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Computer-aided detection (CADe) devices have been shown to increase adenoma detection rates and adenomas per colonoscopy compared to standard colonoscopies. Questions remain about whether CADe colonoscopies are mainly increasing the detection of small, nonneoplastic lesions or if they are detecting more pathologically meaningful polyps. In this analysis, we compare the true histology rate (defined as polyps with confirmation of clinically relevant histopathology) of CADe-identified polyps with polyps identified during standard colonoscopies. Using data from the SKOUT trial, we compared the true histology rate (THR) between CADe and standard colonoscopies. We also conducted a subgroup analysis by patient, procedural, and endoscopist factors. To account for multiple testing of comparisons, we used the false discovery rate. A total of 1423 participants were included (CADe, n = 714; standard, n = 709). Overall, THR was similar between the CADe and standard colonoscopy arms for adenomas, sessile serrated lesions, and large hyperplastic polyps. Higher THR with CADe colonoscopy was observed in some subgroups for adenomas. Endoscopists with 11 to 20 years of experience and procedures occurring after 12 pm had significantly higher adenoma THRs in the CADe cohort. Patients younger than 65 years, male patients, and procedures with a withdrawal time of ≥8 minutes had borderline significance in the CADe device adenoma THR subgroup. CADe colonoscopies may hold the key to improving endoscopic quality measures, provided that the polyps identified by the CADe device are those of clinical relevance. Although the benefit and significance in the CADe group were demonstrated in this analysis, further research is warranted to ensure that the true histology is maintained when applied in real-world applications. [ABSTRACT FROM AUTHOR]

Colonoscopy for colorectal cancer screening is endoscopist dependent, and colonoscopy quality improvement programs aim to improve efficacy. This study evaluated the clinical benefit and safety of using a computer-aided detection (CADe) device in colonoscopy procedures. This randomized study prospectively evaluated the use of a CADe device at 5 academic and community centers by US board-certified gastroenterologists (n = 22). Participants aged ≥40 scheduled for screening or surveillance (≥3 years) colonoscopy were included; exclusion criteria included incomplete procedure, diagnostic indication, inflammatory bowel disease, and familial adenomatous polyposis. Patients were randomized by endoscopist to the standard or CADe colonoscopy arm using computer-generated, random-block method. The 2 primary endpoints were adenomas per colonoscopy (APC), the total number of adenomas resected divided by the total number of colonoscopies; and true histology rate (THR), the proportion of resections with clinically significant histology divided by the total number of polyp resections. The primary analysis used a modified intention-to-treat approach. Between January and September 2021, 1440 participants were enrolled to be randomized. After exclusion of participants who did not meet the eligibility criteria, 677 in the standard arm and 682 in the CADe arm were included in a modified intention-to-treat analysis. APC increased significantly with use of the CADe device (standard vs CADe: 0.83 vs 1.05, P =.002; total number of adenomas, 562 vs 719). There was no decrease in THR with use of the CADe device (standard vs CADe: 71.7% vs 67.4%, P for noninferiority <.001; total number of non-neoplastic lesions, 284 vs 375). Adenoma detection rate was 43.9% and 47.8% in the standard and CADe arms, respectively (P =.065). For experienced endoscopists performing screening and surveillance colonoscopies in the United States, the CADe device statistically improved overall adenoma detection (APC) without a concomitant increase in resection of non-neoplastic lesions (THR). ClinicalTrials.gov registration: NCT04754347. [Display omitted] Colonoscopies are widely performed in the United States to screen for colorectal cancer and detect it before it becomes an issue for patients. By using artificial intelligence during the procedure, detection rates and procedure quality are improved. [ABSTRACT FROM AUTHOR]

Gastrointestinal dysfunction is a frequent and disabling manifestation of autoimmune polyendocrine syndrome type 1 (APS-1), a rare monogenic multiorgan autoimmune disease caused by the loss of central AIRE-controlled immune tolerance. This study aimed to understand the role of the gut microbiome in APS-1 symptoms and potentially alleviate common gastrointestinal symptoms by probiotic intervention. This study characterized the fecal microbiomes of 28 patients with APS-1 and searched for associations with gastrointestinal symptoms, circulating anti-cytokine autoantibodies, and tryptophan-related metabolites. Additionally, daily doses of the probiotic Lactobacillus rhamnosus GG were administered for 3 months. Of 581 metagenomic operational taxonomic units (mOTUs) characterized in total, 14 were significantly associated with patients with APS-1 compared with healthy controls, with 6 mOTUs depleted and 8 enriched in patients with APS-1. Four overabundant mOTUs were significantly associated with severity of constipation. Phylogenetically conserved microbial associations with autoantibodies against cytokines were observed. After the 3-month intervention with the probiotic L rhamnosus GG, a subset of gastrointestinal symptoms were alleviated. L rhamnosus GG abundance was increased postintervention and corresponded with decreased abundances of Alistipes onderdonkii and Collinsella aerofaciens, 2 species positively associated with severity of diarrhea in patients with APS-1. The APS-1 microbiome correlates with several APS-1 symptoms, some of which are alleviated after a 3-month L rhamnosus GG intervention. Autoantibodies against cytokines appear to shape the gut microbiome by positively correlating with a taxonomically consistent group of bacteria. [ABSTRACT FROM AUTHOR]

Colorectal cancer is a heterogeneous disease that develops via stepwise accumulation of well-characterized genetic and epigenetic alterations. We review the genetic changes associated with the development of precancerous colorectal adenomas and their progression to tumors, as well as the effects of defective DNA repair, chromosome instability, microsatellite instability, and alterations in the serrated pathway and DNA methylation. We provide insights into the different molecular subgroups of colorectal tumors that develop via each of these different mechanisms and their associations with patient outcomes. [ABSTRACT FROM AUTHOR]

Hereditary diffuse gastric cancer (HDGC) syndrome results from a germline CDH1 mutation, and microscopic foci of signet-ring carcinoma cells (SRCC) are present in nearly all gastrectomy specimens.1 The lifetime risk of invasive gastric cancer (GC) has been thought to be 70%,2 but recent data have suggested a lower risk of 37%.3 Prophylactic total gastrectomy is considered the standard of care, but many patients choose surveillance endoscopy instead. We sought to define the outcomes in CDH1 -positive individuals who pursued endoscopic surveillance. [ABSTRACT FROM AUTHOR]

The critical role of the gut microbiome in microscopic colitis (MC) is evident by the observation that fecal diversion is associated with resolution of mucosal inflammation while restoration of fecal stream is associated with recurrence of disease.1 Characterization of the composition and function of the gut microbiome in MC therefore could provide insights into disease pathogenesis. [ABSTRACT FROM AUTHOR]

Assessment of tumor tissue heterogeneity via ultrasound has recently been suggested as a method for predicting early response to treatment. The ultrasound backscattering characteristics can assist in better understanding the tumor texture by highlighting the local concentration and spatial arrangement of tissue scatterers. However, it is challenging to quantify the various tissue heterogeneities ranging from fine to coarse of the echo envelope peaks in tumor texture. Local parametric fractal features extracted via maximum likelihood estimation from five well-known statistical model families are evaluated for the purpose of ultrasound tissue characterization. The fractal dimension (self-similarity measure) was used to characterize the spatial distribution of scatterers, whereas the lacunarity (sparsity measure) was applied to determine scatterer number density. Performance was assessed based on 608 cross-sectional clinical ultrasound radiofrequency images of liver tumors (230 and 378 representing respondent and non-respondent cases, respectively). Cross-validation via leave-one-tumor-out and with different k-fold methodologies using a Bayesian classifier was employed for validation. The fractal properties of the backscattered echoes based on the Nakagami model (Nkg) and its extend four-parameter Nakagami-generalized inverse Gaussian (NIG) distribution achieved best results-with nearly similar performance-in characterizing liver tumor tissue. The accuracy, sensitivity and specificity of Nkg/NIG were 85.6%/86.3%, 94.0%/96.0% and 73.0%/71.0%, respectively. Other statistical models, such as the Rician, Rayleigh and K-distribution, were found to not be as effective in characterizing subtle changes in tissue texture as an indication of response to treatment. Employing the most relevant and practical statistical model could have potential consequences for the design of an early and effective clinical therapy. [ABSTRACT FROM AUTHOR]

Familial adenomatous polyposis (FAP) is characterized by high risks of colonic and extracolonic tumors. Recent studies have suggested a rising risk for gastric cancer (GC). We sought to define the spectrum of premalignant gastric polyps in FAP, focusing on high-grade dysplasia (HGD). The gastric phenotypes of 118 patients diagnosed with FAP or attenuated FAP in our Hereditary Gastrointestinal Cancer Registry were retrospectively reviewed. To analyze the clinical features associated with the diagnosis of HGD, we established an age- and sex-matched control group of FAP patients from our cohort without gastric HGD in a 4:1 ratio. The spectrum and frequency of gastric polyps in individuals with FAP included fundic gland polyps (67.9%), hyperplastic polyps/foveolar hyperplasia (19.6%), tubular adenomas (15.2%), foveolar adenomas (10.7%), and pyloric gland adenomas (6.3%). Ten patients (8.9%) exhibited gastric HGD at a mean age of 55 ± 13 years, and HGD was seen in all polyp types. When compared with control subjects, HGD was associated with a high diversity of gastric polyp histology, prior low-grade dysplasia, severe gastric polyposis, and prior Whipple surgery (P = 2.0E-5,.003,.024, and.04, respectively). Two patients (1.7%) with HGD were diagnosed with GC. However, the remaining 8 patients with HGD have been under surveillance for an average of 5.8 ± 4.5 years without progression to GC. Gastric HGD in FAP may be more common than previously appreciated. The natural history of HGD is variable, and most patients with HGD do not appear to progress to GC. [Display omitted] [ABSTRACT FROM AUTHOR]

Gene transfer efficiency and expression stability are key factors to a successful gene therapy approach. In the present work we have developed a combined system for gene transfer that integrates well established non-viral polymeric vectors based on chitosan particles with the properties of phiC31-integrase that promotes a relatively non-immunogenic, site-specific integration, with sustained gene expression. Simultaneously, to overcome one of the major limitations in adeno-associated virus mediated gene transfer – the delivery of large genes – we have tested the capacity of our non-viral vectors to incorporate a large (8 Kb) transgene. Polyplexes were extensively characterized for their size, surface charge, morphology, pDNA complexation, transfection efficiency and transgene expression in vitro using HEK293 cells. Co-transfection with integrase was done by complexation in a single polyplex preparation or the use of two separate polyplex preparations. Transgene expression, GFP and CEP290 (1 Kb and 8 Kb, respectively), was evaluated by fluorescence microscopy, flow cytometry and Western blot analysis. DNA complexation efficiency, particle size and morphology were consistent with gene delivery for all formulations. In contrast, transfection efficiency and transgene expression varied with polymer and polyplex size. Following delivery by chitosan polyplexes, high levels of GFP expression were still visible 16 weeks post-transfection and over-expression of the large transgene was detected at least 6 weeks post-transfection. Polyplexes incorporating phiC1 integrase demonstrate prolonged gene expression of both small (GFP, 1 Kb) and large genes (CEP290, 8 Kb). This approach, using a combined strategy of polymers and integrase may overcome the size limitation found in commonly used adeno-associated virus mediated gene transfer techniques, while maintaining a high safety profile and prolonged, sustained gene expression, thus constituting an alternative for gene delivery. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether technical difficulty of computed tomography (CT)-guided percutaneous lung tumor thermal ablations is altered with the use of high-frequency jet ventilation (HFJV) under general anesthesia (GA) compared with procedures performed with normal respiration (NR) under conscious sedation (CS). Materials and Methods: Thermal ablation treatment sessions performed with NR under CS or HFJV under GA with available anesthesia records and CT fluoroscopic images were retrospectively reviewed; 13 and 33 treatment sessions, respectively, were identified. One anesthesiologist determined the choice of anesthesiologic technique independently. Surrogate measures of procedure technical difficulty--time duration, number of CT fluoroscopic acquisitions, and radiation dose required for applicator placement for each tumor--were compared between anesthesiologic techniques. The anesthesiologist time and complications were also compared. Parametric and nonparametric data were compared by Student independent-samples t test and χ(2) test, respectively. Results: Patients treated with HFJV under GA had higher American Society of Anesthesiologists classifications (mean, 2.66 vs 2.23; P = .009) and smaller lung tumors (16.09 mm vs 27.38 mm; P = .001). The time duration (220.30 s vs 393.94 s; P = .008), number of CT fluoroscopic acquisitions (10.31 vs 19.13; P = .023), and radiation dose (60.22 mGy·cm vs 127.68 mGy·cm; P = .012) required for applicator placement were significantly lower in treatment sessions performed with HFJV under GA. There was no significant differences in anesthesiologist time (P = .20), rate of pneumothorax (P = .62), or number of pneumothoraces requiring active treatment (P = .19). Conclusions: HFJV under GA appears to reduce technical difficulty of CT-guided percutaneous applicator placement for lung tumor thermal ablations, with similar complication rates compared with treatment sessions performed with NR under CS. The technique is safe and may facilitate treatment of technically challenging tumors. [ABSTRACT FROM AUTHOR]

Background & Aims: Rectal bleeding is associated with colorectal cancer. We characterized the evaluation of patients aged 40 years and older with rectal bleeding and identified characteristics associated with inadequate evaluation. Methods: We conducted a retrospective review of records of outpatient visits that contained reports of rectal bleeding for patients aged 40 years and older (N = 480). We studied whether patient characteristics affected whether or not they received a colonoscopy examination within 90 days of presentation with rectal bleeding. Patient characteristics included demographics; family history of colon cancer and polyps; and histories of screening colonoscopies, physical examinations, referrals to specialists at the index visit, and communication of laboratory results. Data were collected from medical records, and patient income levels were estimated based on Zip codes. Results: Nearly half of the patients presenting with rectal bleeding received colonoscopies (48.1%); 81.7% received the procedure within 90 days. A history of a colonoscopy examination was more likely to be reported in white patients compared with Hispanic or Asian patients (P = .012 and P = .006, respectively), and in high-income compared with low-income patients (P = .022). A family history was more likely to be documented among patients with private insurance than those with Medicaid or Medicare (P = .004). A rectal examination was performed more often for patients who were white or Asian, male, and with high or middle incomes, compared with those who were black, Hispanic, female, or with low incomes (P = .027). White patients were more likely to have their laboratory results communicated to them than black patients (P = .001). Conclusions: Sex, race, ethnicity, patient income, and insurance status were associated with disparities in evaluation of rectal bleeding. There is a need to standardize the evaluation of patients with rectal bleeding. [Copyright &y& Elsevier]

Abstract: We revisit the gravitational production of massive Dirac fermions in inflationary cosmology with a focus on clarifying the analytic computation of the particle number density in both the large and the small mass regimes. For the case in which the masses of the gravitationally produced fermions are small compared to the Hubble expansion rate at the end of inflation, we obtain a universal result for the number density that is nearly independent of the details of the inflationary model. The result is identical to the case of conformally coupled scalars up to an overall multiplicative factor of order unity for reasons other than just counting the fermionic degrees of freedom. [Copyright &y& Elsevier]

Abstract: We propose a group theoretic condition which may be applied to extensions of the Standard Model in order to locate regions of parameter space in which the electroweak phase transition is strongly first order, such that electroweak baryogenesis may be a viable mechanism for generating the baryon asymmetry of the universe. Specifically, we demonstrate that the viable corners of parameter space may be identified by their proximity to an enhanced discrete symmetry point. At this point, the global symmetry group of the theory is extended by a discrete group under which the scalar sector is non-trivially charged, and the discrete symmetry is spontaneously broken such that the discrete symmetry relates degenerate electroweak preserving and breaking vacua. This idea is used to investigate several specific models of the electroweak symmetry breaking sector. The phase transitions identified through this method suggest implications for other relics such as dark matter and gravitational waves. [Copyright &y& Elsevier]

Background: Germline mutation of the CDH1 gene, which encodes for the E-cadherin adhesion protein, is rare but confers an estimated lifetime risk of hereditary diffuse gastric cancer of 87%. Fewer than 100 prophylactic total gastrectomies have been reported for this condition. Methods: Patients with germline CDH1 mutation who underwent multidisciplinary counseling followed by prophylactic total gastrectomy were reviewed. Results: Ten patients (6 male, 4 female) with a median age of 42 years (range, 26–51) underwent prophylactic total gastrectomy between 2006 and 2009. Of the 6 families represented, there were 4 missense, 1 frameshift, and 1 splice site mutation. Median time from genetic testing to surgery was 3 months (range, 1–7). All patients had an upper endoscopy before surgery, identifying only 1 patient with a focus of diffuse gastric cancer. After prophylactic total gastrectomy, extensive pathologic analysis demonstrated that 9 patients had up to 77 foci of noninvasive cancer, and 2 of these patients had 4–12 foci of T1 invasive cancer. Median operative time was 213 minutes; there were no anastomotic leaks, and the length of stay was 7–8 days. One patient had a complication within 30 days (pulmonary embolism), and 3 patients had late complications (2 small bowel obstructions and 1 anastomotic stricture). Median weight loss at 6 months was 19%. Conclusion: The majority of patients with germline CDH1 mutation have foci of noninvasive or invasive gastric cancer by middle age. Serial upper endoscopies provide inadequate screening. Prophylactic total gastrectomy is the procedure of choice for definitive treatment. [Copyright &y& Elsevier]

Summary: A vast majority of gene polymorphism studies in renal transplantation focus on short-term outcomes such as acute rejection. The main purpose of this article is to review the literature available and studies that have examined the association between the gene polymorphisms and long-term renal allograft functions. In this review, we focus on commonly reported genes in the renin angiotensin system, transforming growth factor-β gene, and metalloproteinases on the incidence and progression of chronic renal allograft dysfunction. [ABSTRACT FROM AUTHOR]

The acquisition of genomic instability is a crucial feature in tumor development and there are at least 3 distinct pathways in colorectal cancer pathogenesis: the chromosomal instability (CIN), microsatellite instability, and CpG island methylator phenotype pathways. Most cases of colorectal cancer arise through the CIN pathway, which is characterized by widespread imbalances in chromosome number (aneuploidy) and loss of heterozygosity. It can result from defects in chromosomal segregation, telomere stability, and the DNA damage response, although the full complement of genes underlying CIN remains incompletely described. Coupled with the karyotypic abnormalities observed in CIN tumors are the accumulation of a characteristic set of mutations in specific tumor suppressor genes and oncogenes that activate pathways critical for colorectal cancer initiation and progression. Whether CIN creates the appropriate milieu for the accumulation of these mutations or vice versa remains a provocative and unanswered question. The goal of this review is to provide an updated perspective on the mechanisms that lead to CIN and the key mutations that are acquired in this pathway. [Copyright &y& Elsevier]

Background & Aims: Colorectal cancers (CRCs) displaying DNA microsatellite instability (MSI) are associated with a favorable natural history, but the molecular basis for this observation has not been defined. We sought to determine whether the epithelial to mesenchymal transition (EMT) is impaired in MSI-positive CRCs that characteristically have a mutant transforming growth factor−β receptor type II (TGFBR2) gene. Methods: The induction of EMT by transforming growth factor−β1 (TGF-β1) was analyzed by phase contrast microscopy, immunofluorescence, quantitative reverse transcription polymerase chain reaction, immunoblotting, and cellular migration, and invasion assays. Expression of EMT markers was evaluated by immunohistochemistry and quantitative reverse transcription polymerase chain reaction in a series of human colorectal tumors. Results: TGF-β1 induced changes in cellular morphology, gene expression, motility, and invasion consistent with EMT in microsatellite stable (MSS) colon cancer cells, whereas cells with MSI and mutant TGFBR2 were unresponsive to TGF-β1. These effects did not require Smad4, but depended on the recruitment of extracellular signal-regulated kinase. Tumor cells with MSI but wild-type TGFBR2 underwent EMT in response to TGF-β1, indicating that TGFBR2 genotype is a key determinant of the EMT response in tumors with MSI. In human colorectal tumors, expression of EMT markers was significantly associated with adverse clinicopathologic features and the absence of MSI. Conclusions: These findings define a unique genotype−phenotype relationship between TGFBR2 and EMT that may contribute to the improved prognosis consistently observed in colon cancers with MSI. [Copyright &y& Elsevier]

Summary: Leber congenital amaurosis comprises a group of early onset childhood retinal dystrophies, characterized by vision loss, nystagmus, and severe retinal dysfunction. To date, 15 causative genes have been identified that account for the heterogeneous presentation and clinical course. Knowledge of key aspects of phenotype and clinical course can contribute to the determination of a precise genetic etiology using genetic testing. Gene-based therapies are emerging, and knowledge of a patient''s genotype is essential. A review of clinical presentation and disease course, their correlation to specific genotypes, and underlying physiological mechanisms, coupled with the latest results of human gene therapy trials, will assist the clinician in patient diagnosis and counseling. [Copyright &y& Elsevier]

Background & Aims: The molecular alterations that underlie carcinoid tumor pathogenesis remain poorly defined. The homeobox gene HOXC6 was highly up-regulated in human gastrointestinal carcinoid tumors, and we sought to define its pathogenic role. Methods: The functional and physical properties of Hoxc6 were investigated by establishing carcinoid cells that stably overexpressed Hoxc6 or were deficient in Hoxc6. Cellular proliferation assays, luciferase reporter assays, Western blotting, immunoprecipitation, DNA affinity precipitation, and DNA microarray studies were performed. Results: Expression of Hoxc6 in cultured human BON1 carcinoid cells enhanced their proliferation, and knock-down of Hoxc6 inhibited their growth. Hoxc6 activated the oncogenic activator protein-1 signaling pathway through a physical interaction with JunD. Mutations in the homeodomain of Hoxc6 blocked this interaction and inhibited proliferation of carcinoid cells. Of note, Hoxc6 induced the expression of genes that characteristically are up-regulated in carcinoid tumors, including neurotensin and connective tissue growth factor. Conclusions: A novel molecular pathway has been identified that links Hoxc6 with oncogenic signaling through the activator protein-1 pathway in carcinoid tumorigenesis. [Copyright &y& Elsevier]

Background & Aims: Clinical genetic testing can help direct cancer screening for members of Lynch syndrome families; however, there is limited information about family communication of genetic test results. Methods: A total of 174 probands who had genetic testing for Lynch syndrome were enrolled through 4 US cancer genetics clinics. Subjects were asked whether they had disclosed their genetic test results to first-, second-, and third-degree relatives. Univariate and multivariate analyses were used to identify clinical and demographic factors associated with informing immediate and extended family of genetic test results. Results: One hundred seventy-one of 174 probands (98%; 95% confidence interval, 95%–100%) reported that they had disclosed their genetic test result to a first-degree relative. Communication of test results to other relatives occurred significantly less often, with only 109 of 162 (67%; 95% confidence interval, 59%–74%) subjects with second- or third-degree relatives sharing their results. Individuals with a pathogenic mutation were significantly more likely to inform distant relatives than were subjects with a negative or indeterminate test result (odds ratio, 2.49; 95% confidence interval, 1.14–5.40). Probands’ age, sex, and cancer status did not influence communication of genetic test results. Lack of closeness and concerns that relatives would worry or not understand the implications of test results were the primary reasons for not sharing genetic test results. Conclusions: Most individuals who undergo genetic testing for Lynch syndrome share their test results with first-degree family members; however, these results reach more distant relatives significantly less often. Interventions to improve communication of genetic test results to members of the extended family are necessary to provide optimal cancer prevention care to at-risk families. [Copyright &y& Elsevier]

Background & Aims: Thyroid carcinoma is an extraintestinal manifestation of familial adenomatous polyposis (FAP) syndrome, but the precise risk is unknown. The optimal approach for thyroid cancer screening has not been established. We sought to define the prevalence of thyroid cancer and the role of screening ultrasound in FAP patients. Methods: We performed a retrospective chart review of 51 patients with a proven diagnosis of FAP at a single tertiary institution. Clinical records, genetic test results, ultrasound examinations, and histopathology were reviewed. Results: Papillary thyroid cancer was diagnosed in 6 female patients (12%). The mean age of thyroid cancer diagnosis was 33 years, and mean tumor size was 12 mm. However, all patients had additional malignant foci that were small (1–9 mm), and none had suspicious features of malignancy on ultrasound. Of 28 patients who had at least one screening ultrasound, 22 (79%) had thyroid nodules, and 2 (7%) had papillary thyroid carcinoma. Of those with nodules, 68% had multinodular disease. A follow-up ultrasound in 12 patients after a mean of 15 months revealed no changes in either the number or size of nodules. Conclusions: The 12% prevalence of thyroid cancer in this series of FAP patients is significantly higher than in previous reports. Among patients undergoing screening ultrasound, 7% had thyroid cancer. Nodular thyroid disease is very common in FAP. Because small nodules (<9 mm) might also be malignant, close follow-up with ultrasound and fine-needle aspiration might be warranted. [Copyright &y& Elsevier]

Neuroendocrine tumors can develop either sporadically or in association with familial syndromes such as multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2 (MEN2) or von Hippel–Lindau (VHL). A variety of genetic approaches has been utilized to dissect the underlying molecular pathogenesis of these distinctive tumors, including genome-wide screens such as comparative genomic hybridization, loss of heterozygosity and DNA microarray analysis as well as targeted investigations into specific tumor suppressor gene and oncogene candidates. The identification of the MEN1 tumor suppressor gene that underlies the MEN1 syndrome has provided important new insights into tumor pathogenesis. In addition, a number of independent approaches has converged on a pivotal role for regulators of the cell cycle. However, our understanding of the molecular biology of these tumors remains far from complete. In this review we highlight some of the key approaches, findings and implications of these genetic studies. [Copyright &y& Elsevier]

Background & Aims: There is a firm consensus that larger (≥10 mm) colonic polyps should be removed; however, the importance of removing smaller polyps (<10 mm) is more controversial. If computed tomographic colonography (CTC) is used for colorectal cancer screening, the majority of polypoid lesions identified will be less than 10 mm in size. Decision-analytic techniques were used to compare the outcomes of 2 management strategies for smaller (6–9 mm) polyps discovered by CTC. Methods: Hypothetic average-risk patients who had undergone a CTC examination and found to have a small (6–9 mm) polyp were simulated to either: (1) undergo immediate colonoscopy for polypectomy (COLO), or (2) wait 3 years for a repeat CTC examination (WAIT). A Markov model was constructed to analyze outcomes including the number of deaths and cancers after a 3-year follow-up period or time horizon. Values for the model parameters were derived from the published literature and from Surveillance Epidemiology and End Results data, and an extensive sensitivity analysis was performed. Results: The COLO strategy resulted in 14 total deaths per 100,000 patients compared with 79 total deaths in the WAIT strategy, for a difference of 65 deaths. The COLO strategy resulted in 39 cancers per 100,000 patients vs 773 in the WAIT strategy, for a difference of 734 cancers. Sensitivity analysis found that model findings were robust and only sensitive at extreme parameter values. Conclusions: Managing smaller polyps detected on a screening CTC with another CTC examination 3 years later likely will result in more deaths and cancers than immediate colonoscopy and polypectomy. [Copyright &y& Elsevier]

Although there have been tremendous advances in the management of colorectal cancer (CRC), there is still a need for improved therapeutic approaches. On a molecular genetic level, CRC is one of the best-understood solid malignancies, and these insights can serve as a foundation for the design of novel targeted therapies. We present new genetic and epigenetic pathways that highlight the heterogeneous mechanisms in CRC pathogenesis, including the roles of the MYH DNA repair gene and of aberrant DNA hypermethylation and imprinting. We then describe some of the successful targeted therapies that inhibit COX2, EGFR, and VEGF as well as potential new targets that have been revealed by studies of molecular genetics. [Copyright &y& Elsevier]

Background & Aims: Affected individuals with biallelic MYH mutations are believed to display multiple adenomatous polyps without evidence of vertical transmission. Our goal was to determine the detection rate of germline MYH mutations in a high-risk gastrointestinal cancer clinic population by using polyp number as a selection criterion. Methods: Patients were screened for the 2 most common MYH mutations: Y165C and G382D. The complete MYH coding region was sequenced in cases with a heterozygous mutation. Results: Among 45 patients with more than 15 adenomatous polyps not diagnosed with familial adenomatous polyposis, 7 (15.6%) had biallelic MYH mutations. When 122 participants from a high-risk gastrointestinal cancer clinic who did not fulfill these criteria were tested, 2 additional patients with biallelic mutations were identified. Both had young-onset colorectal cancer (age, <50 y) with fewer than 15 polyps. Surprisingly, most of the 9 patients with biallelic MYH mutations reported family histories consistent with the hereditary nonpolyposis colorectal cancer syndrome (HNPCC), with 7 cases meeting at least 1 of the Bethesda criteria, 5 cases fulfilling 3 Bethesda criteria, and 2 cases fulfilling the Amsterdam II criteria. Conclusions: Most individuals with MYH mutations exhibit multiple adenomatous polyps. However, 22% of cases were missed when this was the sole criterion for germline testing. A significant number reported a strong family history of cancer that was consistent with HNPCC. MYH testing thus can be considered for patients who meet clinical criteria for HNPCC in the absence of DNA mismatch repair gene mutations. [Copyright &y& Elsevier]

Background & Aims: Two key genetic events underlying the development of colon cancer are activation of the K-ras and Wnt signaling pathways. We have previously shown that these 2 pathways can cooperate to regulate vascular endothelial growth factor (VEGF) gene expression. The goal of this study was to define the molecular basis for this interaction. Methods: The effects of K-ras Val12 on VEGF and T-cell factor 4 (TCF-4) promoter activity, nuclear levels of β-catenin and β-catenin/TCF-4 complexes, glycogen synthase kinase 3β (GSK-3β) phosphorylation, and GSK-3β kinase activity were measured. LY294002 and PD98059 were used to define the role of specific ras effector pathways. Results: Oncogenic K-ras up-regulated the activity of the VEGF promoter, and selective mutagenesis of TCF-4 binding sites significantly blocked this induction. K-ras Val12 also induced the activity of a heterologous TCF-4 reporter construct in Caco-2 and HeLa cells. LY294002 and dominant negative phosphatidylinositol 3-kinase nearly completely blocked this induction. K-ras Val12 increased the stability of β-catenin, the levels of nuclear β-catenin, and the formation of nuclear β-catenin/TCF-4 complexes, and these effects were also blocked by LY294002. Finally, K-ras Val12 inhibited the kinase activity of total cellular GSK-3β and GSK-3β complexed with Axin. This effect was not mediated through phosphorylation at serine 9 but did depend on phosphatidylinositol 3-kinase. Conclusions: Our results suggest a unique cooperative interaction between 2 critical oncogenic pathways in colorectal tumorigenesis and highlight the pivotal role of GSK-3β. [Copyright &y& Elsevier]

: PurposeTo describe the clinical features of two affected members of an Iranian family with autosomal recessive congenital fibrosis of the extraocular muscles (CFEOM2) and to report their novel mutation in the PHOX2A/ARIX gene.: DesignExperimental study.: Methodssetting: Institutional practice. patient population:Six members of an Iranian family with CFEOM underwent complete ocular examinations including assessment of ocular motility, visual acuity, slit-lamp biomicroscopy, tonometry, and ophthalmoscopy. experimental procedure: Mutation analysis of the PHOX2A gene was performed using polymerase chain reaction amplification of the coding exons and direct sequencing of polymerase chain reaction products. main outcome measure: Presence or absence of mutation in PHOX2A gene in two siblings with exotropia and recessive CFEOM. Exotropia and ptosis were corrected surgically in one of the two siblings.: ResultsThe two affected siblings had bilateral ptosis and exotropia and severe limitation of all extraocular movements. One patient underwent strabismus surgery and ptosis repair. PHOX2A mutation analysis revealed a novel nonsense mutation in exon 2 (439C→T). Both parents and the unaffected siblings were heterozygous,and the two affected siblings were homozygous for this mutation.: ConclusionThe 439C→T mutation in this family changes a glutamine to a stop codon (Q90X) at the beginning of the PHOX2A homeodomain region. This is the fourth CFEOM2 mutation in PHOX2A and the first nonsense mutation to be identified. It confirms PHOX2A as the autosomal recessive CFEOM2 disease gene and provides evidence that the phenotypic differences between PHOX2A mutations in man and mouse do not result from hypomorphic PHOX2A alleles in humans. [Copyright &y& Elsevier]

Congenital choanal atresia (CCA) is the developmental failure of the nasal cavity to communicate with the nasopharynx. Surgical repair is recommended in the first weeks of life in bilateral cases, because in newborns this is a life-threatening situation. This is a case report of a 13-year-old patient complaining of long-term bilateral nasal obstruction and rhinorrea, in whom bilateral choanal atresia was diagnosed by endoscopic exploration and CT scan, and who was treated by an endonasal endoscopic surgical technique. Bilateral choanal atresia is a life-threatening disease in newborns; however, it can be diagnosed in adults with bilateral nasal obstruction and rhinorrea. [Copyright &y& Elsevier]

Atmospheric dispersion in urban environments is highly complex, and a fundamental understanding requires a combination of field tests, laboratory experiments, and simulations. In this study, a transient release dispersion experiment was performed involving a scaled model of Oklahoma City, with the intention of being relevant for Joint Urban 2003 (JU2003) related studies. Flow over the city model was fully turbulent and housed in a water channel, with a characteristic building Reynolds number of 6200. The transient release was achieved by injecting a passive scalar at street level following a square waveform with a frequency of 1 Hz. Magnetic Resonance Imaging (MRI) techniques were leveraged to obtain phase-averaged velocity and concentration measurements over 12 intervals throughout the transient release cycle, with average uncertainties of 5.4% and 2.2% of the bulk velocity and injected concentration, respectively. Velocity and concentration measurements are obtained on three-dimensional grids of roughly 2 million data points each. An investigation of three-dimensional flow and dispersion features is presented, and a control volume encompassing an intersection within the city model is analyzed by applying the scalar transport equation to the experimental data. The phase-averaged measurements enable the calculation of scalar flux time series as well as the transient storage term. Scalar flux and transient storage indicate complex dispersion characteristics, and can potentially be used to infer the turbulent diffusion of contaminant. The MRI datasets can provide a reference for other atmospheric dispersion modelers and experimentalists, and the corresponding analyses demonstrate particular advantages of MRI data for model evaluation. • Experimental study related to JU2003 with measurements at 2 million locations. • Magnetic resonance imaging data provide novel insight into transient release plumes. • Local urban geometries strongly influence contamination and 3D ventilation patterns. • Regions between buildings exhibit longer residence times and asymmetric responses. • Measurements provide a means to calculate scalar flux time series. [ABSTRACT FROM AUTHOR]

Objectives: The objectives of this study were (1) to determine the rate of antibiotic prescribing at ambulatory clinics, and (2) to assess the concordance of antibiotic prescriptions with published guidelines and Food and Drug Administration-approved indications in terms of drug choices and dosing regimen.Design: Cross-sectional study.Setting and Participants: Patients of all ages receiving at least 1 prescription during ambulatory visits in 2016 to 2017 were observed.Outcome Measures: For each of the 3 clinic systems included in this study, oral antibiotic prescribing rates were estimated per patient and per ambulatory visit. Then, the concordance of oral antibiotic prescribing was assessed with respect to (1) choice of agent and (2) the dosing regimen by comparing it to the recommended therapeutic regimen (RTR).Results: A total of 284,348 patients receiving at least 1 prescription were included in the analysis. Between clinics, 17.4 to 43.7 per 100 patients received antibiotics. Of the antibiotics prescribed, 48.9% in Clinic A, 48.0% in Clinic B, and 60.7% in Clinic C were considered to be discordant in terms of drug choice. When the dosing regimen was taken into account in addition to the choice of agent, 72.6% in Clinic A, 76.7% in Clinic B, and 81.6% in Clinic C were discordant based on drug choice or dosing regimen. Of the prescriptions written with a discordant dosing regimen, 91.2% in Clinic A, 79.6% in Clinic B, and 91.0% in Clinic C were at a higher dosage than RTR.Conclusion: Antibiotic prescribing rates vary by clinics, whereas discordant prescribing is consistently prevalent across clinics. More efforts should be put into ambulatory care to address antibiotic misuse problems, and our method could improve ambulatory antimicrobial stewardship programs. [ABSTRACT FROM AUTHOR]