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1.  Estrogen Receptors and Their Implications in Colorectal Carcinogenesis 
Upon binding their cognate receptors, ERα (ESR1) and ERβ (ESR2), estrogens activate intracellular signaling cascades that have important consequences for cellular behavior. Historically linked to carcinogenesis in reproductive organs, estrogens have also been implicated in the pathogenesis of different cancer types of non-reproductive tissues including the colon. ERβ is the predominant estrogen receptor expressed in both normal and malignant colonic epithelium. However, during colon cancer progression, ERβ expression is lost, suggesting that estrogen signaling may play a role in disease progression. Estrogens may in fact exert an anti-tumor effect through selective activation of pro-apoptotic signaling mediated by ERβ, inhibition of inflammatory signals and modulation of the tumor microenvironment. In this review, we analyze the estrogen pathway as a possible therapeutic avenue in colorectal cancer, we report the most recent experimental evidence to explain the cellular and molecular mechanisms of estrogen-mediated protection against colorectal tumorigenesis, and we discuss future challenges and potential avenues for targeted therapy.
PMCID: PMC4313613
estrogen; estrogen receptor; colorectal cancer; tumor immunology; tumor microenvironment
2.  Snapshots in surgery: incidentally discovered cryptorchidism 
Clinical Case Reports  2014;2(5):237.
Key Clinical Message
An 18-year-old was presented with a large inflamed appendix (compressed by the instrument) and a spermatic cord with right undescended testicle (cryptorchidism). Patients who undergo orchiopexy after age 12 years, or no orchiopexy, are 2–6 times as likely to have testicular cancer as those who undergo prepubertal orchiopexy.
PMCID: PMC4302632  PMID: 25614818
Appendicitis; cryptorchidism; orchidectomy; orchiopexy; testicular cancer
3.  Lynch Syndrome: An Updated Review 
Genes  2014;5(3):497-507.
Lynch syndrome is one of the most common cancer susceptibility syndromes. Individuals with Lynch syndrome have a 50%–70% lifetime risk of colorectal cancer, 40%–60% risk of endometrial cancer, and increased risks of several other malignancies. It is caused by germline mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2. In a subset of patients, Lynch syndrome is caused by 3' end deletions of the EPCAM gene, which can lead to epigenetic silencing of the closely linked MSH2. Relying solely on age and family history based criteria inaccurately identifies eligibility for Lynch syndrome screening or testing in 25%–70% of cases. There has been a steady increase in Lynch syndrome tumor screening programs since 2000 and institutions are rapidly adopting a universal screening approach to identify the patients that would benefit from genetic counseling and germline testing. These include microsatellite instability testing and/or immunohistochemical testing to identify tumor mismatch repair deficiencies. However, universal screening is not standard across institutions. Furthermore, variation exists regarding the optimum method for tracking and disclosing results. In this review, we summarize traditional screening criteria for Lynch syndrome, and discuss universal screening methods. International guidelines are necessary to standardize Lynch syndrome high-risk clinics.
PMCID: PMC4198913  PMID: 24978665
Lynch syndrome; genetics; screening; history; CRC clinic
4.  Depth-Dependent Differences in Community Structure of the Human Colonic Microbiota in Health 
PLoS ONE  2013;8(11):e78835.
The aims of this study were to develop techniques for spatial microbial assessment in humans and to establish colonic luminal and mucosal spatial ecology, encompassing longitudinal and cross-sectional axes.
A microbiological protected specimen brush was used in conjunction with a biopsy forceps to sample the colon in nine healthy volunteers undergoing colonoscopy. Terminal Restriction Fragment Length Polymorphism analysis was used to determine the major variables in the spatial organization of the colonic microbiota.
Protected Specimen Brush sampling retrieved region-specific, uncontaminated samples that were enriched for bacterial DNA and depleted in human DNA when compared to biopsy samples. Terminal Restriction Fragment Length Polymorphism analysis revealed a segmentation of bacterial communities between the luminal brush and biopsy-associated ecological niches with little variability across the longitudinal axis of the colon and reduced diversity in brush samples.
These results support the concept of a microbiota with little longitudinal variability but with some degree of segregation between luminal and mucosal communities.
PMCID: PMC3819420  PMID: 24223167
5.  Activation of AMPK Inhibits Cholera Toxin Stimulated Chloride Secretion in Human and Murine Intestine 
PLoS ONE  2013;8(7):e69050.
Increased intestinal chloride secretion through chloride channels, such as the cystic fibrosis transmembrane conductance regulator (CFTR), is one of the major molecular mechanisms underlying enterotoxigenic diarrhea. It has been demonstrated in the past that the intracellular energy sensing kinase, the AMP-activated protein kinase (AMPK), can inhibit CFTR opening. We hypothesized that pharmacological activation of AMPK can abrogate the increased chloride flux through CFTR occurring during cholera toxin (CTX) mediated diarrhea.
Chloride efflux was measured in isolated rat colonic crypts using real-time fluorescence imaging. AICAR and metformin were used to activate AMPK in the presence of the secretagogues CTX or forskolin (FSK). In order to substantiate our findings on the whole tissue level, short-circuit current (SCC) was monitored in human and murine colonic mucosa using Ussing chambers. Furthermore, fluid accumulation was measured in excised intestinal loops.
CTX and forskolin (FSK) significantly increased chloride efflux in isolated colonic crypts. The increase in chloride efflux could be offset by using the AMPK activators AICAR and metformin. In human and mouse mucosal sheets, CTX and FSK increased SCC. AICAR and metformin inhibited the secretagogue induced rise in SCC, thereby confirming the findings made in isolated crypts. Moreover, AICAR decreased CTX stimulated fluid accumulation in excised intestinal segments.
The present study suggests that pharmacological activation of AMPK effectively reduces CTX mediated increases in intestinal chloride secretion, which is a key factor for intestinal water accumulation. AMPK activators may therefore represent a supplemental treatment strategy for acute diarrheal illness.
PMCID: PMC3728293  PMID: 23935921
6.  Constitutive basal and stimulated human small bowel contractility is enhanced in obesity 
Small bowel contractility may be more prominent in obese subjects, such that there is enhanced nutrient absorption and hunger stimulation. However, there is little evidence to support this. This study examined in vitro small bowel contractility in obese patients versus non-obese patients.
Samples of histologically normal small bowel were obtained at laparoscopic Roux-en-Y gastric bypass from obese patients. Control specimens were taken from non-obese patients undergoing small bowel resection for benign disease or formation of an ileal pouch-anal anastamosis. Samples were transported in a pre-oxygenated Krebs solution. Microdissected circular smooth muscle strips were suspended under 1 g of tension in organ baths containing Krebs solution oxygenated with 95% O2/5% CO2 at 37°C. Contractile activity was recorded using isometric transducers at baseline and in response to receptor-mediated contractility using prostaglandin F2a, a nitric oxide donor and substance P under both equivocal and non-adreneregic, non-cholinergic conditions (guanethidine and atropine).
Following equilibration, the initial response to the cholinergic agonist carbachol (0.1 mmol/L) was significantly increased in the obese group (n = 63) versus the lean group (n = 61) with a mean maximum response: weight ratio of 4.58 ± 0.89 vs 3.53 ± 0.74; (p = 0.032). Following washout and re-calibration, cumulative application of substance P and prostaglandin F2a produced concentration-dependent contractions of human small bowel smooth muscle strips. Contractile responses of obese small bowel under equivocal conditions were significantly increased compared with non-obese small bowel (p < 0.05 for all agonists). However, no significant differences were shown between the groups when the experiments were performed under NANC conditions. There were no significant differences found between the groups when challenged with nitric oxide, under either equivocal or NANC conditions.
Stimulated human small bowel contractility is increased in obese patients suggesting faster enteric emptying and more rapid intestinal transit. This may translate into enhanced appetite and reduced satiety.
PMCID: PMC2673225  PMID: 19379492
7.  Unilateral Diaphragmatic Agenesis Precluding Laparoscopic Cholecystectomy 
Complete absence of a hemidiaphragm or diaphragmatic agenesis in adulthood is rare with only one previous report in the literature. Its significance in relation to performing laparoscopic procedures has not been documented previously.
We report a case of previously undiagnosed diaphragmatic agenesis in adulthood precluding laparoscopic cholecystectomy and comprehensively review the literature for papers relevant to diaphragmatic agenesis in adulthood.
Diaphragmatic agenesis in adulthood may complicate and preclude laparoscopic cholecystectomy. The principles of investigation and management of diaphragmatic agenesis complicating laparoscopic surgery are discussed.
In adults with diaphragmatic agenesis and intrathoracic abdominal viscera precluding laparoscopic cholecystectomy, conservative management is recommended.
PMCID: PMC3113182  PMID: 10987407
Diaphragmatic agenesis; Laparoscopic cholecystectomy

Results 1-7 (7)