Linker engineering in anti-TAG-72 antibody fragments optimizes biophysical properties, serum half-life, and high-specificity tumor imaging.

Antibody (Ab) fragments have great clinical potential as cancer therapeutics and diagnostics. Their small size allows for fast clearance from blood, low immunoreactivity, better tumor penetration, and simpler engineering and production. The smallest fragment derived from a full-length IgG that retains binding to its antigen, the single-chain variable fragment (scFV), is engineered by fusing the variable light and variable heavy domains with a peptide linker. Along with switching the domain orientation, altering the length and amino acid sequence of the linker can significantly affect scFV binding, stability, quaternary structure, and other biophysical properties. Comprehensive studies of these attributes in a single scaffold have not been reported, making design and optimization of Ab fragments challenging. Here, we constructed libraries of 3E8, an Ab specific to tumor-associated glycoprotein 72 (TAG-72), a mucinous glycoprotein overexpressed in 80% of adenocarcinomas. We cloned, expressed, and characterized scFVs, diabodies, and higher-order multimer constructs with varying linker compositions, linker lengths, and domain orientations. These constructs dramatically differed in their oligomeric states and stabilities, not only because of linker and orientation but also related to the purification method. For example, protein L-purified constructs tended to have broader distributions and higher oligomeric states than has been reported previously. From this library, we selected an optimal construct, 3E8.G4S, for biodistribution and pharmacokinetic studies and in vivo xenograft mouse PET imaging. These studies revealed significant tumor targeting of 3E8.G4S with a tumor-to-background ratio of 29:1. These analyses validated 3E8.G4S as a fast, accurate, and specific tumor-imaging agent.

Insulin growth factor signaling is regulated by microRNA-486, an underexpressed microRNA in lung cancer.

MicroRNAs (miRNAs) are small 19- to 24-nt noncoding RNAs that have the capacity to regulate fundamental biological processes essential for cancer initiation and progression. In cancer, miRNAs may function as oncogenes or tumor suppressors. Here, we conducted global profiling for miRNAs in a cohort of stage 1 nonsmall cell lung cancers (n = 81) and determined that miR-486 was the most down-regulated miRNA in tumors compared with adjacent uninvolved lung tissues, suggesting that miR-486 loss may be important in lung cancer development. We report that miR-486 directly targets components of insulin growth factor (IGF) signaling including insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R), and phosphoinositide-3-kinase, regulatory subunit 1 (alpha) (PIK3R1, or p85a) and functions as a potent tumor suppressor of lung cancer both in vitro and in vivo. Our findings support the role for miR-486 loss in lung cancer and suggest a potential biological link to p53.

Epigenetic regulation of miR-17~92 contributes to the pathogenesis of pulmonary fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a disease of progressive lung fibrosis with a high mortality rate. In organ repair and remodeling, epigenetic events are important. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally and can target epigenetic molecules important in DNA methylation. The miR-17~92 miRNA cluster is critical for lung development and lung epithelial cell homeostasis and is predicted to target fibrotic genes and DNA methyltransferase (DNMT)-1 expression. OBJECTIVES: We investigated the miR-17~92 cluster expression and its role in regulating DNA methylation events in IPF lung tissue. METHODS: Expression and DNA methylation patterns of miR-17~92 were determined in human IPF lung tissue and fibroblasts and fibrotic mouse lung tissue. The relationship between the miR-17~92 cluster and DNMT-1 expression was examined in vitro. Using a murine model of pulmonary fibrosis, we examined the therapeutic potential of the demethylating agent, 5'-aza-2'-deoxycytidine. MEASUREMENTS AND MAIN RESULTS: Compared with control samples, miR-17~92 expression was reduced in lung biopsies and lung fibroblasts from patients with IPF, whereas DNMT-1 expression and methylation of the miR-17~92 promoter was increased. Several miRNAs from the miR-17~92 cluster targeted DNMT-1 expression resulting in a negative feedback loop. Similarly, miR-17~92 expression was reduced in the lungs of bleomycin-treated mice. Treatment with 5'-aza-2'-deoxycytidine in a murine bleomycin-induced pulmonary fibrosis model reduced fibrotic gene and DNMT-1 expression, enhanced miR-17~92 cluster expression, and attenuated pulmonary fibrosis. CONCLUSIONS: This study provides insight into the pathobiology of IPF and identifies a novel epigenetic feedback loop between miR-17~92 and DNMT-1 in lung fibrosis.

Mathematical model of colitis-associated colon cancer.

As a result of chronic inflammation of their colon, patients with ulcerative colitis or Crohn's disease are at risk of developing colon cancer. In this paper, we consider the progression of colitis-associated colon cancer. Unlike normal colon mucosa, the inflammed colon mucosa undergoes genetic mutations, affecting, in particular, tumor suppressors TP53 and adenomatous polyposis coli (APC) gene. We develop a mathematical model that involves these genes, under chronic inflammation, as well as NF-κB, ß-catenin, MUC1 and MUC2. The model demonstrates that increased level of cells with TP53 mutations results in abnormal growth and proliferation of the epithelium; further increase in the epithelium proliferation results from additional APC mutations. The model may serve as a conceptual framework for further data-based study of the early stage of colon cancer.

Multimodal imaging and detection strategy with 124 I-labeled chimeric monoclonal antibody cG250 for accurate localization and confirmation of extent of disease during laparoscopic and open surgical resection of clear cell renal cell carcinoma.

Renal cell carcinoma (RCC) accounts for approximately 85% to 90% of all primary kidney malignancies, with clear cell RCC (ccRCC) constituting approximately 70% to 85% of all RCCs. This study describes an innovative multimodal imaging and detection strategy that uses (124)I-labeled chimeric monoclonal antibody G250 ((124)I-cG250) for accurate preoperative and intraoperative localization and confirmation of extent of disease for both laparoscopic and open surgical resection of ccRCC. Two cases presented herein highlight how this technology can potentially guide complete surgical resection and confirm complete removal of all diseased tissues. This innovative (124)I-cG250 (ie, (124)I-girentuximab) multimodal imaging and detection approach, which would be clinically very useful to urologic surgeons, urologic medical oncologists, nuclear medicine physicians, radiologists, and pathologists who are involved in the care of ccRCC patients, holds great potential for improving the diagnostic accuracy, operative planning and approach, verification of disease resection, and monitoring for evidence of disease recurrence in ccRCC patients.

Antigen-directed cancer surgery for primary colorectal cancer: 15-year survival analysis.

BACKGROUND: Tumor-associated glycoprotein-72 (TAG-72) is a mucin-like high-molecular-weight glycosylated protein complex overexpressed by many adenocarcinomas. Antigen-directed cancer surgery using radiolabeled anti-TAG-72 murine monoclonal antibodies (muMAbs) has been previously investigated for colorectal cancer. Survival analysis of primary colorectal cancer patients with a minimum of 15-year follow-up after antigen-directed cancer surgery was performed to assess the impact of complete surgical resection of all detectable radiolabeled anti-TAG-72 muMAb. METHODS: Survival analysis was performed on 92 patients (study group) with primary colorectal cancer (July 1990 to August 1995) treated with antigen-directed cancer surgery using (125)I-labeled anti-TAG-72 muMAb. The study group was subdivided into those with no detectable TAG-72 antigen-bearing tissues (TAG-72 negative, N=33) and those with persistent detectable TAG-72 antigen-bearing tissues (TAG-72 positive, N=59) at completion of surgery. Comparisons were made with a control group (546 patients) from the same time period. RESULTS: Study group and control group were demographically similar, as were TAG-72-negative subgroup and TAG-72-positive subgroup. TAG-72-negative subgroup had significantly improved median survival (8.8 versus 2.5 years; P=0.005) and time-dependent survival (45.4% versus 22.0% at 10 years; P=0.002 and 39.4% versus 20.3% at 15 years; P=0.003) compared with TAG-72-positive subgroup. TAG-72 positivity was as an independent predictor of long-term mortality risk, when controlled for pathologic stage of disease. CONCLUSIONS: Absence of detectable TAG-72 antigen within the surgical field at completion of antigen-directed cancer surgery for primary colorectal cancer is of significant prognostic value, conferring a long-term survival advantage to those in whom complete surgical removal of all tissues with detectable radiolabeled anti-TAG-72 muMAb was accomplished.

The cognitive behavior survey: testing for factorial validity and time invariance across two years of medical school.

BACKGROUND: The Cognitive Behavior Survey (CBS) assesses learner behavior in healthcare-related fields. PURPOSE: The study aims were to evaluate the factorial validity of the CBS, which purports to measure three dimensions of learner behavior--conceptualization, reflection, and memorization--and propose and test an alternative model including its time invariance. METHODS: The CBS was administered to 3 cohorts of medical students upon matriculation and at the end of their 1st and 2nd year. RESULTS: Confirmatory factor analysis (CFA) did not support the original CBS model. Exploratory factor analysis (EFA) with an independent sample provided a new model. Retesting the EFA model using CFA with the original sample yielded a model with improved fit and time invariance. CONCLUSIONS: This study provides evidence for the original CBS 3-factor structure but requires alternative scoring for a time-invariant model.

Autopsy Techniques in Patients With History of Radiofrequency Ablation for Atrial Fibrillation.

CONTEXT.­: Esophageal fistula formation is one of the most feared complications of radiofrequency catheter ablation. This procedure and its many variations, such as the "maze," are becoming the mainstream treatment for atrial fibrillation owing to limitations of antiarrhythmic drugs. The incidence of this complication rate has been reported to be from 0.01% to 1%. OBJECTIVE.­: To delineate the importance of using the en bloc Letulle method of dissection for identifying esophageal fistulas for cases with a history of radiofrequency catheter ablation. DESIGN.­: Six autopsy cases with a history of radiofrequency catheter ablation for atrial fibrillation were selected from 1736 autopsies performed between 2009 and 2020. RESULTS.­: The initial presenting symptoms included neurologic symptoms, chest pains, epigastric discomfort, and sepsis. Transesophageal echocardiogram in 4 cases showed no evidence of thrombus or vegetation, however, 2 cases had evidence of atrial esophageal fistula. The autopsy findings included 5 atrial esophageal fistulas and 1 esophagopericardial fistula. Atrial esophageal fistulas were small and could be detected without difficulty when the en bloc Letulle technique was used and would have been easily missed by the Virchow method. The immediate causes of the deaths were myocardial ischemia, septic emboli to brain and heart, hypovolemic shock secondary to exsanguination, stroke, and coagulopathy. CONCLUSIONS.­: To date, this is the largest collection of autopsy cases showing esophageal fistula associated with prior radiofrequency catheter ablation. The Letulle dissection method is preferable in this setting.

Transcription factor ets-2 plays an important role in the pathogenesis of pulmonary fibrosis.

Ets-2 is a ubiquitous transcription factor activated after phosphorylation at threonine-72. Previous studies highlighted the importance of phosphorylated ets-2 in lung inflammation and extracellular matrix remodeling, two pathways involved in pulmonary fibrosis. We hypothesized that phosphorylated ets-2 played an important role in pulmonary fibrosis, and we sought to determine the role of ets-2 in its pathogenesis. We challenged ets-2 (A72/A72) transgenic mice (harboring a mutated form of ets-2 at phosphorylation site threonine-72) and ets-2 (wild-type/wild-type [WT/WT]) control mice with sequential intraperitoneal injections of bleomycin, followed by quantitative measurements of lung fibrosis and inflammation and primary cell in vitro assays. Concentrations of phosphorylated ets-2 were detected via the single and dual immunohistochemical staining of murine lungs and lung sections from patients with idiopathic pulmonary fibrosis. Ets-2 (A72/A72) mice were protected from bleomycin-induced pulmonary fibrosis, compared with ets-2 (WT/WT) mice. This protection was characterized by decreased lung pathological abnormalities and the fibrotic gene expression of Type I collagen, Type III collagen, α-smooth muscle actin, and connective tissue growth factor. Immunohistochemical staining of lung sections from bleomycin-treated ets-2 (WT/WT) mice and from patients with idiopathic pulmonary fibrosis demonstrated increased staining of phosphorylated ets-2 that colocalized with Type I collagen expression and to fibroblastic foci. Lastly, primary lung fibroblasts from ets-2 (A72/A72) mice exhibited decreased expression of Type I collagen in response to stimulation with TGF-ß, compared with fibroblasts from ets-2 (WT/WT) mice. These data indicate the importance of phosphorylated ets-2 in the pathogenesis of pulmonary fibrosis through the expression of Type I collagen and (myo)fibroblast activation.

Multimodal imaging and detection approach to 18F-FDG-directed surgery for patients with known or suspected malignancies: a comprehensive description of the specific methodology utilized in a single-institution cumulative retrospective experience.

BACKGROUND: (18)F-FDG PET/CT is widely utilized in the management of cancer patients. The aim of this paper was to comprehensively describe the specific methodology utilized in our single-institution cumulative retrospective experience with a multimodal imaging and detection approach to (18)F-FDG-directed surgery for known/suspected malignancies. METHODS: From June 2005-June 2010, 145 patients were injected with (18)F-FDG in anticipation of surgical exploration, biopsy, and possible resection of known/suspected malignancy. Each patient underwent one or more of the following: (1) same-day preoperative patient diagnostic PET/CT imaging, (2) intraoperative gamma probe assessment, (3) clinical PET/CT specimen scanning of whole surgically resected specimens (WSRS), research designated tissues (RDT), and/or sectioned research designated tissues (SRDT), (4) micro PET/CT specimen scanning of WSRS, RDT, and/or SRDT, (5) total radioactivity counting of each SRDT piece by an automatic gamma well counter, and (6) same-day postoperative patient diagnostic PET/CT imaging. RESULTS: Same-day (18)F-FDG injection dose was 15.1 (± 3.5, 4.6-26.1) mCi. Fifty-five same-day preoperative patient diagnostic PET/CT scans were performed. One hundred forty-two patients were taken to surgery. Three of the same-day preoperative patient diagnostic PET/CT scans led to the cancellation of the anticipated surgical procedure. One hundred forty-one cases utilized intraoperative gamma probe assessment. Sixty-two same-day postoperative patient diagnostic PET/CT scans were performed. WSRS, RDT, and SRDT were scanned by clinical PET/CT imaging and micro PET/CT imaging in 109 and 32 cases, 33 and 22 cases, and 49 and 26 cases, respectively. Time from (18)F-FDG injection to same-day preoperative patient diagnostic PET/CT scan, intraoperative gamma probe assessment, and same-day postoperative patient diagnostic PET/CT scan were 73 (± 9, 53-114), 286 (± 93, 176-532), and 516 (± 134, 178-853) minutes, respectively. Time from (18)F-FDG injection to scanning of WSRS, RDT, and SRDT by clinical PET/CT imaging and micro PET/CT imaging were 389 (± 148, 86-741) and 458 (± 97, 272-656) minutes, 619 (± 119, 253-846) and 661 (± 117, 433-835) minutes, and 674 (± 186, 299-1068) and 752 (± 127, 499-976) minutes, respectively. CONCLUSIONS: Our multimodal imaging and detection approach to (18)F-FDG-directed surgery for known/suspected malignancies is technically and logistically feasible and may allow for real-time intraoperative staging, surgical planning and execution, and determination of completeness of surgical resection.

Survival Advantage Following TAG-72 Antigen-Directed Cancer Surgery in Patients With Colorectal Carcinoma: Proposed Mechanisms of Action.

Patients with colorectal carcinoma (CRC) continue to have variable clinical outcomes despite undergoing the same surgical procedure with curative intent and having the same pathologic and clinical stage. This problem suggests the need for better techniques to assess the extent of disease during surgery. We began to address this problem 35 years ago by injecting patients with either primary or recurrent CRC with 125I-labeled murine monoclonal antibodies against the tumor-associated glycoprotein-72 (TAG-72) and using a handheld gamma-detecting probe (HGDP) for intraoperative detection and removal of radioactive, i.e., TAG-72-positive, tissue. Data from these studies demonstrated a significant difference in overall survival data (p < 0.005 or better) when no TAG-72-positive tissue remained compared to when TAG-72-positive tissue remained at the completion of surgery. Recent publications indicate that aberrant glycosylation of mucins and their critical role in suppressing tumor-associated immune response help to explain the cellular mechanisms underlying our results. We propose that monoclonal antibodies to TAG-72 recognize and bind to antigenic epitopes on mucins that suppress the tumor-associated immune response in both the tumor and tumor-draining lymph nodes. Complete surgical removal of all TAG-72-positive tissue serves to reverse the escape phase of immunoediting, allowing a resetting of this response that leads to improved overall survival of the patients with either primary or recurrent CRC. Thus, the status of TAG-72 positivity after resection has a significant impact on patient survival.

Medial necrosis in aortic root aneurysm after repair of tetralogy of Fallot.

Aneurysmal dilatation of the aortic root occurs in some patients with tetralogy of Fallot (TOF) late after repair. It can lead to aortic valve insufficiency and rarely to aortic rupture or dissection. Aortic valve or aortic surgery is rarely performed in this group of patients. We present a case of aneurysmal dilatation of the ascending aorta treated with aortic valve sparing root replacement 43 years after the TOF repair. Histological examination of the aortic wall revealed medial necrosis. The implications of those finding and the timing of surgery are discussed.

Metastatic squamous cell carcinoma of the vulva to the lung confirmed with allelotyping.

A squamous-cell carcinoma (SCC) of the lung can be indistinguishable from metastatic SCC of gynecologic origin using common histopathologic techniques; however, establishing tumor origin can be clinically relevant. A patient with a Bartholin gland SCC was found to also have a pulmonary SCC, concerning for metastasis versus synchronous pulmonary primary. Hematoxylin and eosin and immunohistochemistry alone could not differentiate the lesion, and both tumors were human papilloma virus positive. Allelotyping for loss of heterozygosity established the pulmonary lesion as a rare event of vulvar pulmonary metastasis. The patient received palliative chemotherapy instead of curative treatment. Allelotyping for loss of heterozygosity is an effective tool to establish metastasis versus synchronous primary tumors in the presence of multiple lesions, helping to direct appropriate clinical management.

Fibrillary glomerulonephritis with splenic involvement: a detailed autopsy study.

Fibrillary glomerulonephritis (FGN) is characterized by the deposition of IgG-positive, randomly arranged, nonbranching, non-Congophilic fibrils in the glomeruli. The possibility of multiorgan involvement, as in amyloidosis, has been raised. The authors report the first detailed autopsy study on a patient with FGN, with thorough examination of the organs by electron microscopy, colloidal gold immunoelectron microscopy, and immunofluorescence staining. Thin, wavy fibrils (extracellular matrix filaments) ranging from 6 to 17 nm were seen in all other organs, but only kidney and spleen showed the typical rigid, nonbranching fibrils of FGN with specific gold label. This study suggests that FGN is mainly a renal-limited disease with possible involvement of the spleen.

Proteomic Signatures of Thymomas.

Based on the histological features and outcome, the current WHO classification separates thymomas into A, AB, B1, B2 and B3 subtypes. It is hypothesized that the type A thymomas are derived from the thymic medulla while the type B thymomas are derived from the cortex. Due to occasional histological overlap between the tumor subtypes creating difficulties in their separation, the aim of this study was to provide their proteomic characterization and identify potential immunohistochemical markers aiding in tissue diagnosis. Pair-wise comparison of neoplastic and normal thymus by liquid chromatography tandem mass spectrometry (LC-MS/MS) of formalin fixed paraffin embedded tissue revealed 61 proteins differentially expressed in thymomas compared to normal tissue. Hierarchical clustering showed distinct segregation of subtypes AB, B1 and B2 from that of A and B3. Most notably, desmoyokin, a protein that is encoded by the AHNAK gene, was associated with type A thymomas and medulla of normal thymus, by LC-MS/MS and immunohistochemistry. In this global proteomic characterization of the thymoma, several proteins unique to different thymic compartments and thymoma subtypes were identified. Among differentially expressed proteins, desmoyokin is a marker specific for thymic medulla and is potentially promising immunohistochemical marker in separation of type A and B3 thymomas.

A Wearable Goggle Navigation System for Dual-Mode Optical and Ultrasound Localization of Suspicious Lesions: Validation Studies Using Tissue-Simulating Phantoms and an Ex Vivo Human Breast Tissue Model.

Surgical resection remains the primary curative treatment for many early-stage cancers, including breast cancer. The development of intraoperative guidance systems for identifying all sites of disease and improving the likelihood of complete surgical resection is an area of active ongoing research, as this can lead to a decrease in the need of subsequent additional surgical procedures. We develop a wearable goggle navigation system for dual-mode optical and ultrasound imaging of suspicious lesions. The system consists of a light source module, a monochromatic CCD camera, an ultrasound system, a Google Glass, and a host computer. It is tested in tissue-simulating phantoms and an ex vivo human breast tissue model. Our experiments demonstrate that the surgical navigation system provides useful guidance for localization and core needle biopsy of simulated tumor within the tissue-simulating phantom, as well as a core needle biopsy and subsequent excision of Indocyanine Green (ICG)-fluorescing sentinel lymph nodes. Our experiments support the contention that this wearable goggle navigation system can be potentially very useful and fully integrated by the surgeon for optimizing many aspects of oncologic surgery. Further engineering optimization and additional in vivo clinical validation work is necessary before such a surgical navigation system can be fully realized in the everyday clinical setting.

An obesity paradox: an inverse correlation between body mass index and atherosclerosis of the aorta.

BACKGROUND AND AIMS: Morbid obesity generally has been associated with higher morbidity and mortality for a variety of diseases. However, a number of exceptions to this have been reported and referred to as the "obesity paradox." The purpose of the present study was to obtain objective data on aortic atherosclerosis and its relationship to body mass index (BMI, kg/m2), based on autopsy findings in a large cohort of overweight and obese decedents. METHODS: Decedents were ≥18 years who had autopsies between 2003 and 2014, a subset of whom were morbidly obese (BMI≥40). Autopsy findings were reviewed and compared to a control group (BMI<40) who had consecutive autopsies performed between January 2013 and June 2014. Atherosclerosis was assessed by gross pathologic examination using a semiquantitative grading scale (from 0 to 3), and for statistical analysis, the scores were stratified into two groups: nonsevere (<2) or severe (≥2). RESULTS: There were 304 decedents in the study: 66 were morbidly obese (BMI≥40), 94 were either Class I or II obese (BMI 30-40), 127 were either overweight (BMI 25.0-29.9) or normal weight (BMI 20-24.9), and 17 were underweight (BMI<20). Decedents with mild atherosclerosis were significantly younger than those with severe disease (55.2 vs. 67.3, P<.0001). Decedents were further stratified by age and BMI. Univariate analysis revealed that decedents >60 years were more likely to have severe atherosclerosis than those ≤60 years (61% vs. 30%, P<.0001). There was a highly significant (P=.008) inverse relationship between severe aortic atherosclerosis and BMI. Twenty of 66 decedents (30%) with a BMI≥40 had severe atherosclerosis vs. 122 of 238 decedents (51%) with BMIs<40 (P=.001). As BMI increased, the probability of developing severe disease decreased. Hypertension increased the probability of having severe atherosclerosis (54% vs. 33%, P=.007). After adjusting for other covariates, multivariable analysis revealed that age and hypertension were still positively correlated with the severity of atherosclerosis (P=.014 and 0.028, respectively), and the inverse relationship between BMI and atherosclerosis remained (adjusted relative risk of BMI≥40 vs. <40=0.64, 95% confidence interval: 0.4-1; P=.03). CONCLUSIONS: Our data extend the previously described obesity paradox to another disease entity, atherosclerosis of the aorta. Morbid obesity appeared to have a protective effect for developing severe aortic atherosclerosis, for the reasons for which are yet to be determined. However, the mean age at death of decedents with BMIs≥40 was younger than those with BMIs in the 20-30 range (55.9 vs. 63.2 years, P=.001), confirming that morbid obesity was not associated with increased longevity.

Extracting Infrared Spectra of Protein Secondary Structures Using a Library of Protein Spectra and the Ramachandran Plot.

Infrared (IR) spectra from 1200 to 1800 cm(-1) of the pure α-helix and ß-sheet secondary structures have been extracted using a covariant least-squares procedure which relates a library of 40 infrared (IR) solution protein spectra from the work of Dong, Carpenter, and Caughey and amino acid fractions of the proteins based on assignments by STRIDE (secondary structure identification) of Eisenhaber and Argos. The excitonic splitting of the ß-sheet structures is determined for this library of solution proteins. The method is extended to find a set of spectral basis functions that analyze IR spectra of protein samples for α-helix and ß-sheet content. A rigorous error analysis including covariance, the correlations between the input library spectra, was used to justify the results and avoid less meaningful results. The utility of the results on α-helix and ß-sheet regions is demonstrated by detecting protein changes due to cancer in imaging Fourier transform IR (FTIR) spectra of liver tissue slices. This work ends with a method to extract IR spectra of less prominent torsional angle distributions.

Myocardial infarction in sickle cell disease: use of translational imaging to diagnose an under-recognized problem.

Sickle cell disease (SCD) is an inherited disorder in which microvascular occlusion causes complications across multiple organ systems. The precise incidence of myocardial ischemia and infarction (MI), potentially under-recognized microvascular disease-related complications, remains unknown. The absence of typical atherosclerotic lesions seen in other patients with MI suggests a microvascular mechanism of myocardial injury. Cardiac magnetic resonance (CMR) can demonstrate microvascular disease, making it an appealing modality to assess symptomatic SCD patients. We demonstrate in several dramatic instances how CMR is uniquely able to depict cardiac microvascular obstruction in patients with SCD and chest pain, without which the possibility of myocardial injury would almost certainly be otherwise neglected. Much remains unknown regarding ischemic heart disease in patients with SCD including prevalence, detection, and management. Further work to define evaluation and management algorithms for chest pain in SCD and to develop risk assessment tools may reduce sudden cardiac death in this population.