Development of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma.

Antibody engineering can tailor the design and activities of therapeutic antibodies for better efficiency or other advantageous clinical properties. Here we report the development of ISB 1442, a fully human bispecific antibody designed to re-establish synthetic immunity in CD38+ hematological malignancies. ISB 1442 consists of two anti-CD38 arms targeting two distinct epitopes that preferentially drive binding to tumor cells and enable avidity-induced blocking of proximal CD47 receptors on the same cell while preventing on-target off-tumor binding on healthy cells. The Fc portion of ISB 1442 is engineered to enhance complement dependent cytotoxicity, antibody dependent cell cytotoxicity and antibody dependent cell phagocytosis. ISB 1442 thus represents a CD47-BsAb combining biparatopic targeting of a tumor associated antigen with engineered enhancement of antibody effector function to overcome potential resistance mechanisms that hamper treatment of myeloma with monospecific anti-CD38 antibodies. ISB 1442 is currently in a Phase I clinical trial in relapsed refractory multiple myeloma.

The Methyltransferases METTL7A and METTL7B Confer Resistance to Thiol-Based Histone Deacetylase Inhibitors.

Histone deacetylase inhibitors (HDACi) are part of a growing class of epigenetic therapies used for the treatment of cancer. Although HDACis are effective in the treatment of T-cell lymphomas, treatment of solid tumors with this class of drugs has not been successful. Overexpression of the multidrug resistance protein P-glycoprotein (P-gp), encoded by ABCB1, is known to confer resistance to the HDACi romidepsin in vitro, yet increased ABCB1 expression has not been associated with resistance in patients, suggesting that other mechanisms of resistance arise in the clinic. To identify alternative mechanisms of resistance to romidepsin, we selected MCF-7 breast cancer cells with romidepsin in the presence of the P-gp inhibitor verapamil to reduce the likelihood of P-gp-mediated resistance. The resulting cell line, MCF-7 DpVp300, does not express P-gp and was found to be selectively resistant to romidepsin but not to other HDACis such as belinostat, panobinostat, or vorinostat. RNA-sequencing analysis revealed upregulation of the mRNA coding for the putative methyltransferase, METTL7A, whose paralog, METTL7B, was previously shown to methylate thiol groups on hydrogen sulfide and captopril. As romidepsin has a thiol as the zinc-binding moiety, we hypothesized that METTL7A could inactivate romidepsin and other thiol-based HDACis via methylation of the thiol group. We demonstrate that expression of METTL7A or METTL7B confers resistance to thiol-based HDACis and that both enzymes are capable of methylating thiol-containing HDACis. We thus propose that METTL7A and METTL7B confer resistance to thiol-based HDACis by methylating and inactivating the zinc-binding thiol.

METTL7A (TMT1A) and METTL7B (TMT1B) Are Responsible for Alkyl S-Thiol Methyl Transferase Activity in Liver.

S-methylation of drugs containing thiol-moieties often alters their activity and results in detoxification. Historically, scientists attributed methylation of exogenous aliphatic and phenolic thiols to a putative S-adenosyl-L-methionine (SAM)-dependent membrane-associated enzyme referred to as thiol methyltransferase (TMT). This putative TMT appeared to have a broad substrate specificity and methylated the thiol metabolite of spironolactone, mertansine, ziprasidone, captopril, and the active metabolites of the thienopyridine prodrugs, clopidogrel, and prasugrel. Despite TMT's role in the S-methylation of clinically relevant drugs, the enzyme(s) responsible for this activity remained unknown. We recently identified methyltransferase-like protein 7B (METTL7B) as an alkyl thiol methyltransferase. METTL7B is an endoplasmic reticulum-associated protein with similar biochemical properties and substrate specificity to the putative TMT. Yet, the historic TMT inhibitor 2,3-dichloro-α-methylbenzylamine (DCMB) did not inhibit METTL7B, indicating that multiple enzymes contribute to TMT activity. Here we report that methyltransferase-like protein 7A (METTL7A), an uncharacterized member of the METTL7 family, is also a SAM-dependent thiol methyltransferase. METTL7A exhibits similar biochemical properties to METTL7B and putative TMT, including inhibition by DCMB (IC50 = 1.17 µM). Applying quantitative proteomics to human liver microsomes and gene modulation experiments in HepG2 and HeLa cells, we determined that TMT activity correlates closely with METTL7A and METTL7B protein levels. Furthermore, purification of a novel His-GST-tagged recombinant protein and subsequent activity experiments prove that METTL7A can selectively methylate exogenous thiol-containing substrates, including 7α-thiospironolactone, dithiothreitol, 4-chlorothiophenol, and mertansine. We conclude that the METTL7 family encodes for two enzymes, METTL7A and METTL7B, which are now renamed thiol methyltransferase 1A (TMT1A) and thiol methyltransferase 1B (TMT1B), respectively, that are responsible for thiol methylation activity in human liver microsomes. SIGNIFICANCE STATEMENT: We identified methyltransferase-like protein 7A (thiol methyltransferase 1A) and methyltransferase-like protein 7B (thiol methyltransferase 1B) as the enzymes responsible for the microsomal alkyl thiol methyltransferase (TMT) activity. These are the first two enzymes directly associated with microsomal TMT activity. S-methylation of commonly prescribed thiol-containing drugs alters their pharmacological activity and/or toxicity, and identifying the enzymes responsible for this activity will improve our understanding of the drug metabolism and pharmacokinetic (DMPK) properties of alkyl- or phenolic thiol-containing therapeutics.

Arrhythmic Mitral Valve Prolapse and Mitral Annulus Disjunction in Heritable Aortic Disease.

Patients with heritable aortic disease (HAD) have an increased risk of ventricular arrhythmias and sudden cardiac death. Although mitral valve prolapse is common in HAD, mitral annulus disjunction (MAD) has only recently been described in these patients. This under-recognized condition may be a contributing factor to otherwise unexplained ventricular arrhythmias and sudden cardiac death in patients with HAD. This case series describes 3 patients in an adult HAD clinic who have concomitant mitral valve prolapse, MAD, and malignant arrhythmias. These cases may represent a unique disease entity or overlap syndrome, and they introduce MAD as a potential arrhythmogenic risk marker in HAD.

Les patients atteints de maladie aortique héréditaire (MAH) présentent un risque accru d'arythmie ventriculaire et de mort subite d'origine cardiaque. Bien que le prolapsus valvulaire mitral soit fréquent dans les cas de MAH, la disjonction annulaire mitrale (DAM) n'a été décrite que récemment chez ces patients. Cet état méconnu peut être un facteur contribuant à des arythmies ventriculaires autrement inexpliquées et à la mort subite d'origine cardiaque chez les patients atteints de MAH. Cette série de cas décrit trois patients d'une clinique de MAH pour adultes qui présentent un prolapsus valvulaire mitral, une DAM et des arythmies malignes en concomitance. Ces cas peuvent représenter une entité morbide unique ou un syndrome de chevauchement, et laissent entendre que la DAM pourrait être un nouveau marqueur du risque arythmogène associé à la MAH.

Human METTL7B is an alkyl thiol methyltransferase that metabolizes hydrogen sulfide and captopril.

Methylation of alkyl thiols is a biotransformation pathway designed to reduce thiol reactivity and potential toxicity, yet the gene and protein responsible for human alkyl thiol methyltransferase (TMT) activity remain unknown. Here we demonstrate with a range of experimental approaches using cell lines, in vitro systems, and recombinantly expressed enzyme, that human methyltransferase-like protein 7B (METTL7B) catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (AdoMet) to hydrogen sulfide (H2S) and other exogenous thiol small molecules. METTL7B gene modulation experiments, including knockdown in HepG2 cells and overexpression in HeLa cells, directly alter the methylation of the drug captopril, a historic probe substrate for TMT activity. Furthermore, recombinantly expressed and purified wild-type METTL7B methylates several thiol compounds, including H2S, 7α-thiospironolactone, L-penicillamine, and captopril, in a time- and concentration-dependent manner. Typical for AdoMet-dependent small molecule methyltransferases, S-adenosyl-L-homocysteine (AdoHcy) inhibited METTL7B activity in a competitive fashion. Similarly, mutating a conserved aspartate residue, proposed to anchor AdoMet into the active site, to an alanine (D98A) abolished methylation activity. Endogenous thiols such as glutathione and cysteine, or classic substrates for other known small molecule S-, N-, and O-methyltransferases, were not substrates for METTL7B. Our results confirm, for the first time, that METTL7B, a gene implicated in multiple disease states including rheumatoid arthritis and breast cancer, encodes a protein that methylates small molecule alkyl thiols. Identifying the catalytic function of METTL7B will enable future pharmacological research in disease pathophysiology where altered METTL7B expression and, potentially H2S levels, can disrupt cell growth and redox state.

Basis of specificity for a conserved and promiscuous chromatin remodeling protein.

Eukaryotic genomes are organized dynamically through the repositioning of nucleosomes. Isw2 is an enzyme that has been previously defined as a genome-wide, nonspecific nucleosome spacing factor. Here, we show that Isw2 instead acts as an obligately targeted nucleosome remodeler in vivo through physical interactions with sequence-specific factors. We demonstrate that Isw2-recruiting factors use small and previously uncharacterized epitopes, which direct Isw2 activity through highly conserved acidic residues in the Isw2 accessory protein Itc1. This interaction orients Isw2 on target nucleosomes, allowing for precise nucleosome positioning at targeted loci. Finally, we show that these critical acidic residues have been lost in the Drosophila lineage, potentially explaining the inconsistently characterized function of Isw2-like proteins. Altogether, these data suggest an 'interacting barrier model,' where Isw2 interacts with a sequence-specific factor to accurately and reproducibly position a single, targeted nucleosome to define the precise border of phased chromatin arrays.

DNA encodes the genetic instructions for life in a long, flexible molecular chain that is packaged up neatly to fit inside cells. Short sections of DNA are wound around proteins to form bundles called nucleosomes, and then spun into chromatin fibres, a more compact form of DNA. While nucleosomes are a fundamental part of this space-saving packaging process, they also play a key regulatory role in gene expression, which is where genes are decoded into working proteins. Placing nucleosomes at regular intervals along DNA invariably controls which parts of the DNA ­ and which genes ­ the cell's machinery can access and 'read' to make proteins. But the nucleosomes' positions are not fixed, and gene expression is a dynamic process. The cell often uncoils and repackages its DNA while molecular motors called chromatin remodelling proteins move nucleosomes up and down the DNA, exposing some genes and obstructing others. One group of chromatin remodelling proteins are called Imitation Switch (ISWI) complexes. It has long been thought that these complexes position nucleosomes with little regard to the underlying DNA sequence or the genes encoded, that is to say in a non-specific way. However, this theory has not been thoroughly tested. It is possible that ISWI complexes actually place nucleosomes on certain parts of DNA at particular times in an organism's development, or in response to other environmental factors. Except how such precision is achieved remains unknown. To test this alternative theory of nucleosome positioning, Donovan et al. studied ISWI proteins and nucleosomes in common baker's yeast. This involved systematically removing sections of ISWI proteins to see whether the complexes could still position nucleosomes, and which parts of the proteins where essential for the job. By doing so, Donovan et al. identified multiple 'targeting' proteins that bind to ISWI proteins and deliver the complexes to specific target sequences of DNA. From there, the complex remodels the nucleosome, positioning it at a specific distance from its landing site on DNA, as further experiments showed. This research provides a new model for explaining how nucleosomes are positioned to package DNA and control gene expression. Donovan et al. have identified a new mechanism of interaction between nucleosomes and chromatin remodelling proteins of the ISWI variety. It is possible that more interactions of this kind will be discovered with further research.

Cervical cytomegalovirus reactivation, cytokines and spontaneous preterm birth in Kenyan women.

Genital cytomegalovirus (CMV) reactivation is common during the third trimester of pregnancy. We hypothesized that cervical CMV shedding may increase risk of spontaneous preterm birth (sPTB) through the release of inflammatory cytokines in the cervix. We conducted a nested case-control analysis to determine the relationship between CMV shedding and sPTB using data and samples from a prospective cohort study in western Kenya. Women who delivered between 28 + 0 and 33 + 6 weeks gestation were matched by gestational age at sample collection to controls who delivered ≥ 37 + 0 weeks. Levels of CMV DNA and interleukin (IL)-1 beta (ß), IL-6, IL-8 and tumor necrosis factor (TNF)-α were measured in cervical swabs. We used conditional logistic regression to assess relationships between CMV shedding, cervical cytokine levels and sPTB. Among 86 cases and 86 matched controls, cervical CMV levels were not significantly associated with sPTB [odds ratio (OR) = 1·23, 95% confidence interval (CI) = 0·59-2·56], but were significantly associated with higher levels of cervical IL-6 (ß = 0·15, 95% CI = 0·02-0·29) and TNF-α (ß = 0·14, 95% CI = 0·01-0·27). In univariate analysis, higher odds of sPTB was associated with higher cervical IL-6 levels (OR = 1·54, 95% CI = 1·00-2·38), but not with other cervical cytokines. In this cohort of Kenyan women, we did not find a significant association between cervical CMV shedding and sPTB before 34 weeks.

MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells.

Current treatment for patients with metastatic melanoma include molecular-targeted therapies and immune checkpoint inhibitors. However, a subset of melanomas are difficult-to-treat. These melanomas include those without the genetic markers for targeted therapy, non-responsive to immunotherapy, and those who have relapsed or exhausted their therapeutic options. Therefore, it is necessary to understand and explore other biological processes that may provide new therapeutic approaches. One of most appealing is targeting the apoptotic/anti-apoptotic system that is effective against leukemia. We used genetic knockdown and pharmacologic approaches of BH3 mimetics to target anti-apoptotic BCL2 family members and identified MCL1 and BCLXL as crucial pro-survival members in melanoma. We then examined the effects of combining BH3 mimetics to target MCL1 and BCLXL in vitro and in vivo. These include clinical-trial-ready compounds such as ABT-263 (Navitoclax) and S63845/S64315 (MIK655). We used cell lines derived from patients with difficult-to-treat melanomas. In vitro, the combined inhibition of MCL1 and BCLXL resulted in significantly effective cell killing compared to single-agent treatment (p < 0.05) in multiple assays, including sphere assays. The combination-induced cell death was independent of BIM, and NOXA. Recapitulated in our mouse xenograft model, the combination inhibited tumor growth, reduced sphere-forming capacity (p < 0.01 and 0.05, respectively), and had tolerable toxicity (p > 0.40). Taken together, this study suggests that dual targeting of MCL1 and BCLXL should be considered as a treatment option for difficult-to-treat melanoma patients.

Surgical Field Visualization during Functional Endoscopic Sinus Surgery: Comparison of Propofol- vs Desflurane-Based Anesthesia.

OBJECTIVE: To assess if the type of general anesthetic affects bleeding and field visualization during endoscopic sinus surgery. STUDY DESIGN: Prospective, randomized, controlled trial. SETTING: Academic teaching hospital and Veterans Affairs hospital in the United States. SUBJECTS AND METHODS: Seventy patients were randomized to 1 of 3 anesthetic regimens: (1) the volatile anesthetic desflurane (n = 22), (2) intravenous anesthesia with propofol (n = 25), or (3) a combination of propofol and desflurane (n = 23). Intravenous remifentanil was titrated to decrease the mean arterial pressure to 60 to 70 mm Hg but not ≥30% from baseline. Surgical bleeding scores were recorded along with bleeding rates and hemodynamic parameters, including cardiac output and systemic vascular resistance through pulse contour analysis from a radial arterial line. Statistics: multiple comparison tests and regression analyses; α = .05. RESULTS: There were no differences in bleeding rate (median, 0.58, 0.85, 0.57 mL min-1), bleeding score (2.1, 2.0, 2.0), surgery duration (79, 81, 86 minutes), extubation time (9, 7, 8 minutes), recovery room time (65, 61, 61 minutes), or any hemodynamic parameters among groups 1 through 3, respectively. Group 1 required lower remifentanil infusions than group 2 (0.11 vs 0.26 µg kg-1 min-1; P = .01). The bleeding score correlated positively with height (P = .014) and the Lund-MacKay score (P = .013). Bilateral vs unilateral surgery led to longer surgery duration (P = .001) and recovery room time (P = .004). CONCLUSION: When remifentanil is used for controlled hypotension, propofol has no advantage over desflurane to improve surgical field visualization during functional endoscopic sinus surgery.

Is there an advantage to using computer aided detection for the early detection of pulmonary nodules within chest X-Ray imaging?

OBJECTIVE: Using published literature, this research examines whether Computer-aided Detection (CAD) identifies more Pulmonary Nodules (PN) within Chest X-ray (CXR) systems, compared to radiologist diagnosis without CAD. KEY FINDINGS: Although the primary papers were pointing to CAD being a beneficial system in the diagnosis of PN detection, a regression analysis of the data available within these papers showed no correlation between the higher sensitivity of CAD against the detrimental high False Positives (FP) of CAD. Findings of the studies were deemed inconclusive. CONCLUSION: Further research is recommended to review the potential of CAD on CXR PN detection. IMPLICATIONS FOR PRACTICE: CAD acting as a second reader could potentially reduce interpreter error rate.

Proceedings of resources for optimal care of acute care and emergency surgery consensus summit Donegal Ireland.

BACKGROUND: Opportunities to improve emergency surgery outcomes exist through guided better practice and reduced variability. Few attempts have been made to define optimal care in emergency surgery, and few clinically derived key performance indicators (KPIs) have been published. A summit was therefore convened to look at resources for optimal care of emergency surgery. The aim of the Donegal Summit was to set a platform in place to develop guidelines and KPIs in emergency surgery. METHODS: The project had multidisciplinary global involvement in producing consensus statements regarding emergency surgery care in key areas, and to assess feasibility of producing KPIs that could be used to monitor process and outcome of care in the future. RESULTS: Forty-four key opinion leaders in emergency surgery, across 7 disciplines from 17 countries, composed evidence-based position papers on 14 key areas of emergency surgery and 112 KPIs in 20 acute conditions or emergency systems. CONCLUSIONS: The summit was successful in achieving position papers and KPIs in emergency surgery. While position papers were limited by non-graded evidence and non-validated KPIs, the process set a foundation for the future advancement of emergency surgery.

Early life programming and the risk of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, type 2 diabetes and cardiovascular disease and can be considered the hepatic manifestation of the metabolic syndrome. NAFLD represents a spectrum of disease, from the relatively benign simple steatosis to the more serious non-alcoholic steatohepatitis, which can progress to liver cirrhosis, hepatocellular carcinoma and end-stage liver failure, necessitating liver transplantation. Although the increasing prevalence of NAFLD in developed countries has substantial implications for public health, many of the precise mechanisms accounting for the development and progression of NAFLD are unclear. The environment in early life is an important determinant of cardiovascular disease risk in later life and studies suggest this also extends to NAFLD. Here we review data from animal models and human studies which suggest that fetal and early life exposure to maternal under- and overnutrition, excess glucocorticoids and environmental pollutants may confer an increased susceptibility to NAFLD development and progression in offspring and that such effects may be sex-specific. We also consider studies aimed at identifying potential dietary and pharmacological interventions aimed at reducing this risk. We suggest that further human epidemiological studies are needed to ensure that data from animal models are relevant to human health.

Prenatal exposure to very severe maternal obesity is associated with adverse neuropsychiatric outcomes in children.

BACKGROUND: Prenatal maternal obesity has been linked to adverse childhood neuropsychiatric outcomes, including increased symptoms of attention deficit hyperactivity disorder (ADHD), internalizing and externalizing problems, affective disorders and neurodevelopmental problems but few studies have studied neuropsychiatric outcomes among offspring born to very severely obese women or assessed potential familial confounding by maternal psychological distress. METHOD: We evaluated neuropsychiatric symptoms in 112 children aged 3-5 years whose mothers had participated in a longitudinal study of obesity in pregnancy (50 very severe obesity, BMI ⩾40 kg/m2, obese class III and 62 lean, BMI 18.5-25 kg/m2). The mothers completed the Conners' Hyperactivity Scale, Early Symptomatic Syndrome Eliciting Neurodevelopmental Clinical Examination Questionnaire (ESSENCE-Q), Child's Sleep Habits Questionnaire (CSHQ), Strengths and Difficulties Questionnaire (SDQ), and Child Behavior Checklist (CBCL) to assess child neuropsychiatric symptoms. Covariates included child's sex, age, birthweight, gestational age, socioeconomic deprivation levels, maternal age, parity, smoking status during pregnancy, gestational diabetes and maternal concurrent symptoms of anxiety and depression assessed using State Anxiety of Spielberger State-Trait Anxiety Index (STAI) and General Health Questionnaire (GHQ), respectively. RESULTS: Children exposed to prenatal maternal very severe obesity had significantly higher scores in the Conners' Hyperactivity Scale; ESSENCE-Q; total sleep problems in CSHQ; hyperactivity, conduct problems and total difficulties scales of the SDQ; higher externalizing and total problems, anxious/depressed, aggressive behaviour and other problem syndrome scores and higher DSM-oriented affective, anxiety and ADHD problems in CBCL. Prenatal maternal very severe obesity remained a significant predictor of child neuropsychiatric problems across multiple scales independent of demographic factors, prenatal factors and maternal concurrent symptoms of anxiety and depression. CONCLUSIONS: Prenatal maternal very severe obesity is a strong predictor of increased neuropsychiatric problems in early childhood.

Estrogens protect male mice from obesity complications and influence glucocorticoid metabolism.

BACKGROUND: Although the prevalence of obesity is higher among women than men, they are somewhat protected from the associated cardiometabolic consequences. The increase in cardiovascular disease risk seen after the menopause suggests a role for estrogens. There is also growing evidence for the importance of estrogen on body fat and metabolism in males. We hypothesized that that estrogen administration would ameliorate the adverse effects of obesity on metabolic parameters in males. METHODS: Male and female C57Bl/6 mice were fed control or obesogenic (DIO) diets from 5 weeks of age until adulthood. Glucose tolerance testing was performed at 13 weeks of age. Mice were killed at 15 weeks of age and liver and adipose tissue were collected for analysis of gene expression. A second cohort of male mice underwent the same experimental design with the addition of estradiol pellet implantation or sham surgery at 6 weeks. RESULTS: DIO males had greater mesenteric adipose deposition and more severe increases in plasma glucose, insulin and lipids than females. Treatment of males with estradiol from 6 weeks of age prevented DIO-induced increases in adipose tissue mass and alterations in glucose-insulin homeostasis. We also identified sex differences in the transcript levels and activity of hepatic and adipose glucocorticoid metabolizing enzymes. Estrogen treatment feminized the pattern of DIO-induced changes in glucocorticoid metabolism, rendering males similar to females. CONCLUSIONS: Thus, DIO induces sex-specific changes in glucose-insulin homeostasis, which are ameliorated in males treated with estrogen, highlighting the importance of sex steroids in metabolism. Given that altered peripheral glucocorticoid metabolism has been observed in rodent and human obesity, our results also suggest that sexually dimorphic expression and activity of glucocorticoid metabolizing enzymes may have a role in the differential metabolic responses to obesity in males and females.

Sleep characteristics in Goldenhar Syndrome.

OBJECTIVE: To examine the characteristics of sleep in patients with Goldenhar Syndrome. DESIGN: Retrospective review of all polysomnography studies conducted at the University of North Carolina Hospitals between 2003 and 2013 on patients carrying the diagnosis of Goldenhar's Syndrome. RESULTS: A preponderance of patients demonstrated severe obstructive sleep apnea and hypercapnia. CONCLUSIONS: Patients with Goldenhar Syndrome should be screened for sleep apnea and hypercapnia.

Clinical care in craniofacial microsomia: a review of current management recommendations and opportunities to advance research.

Craniofacial microsomia (CFM) is a complex condition associated with microtia, mandibular hypoplasia, and preauricular tags. It is the second most common congenital facial condition treated in many craniofacial centers and requires longitudinal multidisciplinary patient care. The purpose of this article is to summarize current recommendations for clinical management and discuss opportunities to advance clinical research in CFM.

Broadband optimal contrast resolution beamforming.

This paper proposes a novel receive beamformer architecture for broadband imaging systems that uses unique finite impulse response (FIR) filters on each channel. The conventional delay-and-sum (DAS) beamformer applies receive apodization by weighting the signal on each receive channel prior to beam summation. Our proposed FIR beamformer passes the focused receive radio frequency (RF) signals through multi-tap FIR filters on each receive channel prior to summation. The receive FIR filters are constructed to maximize the contrast resolution of the system's spatial response. The broadband FIR beamformer produces spatial point spread functions (PSFs) with narrower mainlobe widths and lower sidelobe levels than spatial PSFs produced by the conventional DAS beamformer. We present simulation results showing that FIR filters of modest tap lengths (3-7) can yield marked improvement in image contrast and point resolution. Specifically we show that 7-tap FIR filters can reduce sidelobe and grating lobe energy by 30dB and improve contrast resolution by as much as 20dB compared to conventional apodization profiles. This improvement in contrast resolution comes at the expense of a decrease in beamformer sensitivity. We investigate the effects of phase aberration and show in simulation results that the multi-tap FIR beamformer outperforms the unaberrated DAS beamformer by 8-12dB even in the presence of moderate aberration characterized by a root-mean-square strength of 28ns and a full-width at half-maximum correlation length of 3.6mm. We show experimental results wherein multi-tap FIR filters decrease sidelobe energy in the resulting 2D spatial response while achieving a narrow mainlobe. We also show results where the FIR beamformer improves the contrast to noise ratio (CNR) in simulated B-mode cyst images by more than 4dB. Our algorithm has the potential to significantly improve ultrasound beamforming in any application where the system response is reasonably well characterized. Furthermore, this algorithm can be used to increase contrast and resolution in one-way beamforming systems such as acousto-optic and opto-acoustic imaging.

Robust finite impulse response beamforming applied to medical ultrasound.

We previously described a beamformer architecture that replaces the single apodization weights on each receive channel with channel-unique finite impulse response (FIR) filters. The filter weights are designed to optimize the contrast resolution performance of the imaging system. Although the FIR beamformer offers significant gains in contrast resolution, the beamformer suffers from low sensitivity, and its performance rapidly degrades in the presence of noise. In this paper, a new method is presented to improve the robustness of the FIR beamformer to electronic noise as well as variation or uncertainty in the array response. A method is also described that controls the sidelobe levels of the FIR beamformer's spatial response by applying an arbitrary weighting function in the filter design algorithm. The robust FIR beamformer is analyzed using a generalized cystic resolution metric that quantifies a beamformer's clinical imaging performance as a function of cyst size and channel input SNR. Fundamental performance limits are compared between 2 robust FIR beamformers - the dynamic focus FIR (DF-FIR) beamformer and the group focus FIR (GF-FIR) beamformer - the conventional delay-and-sum (DAS) beamformer, and the spatial-matched filter (SMF) beamformer. Results from this study show that the new DF- and GF-FIR beamformers are more robust to electronic noise compared with the optimal contrast resolution FIR beamformer. Furthermore, the added robustness comes with only a slight loss in cystic resolution. Results from the generalized cystic resolution metric show that a 9-tap robust FIR beamformer outperforms the SMF and DAS beamformer until receive channel input SNR drops below -5 dB, whereas the 9-tap optimal contrast resolution beamformer's performance deteriorates around 50 dB SNR. The effects of moderate phase aberrations, characterized by an a priori root-mean-square strength of 28 ns and an a priori full-width at half-maximum correlation length of 3.6 mm, are investigate- d on the robust FIR beamformers. Full sets of robust FIR beamformer filter weights are constructed using an in silico model scanner and the L14-5/38 mm probe. Using the derived weights, a series of simulated point target and anechoic cyst B-mode images are generated to investigate further the potential increases in contrast resolution when using the robust FIR beamformers. Under the investigated conditions, the 7-tap optimal contrast resolution beamformer and the 7-tap robust beamformer with added SNR constraint increase lesion detectability by 247 and 137% compared with the conventional DAS beamformer, respectively. Finally, experimental phantom and in vivo images are produced using this novel receive architecture. The simulated and experimental images clearly show a reduction in clutter and an increase in contrast resolution compared with the conventionally beamformed images. This novel receive beamformer can be applied to any conventional ultrasound system where the system response is reasonably well characterized.

Generalized cystic resolution: a metric for assessing the fundamental limits on beamformer performance.

Existing methods for characterizing the imaging performance of ultrasound systems do not clearly quantify the impact of contrast, spatial resolution, and signal-to-noise ratio (SNR). Although the beamplot, contrast resolution metrics, SNR measurements, ideal observer methods, and contrast-detail analysis provide useful information, it remains difficult to discern how changes in system parameters affect these metrics and clinical imaging performance. In this paper, we present a rigorous methodology for characterizing the pulse-echo imaging performance of arbitrary ultrasound systems. Our metric incorporates the 4-D spatio-temporal system response, which is defined as a function of the individual beamformer channel weights. The metric also incorporates the individual beamformer channel electronic SNR. Whereas earlier performance measures dealt solely with contrast resolution or echo signal-to-noise ratio, our metric combines them so that tradeoffs between these parameters are easily distinguishable. The new metric quantifies an arbitrary system's contrast resolution and SNR performance as a function of cyst size, beamformer channel weights, and beamformer channel SNR. We present a theoretical derivation of the unified performance metric and provide simulation and experimental results highlighting the metric's utility. We compare the fundamental performance limits of 2 beamforming strategies: the dynamic focus finite impulse response (FIR) filter beamformer and the spatial matched filter (SMF) beamformer to the performance of the conventional delay-and-sum (DAS) beamformer. Results from this study show that the SMF beamformer and the FIR beamformer offer significant gains in beamformer SNR and contrast resolution compared with the DAS beamformer, respectively. The metric clearly distinguishes the performance of the SMF beamformer, which enhances system sensitivity, from the FIR beamformer, which optimizes system contrast resolution. Finally, the metric provides one quantitative goal for optimizing a broadband beamformer?s contrast resolution performance.

Germline mutation prevalence in the base excision repair gene, MYH, in patients with endometrial cancer.

Germline mutations in the base excision repair gene, MutY human homolog (MYH), have recently been associated with a recessively inherited multiple adenoma polyposis syndrome and colorectal cancer. The spectrum of extracolonic lesions is still being characterized, although preliminary reports suggest that bi-allelic mutation carriers may share some of the clinical features of other hereditary colon cancer syndromes. Of 225 endometrial cancer patients, we identified one individual as a compound heterozygote, carrying mutations Y165C and G382D of MYH, and five individuals with heterozygous defects (three G382D and two Y165C). The patient with the bi-allelic Y165C/G382D mutation also had a sebaceous carcinoma, a feature of Muir-Torre syndrome. Although several intronic polymorphisms were detected in the heterozygous carriers, no other pathogenic variants were identified. While not conclusive, this novel and interesting finding provides evidence that bi-allelic germline mutations in MYH may increase susceptibility to endometrial cancer.