Steven Laken

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Papers by Steven Laken

Clinical Opportunities for Continuous Biosensing and Closed-Loop Therapies

Trends in Chemistry

Continuous glucose monitors (CGMs) and closed-loop drug delivery systems have revolutionized pati... more Continuous glucose monitors (CGMs) and closed-loop drug delivery systems have revolutionized patient care in diabetes and anesthesia. Here, we review the current state of continuous chemical sensor development, titratable drug delivery systems, and closed-loop therapies to identify clinically meaningful trends that, if realized, can have significant impact on medical practice and patient outcome. In particular, we focus on novel wearable and implantable demonstrations that stand to redefine the patient experience. Finally, we put forth a roadmap towards identifying critical unmet clinical opportunities to motivate future technological development towards applications beyond glucose, to both improve patient care across diverse fields of medicine and realize the full potential of these technologies to improve therapeutic outcome. Closed-Loop Therapies Highlights Clinical application of continuous biochemical sensors and closed-loop therapies improves patient care through better patient adherence and greater access to patient data to guide personalized disease management.

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Analysis of short tandem repeat polymorphisms using infrared fluorescence with M18 tailed primers

American Journal of Human Genetics, 1994

The use of short tandem repeat polymorphisms (STRPs) are becoming increasingly important as marke... more The use of short tandem repeat polymorphisms (STRPs) are becoming increasingly important as markers for linkage analysis due to their large numbers of the human genome and their high degree of polymorphism. Fluorescence based detection of the STRP pattern using the LI-COR model 4000S automated DNA sequencer eliminates the need for radioactivity and produces a digitized image that can be

Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome

Research in Immunology, 1998

Peutz-Jeghers syndrome (PJS) is an autosomal dominant condition characterized by intestinal hamar... more Peutz-Jeghers syndrome (PJS) is an autosomal dominant condition characterized by intestinal hamartomatous polyps, mucocutaneous mela nin deposition, and increased risk of cancer. Families with PJS from the Johns Hopkins Polyposis Registry were studied to identify the molecular basis of this syndrome and to characterize the pathogenesis of gastroin testinal hamartomas and adenocarcinomas in PJS patients. Linkage anal ysis in the family originally described by Jeghers in 1949 and five other families confirmed linkage to 19pl3.3 near a recently identified gene responsible for PJS. Germ-line mutations in this gene, S'l'Kll. were iden tified in all six families by sequencing genomic DNA. Analysis of hamar tomas and adenocarcinomas from patients with PJS identified loss of heterozygosity (LOH) of 19p markers near STKil in 70% of tumors.

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Fluid fragmentation from hospital toilets

Hospital-acquired infections represent significant health and financial burdens to society. Clost... more Hospital-acquired infections represent significant health and financial burdens to society. Clostridium difficile (C. difficile) is a particularly challenging bacteria with the potential to cause severe diarrhea and death. One mode of transmission for C. difficile, as well as other pathogens, which has received little attention is the potential air contamination by pathogen-bearing droplets emanating from toilets. In the fluid dynamics video submitted to the APS DFD Gallery of Fluid Motion 2013, we present flow visualizations via high-speed recordings showing the capture of the product of the fluid fragmentation generated by hospital toilet high-pressure flushes. Important quantities of both large and small droplets are observed. We illustrate how high-pressure flushes and cleaning products currently used in hospital toilets result in aggravating, rather than alleviating, the suspension and recirculation of tenacious airborne pathogen-bearing droplets.

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Neural correlates of successful response inhibition in unmedicated patients with late-life depression

The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, 2012

Accumulating evidence implicates a strong association between abnormal frontostriatal-limbic brai... more Accumulating evidence implicates a strong association between abnormal frontostriatal-limbic brain circuits, executive dysfunction, and late-life depression (LLD). The stop signal task (SST) was designed by Rubia et al. for use with functional magnetic resonance imaging (fMRI) to identify the neural correlates of motor response inhibition, a well-characterized executive function. In this study, we compared brain activation between a group of unmedicated participants with LLD and an unmedicated healthy cohort during SST performance. Participants 55-85 years of age were screened, clinically evaluated, and entered into either the LLD (n = 15) or healthy comparison group (n = 13). Both groups underwent neuroimaging while performing the SST under similar conditions. The brain circuitry of successful motor inhibition was evaluated by contrasting the condition of correctly inhibiting responses with the condition of correctly responding to Go signals. Differential areas of brain activation ...

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Conversion of diploidy to haploidy

Nature, Jan 17, 2000

... 2000 Feb 17;403(6771):723-4. Conversion of diploidy to haploidy. Yan H, Papadopoulos N, Marra... more

Genotyping by mass spectrometric analysis of short DNA fragments

Nature biotechnology, 1998

A method has been developed to produce small DNA fragments from PCR products for analysis of defi... more A method has been developed to produce small DNA fragments from PCR products for analysis of defined DNA variations by mass spectrometry. The genomic region to be analyzed is PCR-amplified with primers containing a sequence for the type IIS restriction endonuclease Bpml. Bpml digestion of the resultant PCR products yields fragments as small as seven bases, which are then analyzed by electrospray ionization mass spectrometry. The approach was validated using seven different variants within the APC tumor suppressor gene, in which a perfect correlation was obtained with DNA sequencing. Both the sense and antisense strands were analyzed independently, and several variants can be analyzed simultaneously. These results provide the basis for a generally applicable and highly accurate method that directly queries the mass of variant DNA sequences.

Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome

Cancer research, 1998

Peutz-Jeghers syndrome (PJS) is an autosomal dominant condition characterized by intestinal hamar... more Peutz-Jeghers syndrome (PJS) is an autosomal dominant condition characterized by intestinal hamartomatous polyps, mucocutaneous melanin deposition, and increased risk of cancer. Families with PJS from the Johns Hopkins Polyposis Registry were studied to identify the molecular basis of this syndrome and to characterize the pathogenesis of gastrointestinal hamartomas and adenocarcinomas in PJS patients. Linkage analysis in the family originally described by Jeghers in 1949 and five other families confirmed linkage to 19p13.3 near a recently identified gene responsible for PJS. Germ-line mutations in this gene, STK11, were identified in all six families by sequencing genomic DNA. Analysis of hamartomas and adenocarcinomas from patients with PJS identified loss of heterozygosity (LOH) of 19p markers near STK11 in 70% of tumors. Haplotype analysis indicated that the retained allele carried a germ-line mutation, confirming that STK11 is a tumor suppressor gene. LOH of 17p and 18q was iden...

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The APCI1307K allele and cancer risk in a community-based study of Ashkenazi Jews

Nature genetics, 1998

Mutations in APC are classically associated with familial adenomatous polyposis (FAP), a highly p... more Mutations in APC are classically associated with familial adenomatous polyposis (FAP), a highly penetrant autosomal dominant disorder characterized by multiple intestinal polyps and, without surgical intervention, the development of colorectal cancer (CRC). APC is a tumour-suppressor gene, and somatic loss occurs in tumours. The germline T-to-A transversion responsible for the APC I1307K allele converts the wild-type sequence to a homopolymer tract (A8) that is genetically unstable and prone to somatic mutation. The I1307K allele was found in 6.1% of unselected Ashkenazi Jews and higher proportions of Ashkenazim with family or personal histories of CRC (ref. 2). To evaluate the role of I1307K in cancer, we genotyped 5,081 Ashkenazi volunteers in a community survey. Risk of developing colorectal, breast and other cancers were compared between genotyped I1307K carriers and non-carriers and their first-degree relatives.

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APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis

Gut, 1997

Background-Familial adenomatous polyposis (FAP) is caused by germline mutation of the adenomatous... more Background-Familial adenomatous polyposis (FAP) is caused by germline mutation of the adenomatous polyposis coli (APC) gene on chromosome Sq. Aims-This study assessed genotypephenotype correlations for extraintestinal lesions in FAP. Methods-Mutations of the APC gene were compared with the occurrence of seven extraintestinal mafestations in 475

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Stool DNA mutation testing for colorectal cancer detection: sensitivity and reproducibility

Results: 217 colonoscopies were performed (80% in outpatients). Tissue was obtained in 72 patient... more Results: 217 colonoscopies were performed (80% in outpatients). Tissue was obtained in 72 patients during 74 colonoscopies (2 patients had 2 colonoscopies each). Seventeen patients (23.6%) had biopsies from the colon without polyps or masses, whereas the remaining 55 had polyps removed and/or biopsies obtained from masses. Of those undergoing biopsies from non-polypoid/mass lesions, 11 (64.7%) were normal; 6 had colitis:3 non-specific, 1 microscopic, 1 acute and 1 consistent with IBD. Of the 55 patients with polyps or masses (29 men:mean age 51.4 y; 26 women:mean age 55.4 y), the most common indications for colonoscopy were: BRBPR:17; surveillance for polyps (7) or CRC (3); FMH CRC:10; diarrhea:7; Fe deficiency anemia:7; pain/bloating:7; and guaiac ϩ stools:6. One patient had FAP with cancer in the rectum. In the 54 remaining patients, there were 88 distintc polyps removed; 1 patient had "multiple" diminutive polyps (no number given) and 4 had cancers (1 man and 3 women). Fifty eight (65.9%) polyps were 5 mm; 19 (21.6%):6 -9 mm and, 11 (12.5%)10 mm (in 10 patients). Histologic diagnoses: 53 polyps (60.2%) were tubular adenomas (5 with dysplasia); 3 (3.4%) tubulovillous; 18 (20.5%) hyperplastic and 14 (15.9%) had normal histology or inflammation (all these were Ͻ 5 mm in size). Thirty (51.7%) polyps 5 mm were tubular adenomas. Twenty-seven (30.7%) polyps were single: 17 distal and 10 proximal; 23 of these were tubular adenomas. Of those with multiple polyps (27 patients), 9 (1/3) had their polyps confined to the distal colon and the remaining had polyps proximally. There were 5 cancers: 1 with FAP, 3 without synchronous polyps and located proximally; 1 with rectal cancer and a distal adenoma. Five patients had polyps with dysplasia: 2 with high grade dysplasia (sigmoid and descending); 2 with moderate dysplasia (sigmoid and splenic flexure) and 1 with mild dysplasia (ascending). Conclusions: One-fourth of colonoscopies in Native American harbored polyps and 36.3% (20/55) patients had advanced pathology manifested as large polyps, presence of dysplasia or carcinoma.

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Replication of Functional MRI Detection of Deception

The Open Forensic Science Journal, 2009

Background-Several studies support the use of fMRI for detecting deception. There have been, howe... more Background-Several studies support the use of fMRI for detecting deception. There have been, however, no reported replications on different scanners or at different locations. In a previous study, deception was accurately detected in at least 90% of the participants in two independent cohorts. This study attempted to replicate those findings using a different scanner and location.

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The Neuroscience of Functional Magnetic Resonance Imaging fMRI for Deception Detection

The American Journal of Bioethics, 2007

1. Am J Bioeth. 2007 Sep;7(9):58-60. The neuroscience of functional magnetic resonance imaging fM... more

Can simultaneously acquired electrodermal activity improve accuracy of fMRI detection of deception?

Social Neuroscience, 2009

Observation of changes in autonomic arousal was one of the first methodologies used to detect dec... more Observation of changes in autonomic arousal was one of the first methodologies used to detect deception. Electrodermal activity (EDA) is a peripheral measure of autonomic arousal and one of the primary channels used in polygraph exams. In an attempt to develop a more central measure to identify lies, the use of functional magnetic resonance imaging (fMRI) to detect deception is being investigated. We wondered if adding EDA to our fMRI analysis would improve our diagnostic ability. For our approach, however, adding EDA did not improve the accuracy in a laboratory-based deception task. In testing for brain regions that replicated as correlates of EDA, we did find significant associations in right orbitofrontal and bilateral anterior cingulate regions. Further work is required to test whether EDA improves accuracy in other testing formats or with higher levels of jeopardy.

Analysis of masked mutations in familial adenomatous polyposis

Proceedings of the National Academy of Sciences, 1999

Familial adenomatous polyposis (FAP) is an autosomal-dominant disease characterized by the develo... more Familial adenomatous polyposis (FAP) is an autosomal-dominant disease characterized by the development of hundreds of adenomatous polyps of the colorectum. Approximately 80% of FAP patients can be shown to have truncating mutations of the APC gene. To determine the cause of FAP in the other 20% of patients, MAMA (monoallelic mutation analysis) was used to independently examine the status of each of the two APC alleles. Seven of nine patients analyzed were found to have significantly reduced expression from one of their two alleles whereas two patients were found to have full-length expression from both alleles. We conclude that more than 95% of patients with FAP have inactivating mutations in APC and that a combination of MAMA and standard genetic tests will identify APC abnormalities in the vast majority of such patients. That no APC expression from the mutant allele is found in some FAP patients argues strongly against the requirement for dominant negative effects of APC mutations. The results also suggest that there may be at least one additional gene, besides APC, that can give rise to FAP.

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Mechanisms underlying losses of heterozygosity in human colorectal cancers

Proceedings of the National Academy of Sciences, 2001

Losses of heterozygosity are the most common molecular genetic alteration observed in human cance... more Losses of heterozygosity are the most common molecular genetic alteration observed in human cancers. However, there have been few systematic studies to understand the mechanism(s) responsible for losses of heterozygosity in such tumors. Here we report a detailed investigation of the five chromosomes lost most frequently in human colorectal cancers. A total of 10,216 determinations were made with 88 microsatellite markers, revealing 245 chromosomal loss events. The mechanisms of loss were remarkably chromosome-specific. Some chromosomes displayed complete loss such as that predicted to result from mitotic nondisjunction. However, more than half of the losses were associated with losses of only part of a chromosome rather than a whole chromosome. Surprisingly, these losses were due largely to structural alterations rather than to mitotic recombination, break-induced replication, or gene conversion, suggesting novel mechanisms for the generation of much of the aneuploidy in this common tumor type.

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CDX2 is mutated in a colorectal cancer with normal APC/β-catenin signaling

Oncogene, 1999

The majority of human colorectal cancers have elevated b-catenin/TCF regulated transcription due ... more The majority of human colorectal cancers have elevated b-catenin/TCF regulated transcription due to either inactivating mutations of the APC tumor suppressor gene or activating mutations of b-catenin. Surprisingly, one commonly used colorectal cancer cell line was found to have intact APC and b-catenin and no demonstrable b-catenin/TCF regulated transcription. However, this line did possess a truncating mutation in one allele of CDX2, a gene whose inactivation has recently been shown to cause colon tumorigenesis in mice. Expression of CDX2 was found to be induced by restoring expression of wild type APC in a colorectal cancer cell line. These ®ndings raise the intriguing possibility that CDX2 contributes to APC's tumor suppressive eects.

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Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC

Nature Genetics, 1997

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Functional MRI Detection of Deception After Committing a Mock Sabotage Crime*

Journal of Forensic Sciences, 2009

Using Blood Oxygen Level Dependent (BOLD) functional MRI (fMRI) to detect deception is feasible i... more Using Blood Oxygen Level Dependent (BOLD) functional MRI (fMRI) to detect deception is feasible in simple laboratory paradigms. A mock sabotage scenario was used to test whether this technology would also be effective in a scenario closer to a real-world situation. Healthy, nonmedicated adults were recruited from the community, screened, and randomized to either a Mockcrime group or a No-crime group. The Mock-crime group damaged and stole compact discs (CDs), which contained incriminating video footage, while the No-crime group did not perform a task. The Mock-crime group also picked up an envelope from a researcher, while the No-crime group did not perform this task. Both groups were instructed to report that they picked up an envelope, but did not sabotage any video evidence. Participants later went to the imaging center and were scanned while being asked questions regarding the mock crime. Participants also performed a simple laboratory based fMRI deception testing (Ring-Watch testing). The Ring-Watch testing consisted of "stealing" either a watch or a ring. The participants were instructed to report that they stole neither object. We correctly identified deception during the Ring-Watch testing in 25 of 36 participants (Validated Group). In this Validated Group for whom a determination was made, computer-based scoring correctly identified nine of nine Mock-crime participants (100% sensitivity) and five of 15 No-crime participants (33% specificity). BOLD fMRI presently can be used to detect deception concerning past events with high sensitivity, but low specificity.

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Estimation of carrier frequency of a 2.7 kb deletion allele of the P gene associated with OCA2 in African‐Americans

Human Mutation, 1996

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