteomic assay, we estimated the effect using CFI levels from 24 rs141853578 positive GA patients; each 1 SD (3.5µg/mL) reduction in CFI was associated with 1.67 fold increased odds of AAMD (95% CI 1.40-2.00, P=1.85×10-8). Conclusion and relevance: Excellent concordance in direction and effect size derived from rare and common variant calculations provide good genetic evidence for a potentially causal role of lower CFI level increasing AAMD risk.

A Discussion on Bio-Fluorescent Particle Counters: Summary of the Process and Environmental Monitoring Methods Working Group Meeting with the FDA Emerging Technology Team.

The Process and Environmental Monitoring Methods Working Group, composed of members from industry and instrument manufacturers, met with the FDA Emerging Technology Team to discuss bio-fluorescent particle counting technology, a type of rapid microbiological method. This is a summary of the meeting including submitted questions and answers, and the Process and Environmental Monitoring Methods Working Group's understanding of the FDA Emerging Technology Team's points made.

COVID-19: Implications for Supply Chain Management.

The COVID-19 pandemic has created global health and economic disruption. Hospitals and other healthcare providers have been hit particularly hard. While efforts to effectively treat and eradicate the coronavirus continue, so do the efforts of supply chains to support the provision of patient care in the event of a resurgence or future pandemic. Supply chain leaders must continuously evaluate their strategic and tactical positions to address critical supply needs. Whether the supply chain can meet expectations remains uncertain, given rolling supply shortages of personal protective equipment (PPE) and other medical-surgical supplies as healthcare providers resume prepandemic levels of operations. The ability to ensure a reliable, sustainable supply of critical PPE in the near term will remain a challenge. Longer-term substantive changes to the function and performance of healthcare supply chains will be necessary across multiple areas to meet demand more effectively during a crisis.

The genetics of bipolar disorder.

Bipolar disorder (BD) is one of the most heritable mental illnesses, but the elucidation of its genetic basis has proven to be a very challenging endeavor. Genome-Wide Association Studies (GWAS) have transformed our understanding of BD, providing the first reproducible evidence of specific genetic markers and a highly polygenic architecture that overlaps with that of schizophrenia, major depression, and other disorders. Individual GWAS markers appear to confer little risk, but common variants together account for about 25% of the heritability of BD. A few higher-risk associations have also been identified, such as a rare copy number variant on chromosome 16p11.2. Large scale next-generation sequencing studies are actively searching for other alleles that confer substantial risk. As our understanding of the genetics of BD improves, there is growing optimism that some clear biological pathways will emerge, providing a basis for future studies aimed at molecular diagnosis and novel therapeutics.

CMV Ileitis: To Treat or Not to Treat? Implications of Initiating Biologic Therapy for Concurrent Crohn's Disease.

Cytomegalovirus (CMV) enteritis is traditionally thought to be a self-limited infection in immunocompetent individuals. Consequently, current guidelines recommend against treating nonimmunocompromised patients with antiviral therapy. Conversely, recent data suggests that spontaneous resolution occurs less frequently than previously believed; furthermore, mortality rate in immunocompetent individuals is similar to that of the immunosuppressed. We present a case of a 43-year-old male who was simultaneously diagnosed with CMV ileitis and Crohn's Disease. When discovered concomitantly, there is no guidance in the current medical literature regarding the benefit of antiviral treatment of the CMV infection prior to initiating biologic therapy versus the risks of withholding treatment, as is currently recommended for nonimmunosuppressed individuals.

Measurement of Allergen-Specific Inhibitory Antibody Activity.

Specific allergen immunotherapy (AIT) is an effective treatment for IgE-mediated allergic diseases and involves T- and B-cell-mediated events. IgE receptors on the surface of antigen-presenting cells facilitate the presentation of allergens in the presence of specific IgE antibody resulting in T-cell activation. Interference with these IgE-dependent mechanisms by "blocking" IgG antibodies suppresses pro-inflammatory Th2 cell responses and manifests as a reduction in allergic responses in vivo.In vitro assays used to measure the inhibition of binding of allergen-IgE complexes have previously utilized proliferation of antigen-specific T-cell clones as an assay readout. Here we describe two simplified assays to measure allergen binding without the complexity of generating T-cell clones. The IgE-facilitated allergen binding assay (IgE-FAB) utilizes flow cytometry to measure the binding of allergen-IgE complexes to EBV-transformed B cells. The enzyme-linked immunosorbent-facilitated antigen binding (ELIFAB) assay uses standard ELISA-based techniques to measure allergen-IgE binding to plate-bound CD23, the low-affinity IgE receptor expressed on B cells.

Draft genome sequence of the moderately halophilic bacterium Halobacillus sp. BBL2006.

We present the draft genome sequence of Halobacillus sp. BBL2006, a moderately halophilic, gram positive bacterium isolated from a sulfidic salt spring in Big Bone Lick State Park, Boone County, Kentucky. The genome of Halobacillus sp. BBL2006 was 3,988,138 bp in length with a GC content of 41.6%. Genome analysis identified 4331 open reading frames including genes for antibiotic resistance and tolerance to heavy metals. The draft genome was deposited at DDBJ/EMBL/GenBank (DNA Databank of Japan/European Molecular Biology Laboratory/Genbank) (JRNX00000000).

An APRIL-based chimeric antigen receptor for dual targeting of BCMA and TACI in multiple myeloma.

B-cell maturation antigen (BCMA) is a promising therapeutic target for multiple myeloma (MM), but expression is variable, and early reports of BCMA targeting chimeric antigen receptors (CARs) suggest antigen downregulation at relapse. Dual-antigen targeting increases targetable tumor antigens and reduces the risk of antigen-negative disease escape. "A proliferation-inducing ligand" (APRIL) is a natural high-affinity ligand for BCMA and transmembrane activator and calcium-modulator and cyclophilin ligand (TACI). We quantified surface tumor expression of BCMA and TACI on primary MM cells (n = 50). All cases tested expressed BCMA, and 39 (78%) of them also expressed TACI. We engineered a third-generation APRIL-based CAR (ACAR), which killed targets expressing either BCMA or TACI (P < .01 and P < .05, respectively, cf. control, effector-to-target [E:T] ratio 16:1). We confirmed cytolysis at antigen levels similar to those on primary MM, at low E:T ratios (56.2% ± 3.9% killing of MM.1s at 48 h, E:T ratio 1:32; P < .01) and of primary MM cells (72.9% ± 12.2% killing at 3 days, E:T ratio 1:1; P < .05, n = 5). Demonstrating tumor control in the absence of BCMA, we maintained cytolysis of primary tumor expressing both BCMA and TACI in the presence of a BCMA-targeting antibody. Furthermore, using an intramedullary myeloma model, ACAR T cells caused regression of an established tumor within 2 days. Finally, in an in vivo model of tumor escape, there was complete ACAR-mediated tumor clearance of BCMA+TACI- and BCMA-TACI+ cells, and a single-chain variable fragment CAR targeting BCMA alone resulted in outgrowth of a BCMA-negative tumor. These results support the clinical potential of this approach.

Nasal IgA Provides Protection against Human Influenza Challenge in Volunteers with Low Serum Influenza Antibody Titre.

In spite of there being a number of vaccines, influenza remains a significant global cause of morbidity and mortality. Understanding more about natural and vaccine induced immune protection against influenza infection would help to develop better vaccines. Virus specific IgG is a known correlate of protection, but other factors may help to reduce viral load or disease severity, for example IgA. In the current study we measured influenza specific responses in a controlled human infection model using influenza A/California/2009 (H1N1) as the challenge agent. Volunteers were pre-selected with low haemagglutination inhibition (HAI) titres in order to ensure a higher proportion of infection; this allowed us to explore the role of other immune correlates. In spite of HAI being uniformly low, there were variable levels of H1N1 specific IgG and IgA prior to infection. There was also a range of disease severity in volunteers allowing us to compare whether differences in systemic and local H1N1 specific IgG and IgA prior to infection affected disease outcome. H1N1 specific IgG level before challenge did not correlate with protection, probably due to the pre-screening for individuals with low HAI. However, the length of time infectious virus was recovered from the nose was reduced in patients with higher pre-existing H1N1 influenza specific nasal IgA or serum IgA. Therefore, IgA contributes to protection against influenza and should be targeted in vaccines.

Development of an objective gene expression panel as an alternative to self-reported symptom scores in human influenza challenge trials.

BACKGROUND: Influenza challenge trials are important for vaccine efficacy testing. Currently, disease severity is determined by self-reported scores to a list of symptoms which can be highly subjective. A more objective measure would allow for improved data analysis. METHODS: Twenty-one volunteers participated in an influenza challenge trial. We calculated the daily sum of scores (DSS) for a list of 16 influenza symptoms. Whole blood collected at baseline and 24, 48, 72 and 96 h post challenge was profiled on Illumina HT12v4 microarrays. Changes in gene expression most strongly correlated with DSS were selected to train a Random Forest model and tested on two independent test sets consisting of 41 individuals profiled on a different microarray platform and 33 volunteers assayed by qRT-PCR. RESULTS: 1456 probes are significantly associated with DSS at 1% false discovery rate. We selected 19 genes with the largest fold change to train a random forest model. We observed good concordance between predicted and actual scores in the first test set (r = 0.57; RMSE = -16.1%) with the greatest agreement achieved on samples collected approximately 72 h post challenge. Therefore, we assayed samples collected at baseline and 72 h post challenge in the second test set by qRT-PCR and observed good concordance (r = 0.81; RMSE = -36.1%). CONCLUSIONS: We developed a 19-gene qRT-PCR panel to predict DSS, validated on two independent datasets. A transcriptomics based panel could provide a more objective measure of symptom scoring in future influenza challenge studies. Trial registration Samples were obtained from a clinical trial with the ClinicalTrials.gov Identifier: NCT02014870, first registered on December 5, 2013.

Sudden Death in a Diver: A Diagnostic Conundrum.

We discuss the case of an experienced diver who ran out of air during his final ascent while scuba diving. He lost consciousness rapidly after surfacing and despite immediate cardiopulmonary resuscitation, could not be revived. On arrival at the emergency department he was noted to have copious amounts of blood in his upper airway and had developed extensive subcutaneous emphysema. Large amounts of air were observed in the central circulation following a postmortem computerized tomography scan as well as pneumomediastinum, a small right-sided hemothorax, and extensive subcutaneous emphysema. We discuss several potential pathophysiological mechanisms that might explain these findings. Finally, we end with a recommendation for an expedient whole-body postmortem computerized tomography scan and autopsy by a suitably qualified pathologist in the investigation of all dive-related fatalities, where possible.

Eosinophilic Esophagitis with Dysphagia and Food Impaction in a Young Adult.

BACKGROUND: Eosinophilic esophagitis (EoE) is an emerging esophageal disease associated with dysphagia and food impaction. Practice guidelines have only recently been developed. It affects 1/1000 individuals, predominantly young men. As this demographic represents a substantial portion of the military aviation population, aerospace medicine clinicians should be familiar with this diagnosis when evaluating dysphagia or impactions. CASE REPORT: A 23-yr-old Caucasian man, a U.S. Air Force air traffic controller, presented to Flight Medicine following an episode of food impaction requiring evaluation in the local emergency department. The patient reported a 5-yr history of recurrent episodes of food lodging in his throat, requiring fluid and body repositioning for resolution. Medical history was significant for eczema. Upper endoscopy revealed an abnormal esophagus with macroscopic features of EoE and biopsies were also consistent with EoE. After further work-up, the patient was diagnosed with EoE and treated. Significant symptom improvement was noted after 2 mo of therapy. DISCUSSION: This case outlines the evaluation of food impaction as well as the diagnostic criteria for EoE, which is a disease that affects patients with demographics common to the military aviation community. As the diagnostic and treatment guidelines for EoE are relatively new, it may easily be overlooked by the primary care physician, causing a delay in subspecialist consultation, thus delaying treatment. EoE is a condition with symptoms that pose high risk to the performance of aircrew duties; therefore, flight surgeons must be familiar with the aeromedical standards that accompany this diagnosis.

Syphilitic hepatitis uncommon presentation of an old scourge.

BACKGROUND: Giant cell hepatitis is a rare entity in adults, accounting for 0.1% to 0.25% of liver disease in adults. Postinfantile giant cell hepatitis is often characterized by multinucleated giant cells on liver biopsy and a fulminant hepatitis. CASE REPORT: An active duty 36-year-old African-American male deployed to Kabul, Afghanistan, presented with jaundice 2 weeks after starting a testosterone analogue. He discontinued the supplement, but his jaundice persisted with up-trending bilirubin. Serologic testing was negative for hepatitis A, B, C, and E; cytomegalovirus; Epstein-Barr virus; herpes simplex virus; and human immunodeficiency virus. Evaluation for autoimmune hepatitis was negative. Magnetic resonance cholangiopancreatography was negative for obstruction. Liver biopsy revealed giant cell transformation of numerous hepatocytes and cholestatic hepatitis. Rapid plasma reagin was positive without physical findings. Treponema pallidum hemagglutination assays confirmed the diagnosis of latent syphilis. He was started on penicillin treatment with rapid improvement of bilirubin, creatinine, and hepatic synthetic function, all of which eventually normalized. CONCLUSION: Postinfantile giant cell hepatitis is a severe form of hepatitis that has several different potential etiologies, 2 of which were present in this patient: androgenic supplements and infection. This case highlights syphilis as an unusual but treatable cause of giant cell hepatitis. Testing for syphilis should be considered in any persistent liver injury.

Characterisation of a wild-type influenza (A/H1N1) virus strain as an experimental challenge agent in humans.

BACKGROUND: Human challenge models using respiratory viruses such as influenza are increasingly utilised in the development of novel vaccines and anti-viral modalities and can provide preliminary evidence of protection before evaluation in field trials. We describe the results of a clinical study characterising an A/H1N1 influenza challenge virus in humans. METHODS: The challenge agent, influenza A/California/2009 (H1N1), was manufactured under cGMP conditions and characterised in accordance with regulatory guidelines. A dose-ascending open-label clinical study was conducted in 29 healthy young adults screened sero-negative to the challenge strain. Subjects were intranasally inoculated with three increasing doses of virus and physician-reported signs, subjected-reported symptoms, viral shedding and immunological responses were monitored. RESULTS: A dose-dependent increase in clinical signs and symptoms was observed with 75% of subjects developing laboratory-confirmed illness at the highest inoculum (3.5 × 10(6) TCID50). At the highest dose, physician or subject-reported signs of infection were classified as mild (all subjects), moderate (50%) and severe (16%) with peak symptoms recorded four days after infection. Clinical signs were correlated with nasal mucus weight (P < .001) and subject-reported symptoms (P < .001). Geometric mean peak viral shedding was log10 5.16 TCID50 and occurred three days after inoculation with a median duration of five days. The safety profile was such that physiological responses to viral infection were mainly restricted to the upper airways but were not of such severity to be of clinical concern. CONCLUSIONS: A highly characterised wild-type Influenza A/California/2009 (H1N1) virus manufactured for clinical use was shown to induce a good infectivity profile in human volunteers. This clinical challenge model can be used for evaluating potential efficacy of vaccines and anti-viral therapeutics. TRIAL REGISTRATION: NCT02014870.