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Background: Recent studies suggest that lymph node ratio (LNR) has significantly better prognostic power than N-status in patients with colorectal cancer, in particular when the number of evaluated lymph nodes (LNs) was insufficient. The aim of this study was to assess the prognostic value of LNR in patients with resected synchronous colorectal liver metastases (SCLMs) and less than 12 examined LNs. Methods: A prospectively maintained database of patients with resected SCLMs was queried for patients with less than 12 LNs evaluated at the time of surgery. X-tile software was used to determine the LNR cutoff value able to divide the patients in two subgroups with distinct prognosis. Overall survival (OS) and disease-free survival (DFS) rates were compared by log-rank test. A multivariate Cox regression analysis identified independent prognostic factors. Results: A cutoff LNR value of 0.22 divided patients into Low-LNR group (35 patients) and High-LNR group (36 patients). Both OS and DFS rates were significantly higher in Low-LNR group than those in High-LNR group. Independent predictors of poor OS were High-LNR (HR: 2.841, 95% CI: 1.480–5.453, p value = 0.002), bilobar SCLMs (HR: 2.253, 95% CI: 1.144–4.437, p value = 0.019) and lack of adjuvant chemotherapy (HR: 2.702, 95% CI: 1.448–5.043, p value = 0.002), while the only independent predictor of poor DFS was High-LNR (HR: 2.531, 95% CI: 1.259–5.090, p value = 0.009). Conclusions: LNR > 0.22 was independently associated with poor OS and DFS in patients with resected SCLMs and less than 12 evaluated LNs. [ABSTRACT FROM AUTHOR]

Ever since their discovery, microRNAs (miRNAs) have been the subject of intense investigation of their roles in cells and tissues, both normal and disease state. Although some of the precise mechanisms of biogenesis and actions of miRNAs remain debatable, the fact that miRNAs are dysregulated in diseases such as cancer is undisputed. For many miRNA species, computational databases predict often numerous targets; however, experimental verification in vitro and in vivo is still lacking. For some miRNAs, species-specific targets have been validated; nevertheless, the precise mechanisms those targets act in and whether they are the only truly important ones remain to be discovered. The authors take a closer look at the current status of the role of miRNAs in the diagnosis and biology of cholangiocarcinomas where the perhaps biggest impact in the short term comes from the use of biomarkers in the early diagnosis. [ABSTRACT FROM AUTHOR]

Presents a study where microarrays were hybridized to labeled RNA obtained from several colonic specimens in order to discover global gene expression patterns characterizing subgroups of colon cancer. Information on colorectal cancer; Importance of the early detection of colon cancer in the premalignant stages; Application of the software program Significant Analysis of Microarrays to identify genes whose expression were used to distinguish between normal and cancerous colonic epithelium.

Epigenetics refers to heritable changes in gene expression that are, unlike mutations, not attributable to alterations in DNA sequence. Two predominant epigenetic mechanisms are DNA methylation and histone modification. Epigenetic regulation of gene expression has emerged as a fundamental pathway in the pathogenesis of numerous malignancies, including cancers of the digestive system—in fact, many exciting discoveries in epigenetics have come out of the study of cancers of the gastrointestinal tract and hepatobiliary tree. Epigenetic modifications of DNA in cancer and precancerous lesions offer the promise of novel biomarkers for early cancer detection, prediction, prognosis, and response to treatment. Furthermore, reversal of epigenetic changes represents a potential target of novel therapeutic strategies and medication design. In the future, innovative diagnostic tests and treatment regimens will likely be based on epigenetic mechanisms and be incorporated into the gastroenterologist’s practice.Am J Gastroenterol 2009; 104:1910–1912; doi:10.1038/ajg.2008.145 [ABSTRACT FROM AUTHOR]

The article presents a study which reported an injectable, biodegradable, mechanically fragmented nanofiber-hydrogel composite (mfNHC) loaded with adipose-derived stem cells (ADSCs) for the treatment of fistulas in a rat model of Crohn's disease-perianal fistulas (CD-PAF). Topics discussed include fabrication of mfNHC with tunable stiffness and pore size, in vivo volume retention of injected mfNHC, and retention of ADSC within mfNHC.

INTRODUCTION: The response to SARS-CoV-2 vaccination of patients with inflammatory bowel disease (IBD) on immune-modifying therapies requires further investigation because previous studies indicate that patients on immune therapy might have decreased antibody concentrations. METHODS: We present the antireceptor binding domain antibody response over a period of 3 months in 217 patients with IBD who completed standard 2-dose SARS-CoV-2 mRNA vaccine series. RESULTS: Almost all (98.6%) IBD vaccine recipients had a positive antireceptor binding domain antibody response at least 3 months after vaccination. Decreased antibody titers at 3 months were seen in a subset of patients on antitumor necrosis factor-alpha. Approximately 10% of the participants with high-titer antibodies at 1 month had a decrease to low-positive titers at 3 months, which was mostly observed in those on combination therapy and antitumor necrosis factor-alpha monotherapy. DISCUSSION: Larger longitudinal studies are required to define the response in IBD population and its clinical impact. [ABSTRACT FROM AUTHOR]

Gastrointestinal (GI) strictures are difficult to treat in a variety of disease processes. Currently, there are no Food and Drug Administration (FDA) approved drugs for fibrosis in the GI tract. One of the limitations to developing anti-fibrotic drugs has been the lack of a reproducible, relatively inexpensive, large animal model of fibrosis-driven luminal stricture. This study aimed to evaluate the feasibility of creating a model of luminal GI tract strictures. Argon plasma coagulation (APC) was applied circumferentially in porcine esophagi in vivo. Follow-up endoscopy (EGD) was performed at day 14 after the APC procedure. We noted high grade, benign esophageal strictures (n = 8). All 8 strictures resembled luminal GI fibrotic strictures in humans. These strictures were characterized, and then successfully dilated. A repeat EGD was performed at day 28 after the APC procedure and found evidence of recurrent, high grade, fibrotic, strictures at all 8 locations in all pigs. Pigs were sacrificed and gross and histologic analyses performed. Histologic examination showed extensive fibrosis, with significant collagen deposition in the lamina propria and submucosa, as well as extensive inflammatory infiltrates within the strictures. In conclusion, we report a porcine model of luminal GI fibrotic stricture that has the potential to assist with developing novel anti-fibrotic therapies as well as endoscopic techniques to address recurring fibrotic strictures in humans. [ABSTRACT FROM AUTHOR]

The biliary system is routinely accessed for clinical purposes via endoscopic retrograde cholangiopancreatography (ERCP). We previously pioneered ERCP-mediated hydrodynamic injection in large animal models as an innovative gene delivery approach for monogenic liver diseases. However, the procedure poses potential safety concerns related mainly to liver or biliary tree injury. Here, we sought to further define biliary hydrodynamic injection parameters that are well-tolerated in a human-sized animal model. ERCP was performed in pigs, and hydrodynamic injection carried out using a novel protocol to reduce duct wall stress. Each pig was subjected to multiple repeated injections to expedite testing and judge tolerability. Different injection parameters (volume, flow rate) and injection port diameters were tested. Vital signs were monitored throughout the procedure, and liver enzyme panels were collected pre- and post-procedure. Pigs tolerated repeated biliary hydrodynamic injections with only occasional, mild, isolated elevation in aspartate aminotransferase (AST), which returned to normal levels within one day post-injection. All other liver tests remained unchanged. No upper limit of volume tolerance was reached, which suggests the biliary tree can readily transmit fluid into the vascular space. Flow rates up to 10 mL/sec were also tolerated with minimal disturbance to vital signs and no anatomic rupture of bile ducts. Measured intrabiliary pressure was up to 150 mmHg, and fluid-filled vesicles were induced in liver histology at high flow rates, mimicking the changes in histology observed in mouse liver after hydrodynamic tail vein injection. Overall, our investigations in a human-sized pig liver using standard clinical equipment suggest that ERCP-guided hydrodynamic injection will be safely tolerated in patients. Future investigations will interrogate if higher flow rates and pressure mediate higher DNA delivery efficiencies. [ABSTRACT FROM AUTHOR]

Patients with ulcerative colitis are typically suspected of an inflammatory flare based on suggestive symptoms of inflammation. The aim of this study was to evaluate the impact of inflammation on colonic motility and rectal sensitivity from active to recovery of inflammation. Male rats were given drinking water with 5% dextran sulfate sodium for 7 days. Inflammation, intestinal motor and sensory functions were investigated weekly for 6 weeks. (1) The disease activity index score, fecal calprotectin and tumor necrosis factor alpha were increased from Day 0 to Day 7 (active inflammation) and then decreased gradually until recovery. (2) Distal colon transit was accelerated on Day 7, and then remained unchanged. Whole gut transit was delayed on Day 7 but accelerated from Day 14 to Day 42. (3) Rectal compliance was unaffected from Day 0 to Day 7, but decreased afterwards. (4) Rectal hypersensitivity was noted on Day 7 and persistent. (5) Plasma acetylcholine was decreased on Day 7 but increased from Day 14 to Day 42. Nerve growth factor was increased from Day 7 to Day 42. DSS-induced inflammation leads to visceral hypersensitivity that is sustained until the resolution of inflammation, probably mediated by NGF. Rectal compliance is reduced one week after the DSS-induced inflammation and the reduction is sustained until the resolution of inflammation. Gastrointestinal transit is also altered during and after active colonic inflammation. [ABSTRACT FROM AUTHOR]

The article provide first-in-class evidence that shape-changing and self-latching microdevices enhance the efficacy of extended drug delivery. It mentions about the extended-release gastrointestinal (GI) luminal delivery substantially increases the ease of administration of drugs and consequently the adherence to therapeutic regimens.

Background: BRCA-1 associated protein (BAP1) is a de-ubiquitinating enzyme that regulates gene expression. Recently, the BAP1 mutation and its involvement in cancer survival have been reported in a range of tumor types, including uveal melanoma, mesothelioma, renal cancers, and biliary tract cancers. However, the frequency of BAP1 mutation and down-regulation varies among tumor types, and little is known about the function of BAP1 silencing in cancer cells. Gallbladder carcinoma (GBC) is a type of biliary tract cancer with a poor prognosis. Few mutational studies have investigated the role of BAP1 in GBC, and no functional study in vitro-, or clinical studies about cancer survival have been done. Methods: GBC cells were studied by following the small interfering RNA mediated silencing of BAP1 with regard to proliferation, migration, invasion, and drug sensitivity. We carried out genomic, epigenomic and immunohistochemical analyses to detect somatic BAP1 alterations in 47 GBC patients undergoing surgical resection. Results: BAP1 depletion resulted in increased migration and invasion, but not proliferation, and also resulted in decreased sensitivity to bortezomib, a proteasome inhibitor. Suppressed expression of BAP1 occurred in 22 GBC cases (46.8%) and showed a strong trend toward a worse median survival time of 13.3 months (95% CI, 17.6–62.6) (p = 0.0034). Sanger sequencing revealed a loss-of-function mutation of BAP1 in 11 out of these 22 GBC cases (50%) with low BAP1 expression, whereas 2 out of 25 GBC cases (8%) were detected in cases with high BAP1 expression. Partial changes in methylation were observed in 6 out of 47 cases, but methylation did not show a strong relationship to BAP1 expression or to the prognosis. Conclusion: Our findings showed that genetic mutations are involved in BAP1 down-regulation, leading to promotion of the invasive character of cancer cells and poor prognosis in GBC. [ABSTRACT FROM AUTHOR]

We report on a therapeutic approach using thermoresponsive multi-fingered drug eluting devices. These therapeutic grippers referred to as theragrippers are shaped using photolithographic patterning and are composed of rigid poly(propylene fumarate) segments and stimuli-responsive poly(N-isopropylacrylamide-co-acrylic acid) hinges. They close above 32°C allowing them to spontaneously grip onto tissue when introduced from a cold state into the body. Due to porosity in the grippers, theragrippers could also be loaded with fluorescent dyes and commercial drugs such as mesalamine and doxorubicin, which eluted from the grippers for up to seven days with first order release kinetics. In an in vitro model, theragrippers enhanced delivery of doxorubicin as compared to a control patch. We also released theragrippers into a live pig and visualized release of dye in the stomach. The design of such tissue gripping drug delivery devices offers an effective strategy for sustained release of drugs with immediate applicability in the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

We report on a therapeutic approach using thermo-responsive multi-fingered drug eluting devices. These therapeutic grippers referred to as theragrippers are shaped using photolithographic patterning and are composed of rigid poly(propylene fumarate) segments and stimuli-responsive poly(N-isopropylacrylamide-co-acrylic acid) hinges. They close above 328C allowing them to spontaneously grip onto tissue when introduced from a cold state into the body. Due to porosity in the grippers, theragrippers could also be loaded with fluorescent dyes and commercial drugs such as mesalamine and doxorubicin, which eluted from the grippers for up to seven days with first order release kinetics. In an in vitro model, theragrippers enhanced delivery of doxorubicin as compared to a control patch. We also released theragrippers into a live pig and visualized release of dye in the stomach. The design of such tissue gripping drug delivery devices offers an effective strategy for sustained release of drugs with immediate applicability in the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

Through exomic sequencing of 32 intrahepatic cholangiocarcinomas, we discovered frequent inactivating mutations in multiple chromatin-remodeling genes (including BAP1, ARID1A and PBRM1), and mutation in one of these genes occurred in almost half of the carcinomas sequenced. We also identified frequent mutations at previously reported hotspots in the IDH1 and IDH2 genes encoding metabolic enzymes in intrahepatic cholangiocarcinomas. In contrast, TP53 was the most frequently altered gene in a series of nine gallbladder carcinomas. These discoveries highlight the key role of dysregulated chromatin remodeling in intrahepatic cholangiocarcinomas. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is a highly lethal malignant tumor arising from the biliary tract epithelium. Interleukin-6 (IL-6) is a major mediator of inflammation and contributor to carcinogenesis within the biliary tree. Previous studies suggested that enforced IL-6 contributes to cholangiocarcinogenesis through hypermethylation of several genes implicated in CCA. However, the precise mechanisms of IL-6 effects in CCA remain unclear. We now demonstrate that microRNA (miR)-370 is underexpressed in a large cohort of human CCA vs. normal liver tissues. In addition, we show that IL-6 induces a time-dependent silencing of miR-370. In addition, demethylation of CCA cells results in upregulation of miR-370. Furthermore, we demonstrate that miR-370 is imprinted, and that the Intergenic Differentially Methylated Region (IG-DMR) responsible for imprinting regulation of this genomic locus is hypermethylated in response to IL-6 treatment. In addition, the IG-DMR is hypermethylated in human CCA specimens compared to normal matched controls, in the same location as the IL-6 induced hypermethylation. Finally, miR-370 was found to regulate WNT10B in luciferase as well as western blotting experiments. Our data indicate that the paternal allele of miR-370 is normally silenced through genomic imprinting and that the overexpression of IL-6 in CCA effectively suppresses the expression of miR-370 from the maternal allele, lending support to the theory that miR-370 silencing in human CCA follows a classic two-hit mechanism. [ABSTRACT FROM AUTHOR]

Hypermethylation of the promoter of the tumor suppressor gene, adenomatous polyposis coli (APC), occurs in various malignancies, including hepatocellular carcinoma (HCC). However, reports on the specificity of the methylation of the APC gene for HCC have varied. To gain insight into how these variations occur, bisulfite PCR sequencing was performed to analyze the methylation status of both sense and antisense strands of the APC gene in samples of HCC tissue, matched adjacent non-HCC liver tissue, hepatitis, cirrhosis, and normal liver tissues. DNA derived from fetal liver and 12 nonhepatic normal tissue was also examined. These experiments revealed liver-specific, antisense strand-biased CpG methylation of the APC gene and suggested that, although methylation of the antisense strand of the APC gene exists in normal liver and other non-HCC disease liver tissue, methylation of the sense strand of the APC gene occurs predominantly in HCC. To determine the effect of the DNA strand on the specificity of the methylated APC gene as a biomarker for HCC detection, quantitative methylation-specific PCR assays for sense and antisense strand DNA were developed and performed on DNA isolated from HCC (n = 58), matched adjacent non-HCC (n = 58), cirrhosis (n = 41), and hepatitis (n = 39). Receiver operating characteristic curves were constructed. With the cutoff value set at the limit of detection, the specificity of sense and antisense strand methylation was 84% and 43%, respectively, and sensitivity was 67.2% and 72.4%, respectively. This result demonstrated that the identity of the methylated DNA strand impacted the specificity of APC for HCC detection. Interestingly, methylation of the sense strand of APC occurred in 40% of HCCs from patients with serum AFP levels less than 20 ng/mL, suggesting a potential role for APC as a biomarker to complement AFP in HCC screening. [ABSTRACT FROM AUTHOR]

DNA hypermethylation is a common epigenetic abnormality in colorectal cancers (CRCs) and a promising class of CRC screening biomarkers. We conducted a genome-wide search for novel neoplasia-specific hypermethylation events in the colon. We applied methylation microarray analysis to identify loci hypermethylated in 17 primary CRCs relative to eight non-neoplastic colonic mucosae (NCs) from neoplasia-free subjects. These CRC-associated hypermethylation events were then individually evaluated for their ability to discriminate neoplastic from nonneoplastic cases, based on real-time quantitative methylation-specific PCR (qMSP) assays in 113 colonic tissues: 51 CRCs, nine adenomas, 19 NCs from CRC patients (CRC-NCs), and 34 NCs from neoplasia-free subjects (control NCs). A strict microarray data filtering identified 169 candidate CRC-associated hypermethylation events. Fourteen of these 169 loci were evaluated using qMSP assays. Ten of these 14 methylation events significantly distinguished CRCs from age-matched control NCs (P<0.05 by receiver operator characteristic curve analysis); methylation of visual system homeobox 2 (VSX2) achieved the highest discriminative accuracy (83.3% sensitivity and 92.3% specificity, PP<1P<10-6), followed by BEN domain containing 4 (BEND4), neuronal pentraxin I (NPTX1), ALX homeobox 3 (ALX3), miR-34b, glucagon-like peptide 1 receptor (GLP1R), BTG4, homer homolog 2 (HOMER2), zinc finger protein 583 (ZNF583), and gap junction protein, gamma 1 (GJC1). Adenomas were significantly discriminated from control NCs by hypermethylation of VSX2, BEND4, NPTX1, miR-34b, GLP1R, and HOMER2 (PP<0.05). CRC-NCs were significantly distinguished from control NCs by methylation of ALX3 (PP<1P<10-4). In conclusion, systematic methylome-wide analysis has identified ten novel methylation events in neoplastic and non-neoplastic colonic mucosae from CRC patients. These potential biomarkers significantly discriminate CRC patients from controls. Thus, they merit further evaluation in stool- and circulating DNA-based CRC detection studies. [ABSTRACT FROM AUTHOR]

We demonstrate a methodology that utilizes the specificity of enzyme-substrate biomolecular interactions to trigger miniaturized tools under biocompatible conditions. Miniaturized grippers were constructed using multilayer hinges that employed intrinsic strain energy and biopolymer triggers, as well as ferromagnetic elements. This composition obviated the need for external energy sources and allowed for remote manipulation of the tools. Selective enzymatic degradation of biopolymer hinge components triggered closing of the grippers; subsequent reopening was achieved with an orthogonal enzyme. We highlight the utility of these enzymatically triggered tools by demonstrating the biopsy of liver tissue from a model organ system and gripping and releasing an alginate bead. This strategy suggests an approach for the development of smart materials and devices that autonomously reconfigure in response to extremely specific biological environments. [ABSTRACT FROM AUTHOR]

Cancers have been revealed to be extremely heterogenous in terms of the frequency and types of mutations present in cells from different malignant tumors. Thus, it is likely that uniform clinical treatment is not optimal for all patients, and that the development of individualized therapeutic regimens may be beneficial. We describe the generation of multiple, unique small peptides nine to thirty-four amino acids in length which, when labeled with the radioisotope 32P, bind with vastly differing efficiencies to cell lines derived from different colon adenocarcinomas. In addition, the most effective of these peptides permanently transfers the 32P radioisotope to colorectal cancer cellular proteins within two hours at a rate that is more than 150 times higher than in cell lines derived from other cancers or from the normal tissues tested. Currently, the only two FDA-approved radioimmunotherapeutic agents in use both employ antibodies directed against the B cell marker CD20 for the treatment of non-Hodgkin's lymphoma. By using the method described herein, large numbers of different 32Plabeled peptides can be readily produced and assayed against a broad spectrum of cancer types. This report proposes the development and use of 32P-labeled peptides as potential individualized peptide-binding therapies for the treatment of colon adenocarcinoma patients. [ABSTRACT FROM AUTHOR]

Frequent loss of heterozygosity (LOH) on human chromosome 7q31 has been reported in numerous malignancies. Suppressor of tumorigenicity 7 (ST7) has been identified as a candidate tumor suppressor gene in this region. To identify whether 7q31 and genetic alterations of ST7 were involved in human esophageal carcinogenesis, we performed LOH mapping of a 5.4 cM region at 7q31-q35 in 43 primary esophageal carcinomas, as well as mutational analyses of the ST7 gene in tumors with LOH in this region. Of 43 tumors, 12 (28%) showed LOH at 7q31–q35. These included four (22%) of 18 squamous cell carcinomas and eight (32%) of 25 adenocarcinomas. The peak LOH locus was D7S480, lying 4.2 Mb telomeric to ST7 and showing LOH in eight of 37 informative tumors, or 22%. No mutations were found in the entire coding or flanking intronic regions of the ST7 gene among 12 tumors with 7q-LOH. In addition, quantitative RT–PCR analyses of ST7 mRNA expression levels in 11/13 normal-tumor pairs failed to show more than a 50% decrease in tumor ST7 mRNA relative to matched normal tissues. These data suggest that LOH at 7q31–q35 is involved in the origin or progression of at least a subset of esophageal carcinomas, but that ST7 is not the target gene of this somatic event.Oncogene (2003) 22, 467–470. doi:10.1038/sj.onc.1206125 [ABSTRACT FROM AUTHOR]