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Background: Pre-procedural COVID-19 testing in patients scheduled for elective cases have become routine to reduce the risk of COVID-19 exposure and pulmonary complications related to perioperative COVID-19 infection, and to reduce the use of specific hospital resources among other reasons. This study evaluates the efficacy of universal COVID-19 testing for elective procedures., Methods: Single institution retrospective observational study from July 2020 through August 2021., Results: There were a total of 499 unique patients who were scheduled for 581 surgeries or procedures. A total of 569 anterior nares reverse transcriptase polymerase chain reaction (RT-PCR) tests were completed before scheduled procedure. There were 2 (0.35%) positive COVID tests, both of whom were asymptomatic and unvaccinated at time of testing, and 13 (2.2%) cancelled cases overall. The total cost for labor and materials during this period was $19,738, with each RT-PCR test costing $34.69 and each true positive test costing $9,869., Conclusions: Given the low COVID-19 positivity in the elective procedural patient population, testing protocols for elective procedures should be re-evaluated as the pandemic evolves., Competing Interests: Declaration of competing interest We have not conflicts of interest to disclose. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Literature on the epidemiology of gastric cancer metastasis is limited, although outcomes are known to be poor. We describe patterns of gastric cancer metastasis and treatment in the United States., Methods: Patients with metastatic gastric adenocarcinoma were identified in the NCDB from 2004 to 2016. We describe univariate associations between sites of metastasis and clinicopathologic characteristics and treatment modalities, using chi-square and Kruskal-Wallis tests. Overall survival was calculated using Kaplan-Meier estimation., Results: 43% (n = 2028) of patients presented with peritoneal metastases, 26% (n = 1228) with liver metastases, 20% (n = 941) with distant nodes, and 11% (n = 552) with bone, brain or lung metastases. Compared to liver metastases, peritoneal metastases were more likely from an antral primary site (28% v. 16%); associated with signet ring histology (34% v. 6%); tumor grade of III/IV (85% vs. 60%) (p < 0.0001 for all). Isolated metastasis to distant lymph nodes had the longest median overall survival (7.6 months, p < 0.0001)., Conclusions: Most patients with metastatic gastric cancer in the USA present with peritoneal disease. Predictors for peritoneal metastases include primary antral site, signet ring histology and higher tumor grades., (Published by Elsevier Inc.)

Introduction: Psychosocial distress screening of cancer patients is an American College of Surgeons Commission on Cancer mandate for accredited cancer programs. We evaluated psychosocial distress in breast cancer patients to characterize risk factors for high distress scores at a safety net hospital., Materials and Methods: The psychosocial distress screening form includes a list of potential issues and a distress score scaled from 1 through 10. Psychosocial distress screening results were retrospectively analyzed, along with patient demographics and clinical data. Cochran-Mantel-Haenszel test was applied to identify predictors for high distress scores, which were defined as a score of 5 and greater., Results: 775 distress screens were completed by 171 breast cancer patients. High distress scores were reported in 21.3%. Patients who had no evidence of disease at time of screening were less likely to report a high distress score compared to those who were newly diagnosed or in active treatment (odds ratio 0.51, 95% CI, 0.38-0.68, P< .0001). Patients with high distress scores were more likely to report concerns with insurance (29.1% vs. 7.6%, P< .0001), transportation (16.4% vs. 4.6%, P< .0001), housing (15.2% vs 2.1%, P< .0001), sadness/depression (63.6% vs. 14.1, P< .0001), and physical issues (89.1% vs. 52.8%, P< .0001)., Conclusion: Status of cancer at time of screening, particularly newly diagnosed cancer and active treatment of cancer were associated with high distress scores in this patient group. While there should be an emphasis to ensure patients with these risk factors receive psychosocial distress screening, routine periodic screening for all patients should continue to be implemented to ensure quality cancer care., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Cholelithiasis referrals often present with concomitant or isolated atypical symptoms such as reflux, bloating, or epigastric pain. We sought to identify the impact of preoperative symptomatology of atypical or dyspepsia-type biliary colic on operative and non-operative clinical outcomes., Methods: A retrospective review of patients referred for gallstone disease from 2014 to 2018 at a single institution in Los Angeles County was performed., Results: Of 746 patients evaluated for gallstone disease, 87.4% (n = 652) underwent cholecystectomy - 90.8% (n = 592) had symptom resolution postoperatively whereas 9.2% (n = 60) did not. Over half presented with concomitant atypical and/or dyspepsia symptoms (n = 411). Heartburn/reflux was significantly associated with unresolved symptoms postoperatively (OR 2.1,1.0-4.4, p = 0.04). Overall, 11.1% (n = 83) of all 746 patients and 20.2% of patients with atypical and/or dyspepsia symptoms improved with medical management of gastritis or Helicobacter pylori triple therapy pre/post-operatively., Conclusion: Atypical biliary colic and/or dyspepsia is associated with unresolved symptoms following cholecystectomy. Such patients may benefit from H. pylori testing or PPI trial prior to cholecystectomy., Competing Interests: Declaration of competing interest All authors do not have any financial or personal conflicts of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Lipomatous masses are the most common soft tissue tumors. While the majority are benign lipomas, it is important to identify those masses that are malignant prior to excision. Current guidelines recommend core needle biopsy (CNB) for all lipomatous masses larger than 3-5 cm. The objective of this study was to determine if routine preoperative CNB based on mass size is necessary, or if radiographic features can guide the need for CNB., Materials and Methods: Patients who underwent excision of extremity or truncal lipomatous masses at a single institution from October 2014 to July 2017 were retrospectively reviewed. By protocol, preoperative imaging was routinely obtained for all masses larger than 5 cm. High-risk radiographic features (intramuscular location, septations, nonfat nodules, heterogeneity, and ill-defined margins) and surgical pathology were evaluated to determine patients most likely to benefit from preoperative CNB., Results: Of 178 patients, 2 (1.1%) had malignant tumors on surgical pathology. All masses smaller than 5 cm were benign and, if imaging was obtained, had two or fewer high-risk radiographic features. Both of the patients with malignant tumors had masses larger than 5 cm, preoperative imaging that showed at least four high-risk radiographic features, and underwent CNB prior to excision., Conclusions: The overall rate of malignancy is very low. The results of this study suggest that lipomatous masses smaller than 5 cm without concerning clinical characteristics do not require preoperative imaging or CNB. Conversely, lipomatous masses larger than 5 cm should undergo routine MRI with subsequent CNB if multiple high-risk radiographic features are present., (Copyright © 2019 Elsevier Inc. All rights reserved.)

While significant advances have been made in the treatment of many different solid tumors, pancreatic cancer remains a glaring exception. Overall 5-year survival rates for pancreatic cancer remain in the single digits. While newer chemotherapy regimens such as FOLFIRINOX and nab-paclitaxel/gemcitabine have demonstrated modest improvement in survival benefit for metastatic disease and have improved the resectability rates of previously borderline or locally advanced tumors, clinically significant improvements from immunotherapy and targeted therapy remain to be demonstrated. Regardless, a wealth of basic science research in pancreatic cancer has been directed at understanding its aggressive biology and its resistance to therapy. We present a brief summary of key areas of laboratory research and its translation to clinical care.

Background: Robotic surgery is increasingly adopted into surgical practice, but it remains unclear what level of robotic training general surgery residents receive. The purpose of our study was to assess the variation in robotic surgery training amongst general surgery residency programs in the United States., Methods: A web-based survey was sent to 277 general surgery residency programs to determine characteristics of resident experience and training in robotic surgery., Results: A total of 114 (41%) programs responded. 92% (n = 105) have residents participating in robotic surgeries; 68%(n = 71) of which have a robotics curriculum, 44%(n = 46) track residents' robotic experience, and 55%(n = 58) offer formal recognition of training completion. Responses from university-affiliated (n = 83) and independent (n = 31) programs were not significantly different., Conclusions: Many general surgery residencies offer robotic surgery experience, but vary widely in requisite components, formal credentialing, and case tracking. There is a need to adopt a standardized training curriculum and document resident competency., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: It has become increasingly important to expose surgical residents to robotic surgery as its applications continue to expand. Single-site robotic cholecystectomy (SSRC) is an excellent introductory case to robotics. Resident involvement in SSRC is known to be feasible. Here, we sought to determine whether it is safe to introduce SSRC to junior residents., Materials and Methods: A total of 98 SSRC cases were performed by general surgery residents between August 2015 and August 2016. Cases were divided into groups based on resident level: second- and third-years (juniors) versus fourth- and fifth-years (seniors). Patient age, gender, race, body mass index, and comorbidities were recorded. The number of prior laparoscopic cholecystectomies completed by participating residents was noted. Outcomes including operative time, console time, rate of conversion to open cholecystectomy, and complication rate were compared between groups., Results: Juniors performed 54 SSRC cases, whereas seniors performed 44. There were no significant differences in patient age, gender, race, body mass index, or comorbidities between the two groups. Juniors had less experience with laparoscopic cholecystectomy. There was no significant difference in mean operative time (92.7 min versus 98.0 min, P = 0.254), console time (48.7 min versus 50.8 min, P = 0.639), or complication rate (3.7% versus 2.3%, P = 0.68) between juniors and seniors., Conclusions: SSRC is an excellent way to introduce general surgery residents to robotics. This study shows that with attending supervision, SSRC is feasible and safe for both junior and senior residents with very low complication rates and no adverse effect on operative time., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Single-site robotic cholecystectomy (SSRC) accounts for most of the robotic surgery cases performed by general surgeons at our institution since acquiring the da Vinci Si Surgical SystemTM (Intuitive Surgical, Inc., Sunnyvale, CA) in 2014. We sought to determine whether a SSRC program is safe to start in a public teaching hospital and to determine whether resident participation in this procedure is feasible. Data on age, gender, race, BMI, total operative time, length of stay, comorbidities, and conversion from laparoscopic to open surgery were examined for elective SSRC and laparoscopic cholecystectomies (LCs) performed by two faculty surgeons between February 2015 and August 2015. Thirty-eight patients underwent elective SSRC, whereas 27 patients underwent LC. Residents participated as operating surgeons for some portion of the case in 15 SSRC cases and in all LC cases. There were no significant differences in operative time, length of stay, or 30-day readmission rates, regardless of resident involvement. Patients in the SSRC group had a significantly lower BMI (25.8 vs 33.7, P = 0.008). This study suggests that resident participation does not increase complications or total operative time and that SSRC is a safe procedure to start in a public teaching hospital after proper faculty and resident training.

Background & Aims: Recently, we reported that liver Label Retaining Cancer Cells (LRCC) can initiate tumors with only 10 cells and are relatively resistant to the targeted drug Sorafenib, a standard of practice in advanced hepatocellular carcinoma (HCC). LRCC are the only cancer stem cells (CSC) isolated alive according to a stem cell fundamental function, asymmetric cell division. Metformin has been reported to preferentially target many other types of CSC of different organs, including liver. It's important to know if LRCC, a novel class of CSC, are relatively resistant to metformin, unlike other types of CSC. As metformin inhibits the Sorafenib-Target-Protein (STP) PI3K, and LRCC are newly described CSC, we undertook this study to test the effects of Metformin on Sorafenib-treated HCC and HCC-derived-LRCC., Methods: We tested various STP levels and phosphorylation status, associated genes' expression, proliferation, viability, toxicity, and apoptosis profiles, before and after treatment with Sorafenib with/without Metformin., Results: Metformin enhances the effects of Sorafenib on HCC, and significantly decreased viability/proliferation of HCC cells. This insulin-independent effect was associated with inhibition of multiple STPs (PKC, ERK, JNK and AKT). However, Metformin increased the relative proportion of LRCCs. Comparing LRCC vs. non-LRCC, this effect was associated with improved toxicity and apoptosis profiles, down-regulation of cell death genes and up-regulation of cell proliferation and survival genes in LRCC. Concomitantly, Metformin up-regulated pluripotency, Wnt, Notch and SHH pathways genes in LRCC vs. non-LRCC., Conclusions: Metformin and Sorafenib have enhanced anti-cancer effects. However, in contradistinction to reports on other types of CSC, Metformin is less effective against HCC-derived-CSC LRCC. Our results suggest that combining Metformin with Sorafenib may be able to repress the bulk of tumor cells, but as with other anti-cancer drugs, may leave LRCC behind leading to cancer recurrence. Therefore, liver LRCC, unlike other types of CSC, are relatively resistant to the reported anti-cancer stem cell drug metformin. This is the first report that there is a type of CSC that is not relatively resistant to the CSC-targeting drug. Our findings suggest that a drug targeting LRCC may be critically needed to target CSC and prevent cancer recurrence. These may significantly contribute to the understanding of Metformin's anti-cancer effects and the development of novel drugs targeting the relatively resistant LRCC.

Objective: The standard therapy for advanced hepatocellular carcinoma (HCC) is sorafenib, with most patients experiencing disease progression within 6 months. Label-retaining cancer cells (LRCC) represent a novel subpopulation of cancer stem cells (CSC). The objective was to test whether LRCC are resistant to sorafenib., Methods: We tested human HCC derived LRCC and non-LRCC before and after treatment with sorafenib., Results: LRCC derived from human HCC are relatively resistant to sorafenib. The proportion of LRCC in HCC cell lines is increased after sorafenib while the general population of cancer cells undergoes growth suppression. We show that LRCC demonstrate improved viability and toxicity profiles, and reduced apoptosis, over non-LRCC. We show that after treatment with sorafenib, LRCC upregulate the CSC marker aldehyde dehydrogenase 1 family, wingless-type MMTV-integration-site family, cell survival and proliferation genes, and downregulate apoptosis, cell cycle arrest, cell adhesion and stem cells differentiation genes. This phenomenon was accompanied by non-uniform activation of specific isoforms of the sorafenib target proteins extracellular-signal-regulated kinases and v-akt-murine-thymoma-viral-oncogene homologue (AKT) in LRCC but not in non-LRCC. A molecular pathway map for sorafenib treated LRCC is proposed., Conclusions: Our results suggest that HCC derived LRCC are relatively resistant to sorafenib. Since LRCC can generate tumours with as few as 10 cells, our data suggest a potential role for these cells in disease recurrence. Further investigation of this phenomenon might provide novel insights into cancer biology, cancer recurrence and drug resistance with important implications for the development of novel cancer therapies based on targeting LRCC.

Importance: Survival varies widely in patients with stage III melanoma. The existence of clinical significance for positive nonsentinel lymph node (NSLN) status would warrant consideration for incorporation into the American Joint Committee on Cancer staging system and better prediction of survival., Objective: To evaluate whether disease limited to sentinel lymph nodes (SLNs) represents different clinical significance than disease spread into NSLNs., Design, Setting, and Participants: The database of the John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, California, was queried for all patients with SLNs positive for cutaneous melanoma who subsequently underwent completion lymph node dissection., Main Outcomes and Measures: Disease-free survival, melanoma-specific survival (MSS), and overall survival., Results: A total of 4223 patients underwent SLN biopsy from 1986 to 2012. Of these patients, 329 had a tumor-positive SLN. Of the 329, 250 patients (76.0%) had no additional positive nodes and 79 (24.0%) had a tumor-positive NSLN. Factors predictive of NSLN positivity included older age (P = .04), greater Breslow thickness (P < .001), and ulceration (P < .02). Median overall survival was 178 months for the SLN-only positive group and 42.2 months for the NSLN positive group (5-year overall survival, 72.3% and 46.4%, respectively). Median MSS was not reached for the SLN-only positive group and was 60 months for the NSLN positive group (5-year MSS, 77.8% and 49.5%, respectively). On multivariate analysis, NSLN positivity had a strong association with recurrence (hazard ratio [HR], 1.75; 95% CI, 1.23-2.50; P = .002), shorter overall survival (HR, 2.24; 95% CI, 1.48-3.40; P < .001), and shorter MSS (HR, 2.23; 95% CI, 1.46-3.07; P < .001). To further control for the effects of total positive lymph nodes, comparison was done for patients with only N2 disease (2-3 total positive lymph nodes); the results of this comparison confirmed the independent effect of NSLN status (MSS; P = .04)., Conclusions and Relevance: Nonsentinel lymph node positivity is one of the most significant prognostic factors in patients with stage III melanoma. Subclassification of melanoma by NSLN tumor status should be considered for the American Joint Committee on Cancer staging system.

Aim: To investigate the prognostic significance of the primary site of disease for small bowel carcinoid (SBC) using a population-based analysis., Methods: The Surveillance, Epidemiology and End Results (SEER) database was queried for histologically confirmed SBC between the years 1988 and 2009. Overall survival (OS) and disease-specific survival (DSS) were analyzed using the Kaplan-Meier method and compared using Log rank testing. Log rank and multivariate Cox regression analyses were used to identify predictors of survival using age, year of diagnosis, race, gender, tumor histology/size/location, tumor-node-metastasis stage, number of lymph nodes (LNs) examined and percent of LNs with metastases., Results: Of the 3763 patients, 51.2% were male with a mean age of 62.13 years. Median follow-up was 50 mo. The 10-year OS and DSS for duodenal primaries were significantly better when compared to jejunal and ileal primaries (P = 0.02 and < 0.0001, respectively). On multivariate Cox regression analysis, after adjusting for multiple factors, primary site location was not a significant predictor of survival (P = 0.752 for OS and P = 0.966 DSS) while age, number of primaries, number of LNs examined, T-stage and M-stage were independent predictors of survival., Conclusion: This 21-year, population-based study of SBC challenges the concept that location of the primary lesion alone is a significant predictor of survival.

Background: The 7th edition of the AJCC Cancer Staging Manual (AJCC-7) includes substantial changes for colon cancer (CC), which are particularly complex in patients with stage II and III disease. We used a national cancer database to determine if these changes improved prediction of survival., Study Design: The database of the Surveillance, Epidemiology and End Results Program was queried to identify patients with pathologically confirmed stage I to III CC diagnosed between 1988 and 2008. Colon cancer was staged by the 6(th) edition of the AJCC Cancer Staging Manual (AJCC-6) and then restaged by AJCC-7. Five-year disease-specific survival and overall survival were compared., Results: After all exclusion criteria were applied, AJCC-6 and AJCC-7 staging was possible in 157,588 patients (68.9%). Bowker's test of symmetry showed that the number of patients per substage was different for AJCC-6 and AJCC-7 (p < 0.001). The Akaike information criteria comparison showed superior fit with the AJCC-7 model (p < 0.001). However, although AJCC-7 staging yielded a progressive decrease in disease-specific survival and overall survival of patients with stage IIA (86.3% and 72.4%, respectively), IIB (79.4% and 63.2%, respectively), and IIC (64.9% and 54.6%, respectively) CC, disease-specific survival and overall survival of patients with stage IIIA disease increased (89% and 79%, respectively). Subset analysis of patients with >12 lymph nodes examined did not affect this observation., Conclusions: The AJCC-7 staging of CC does not address all survival discrepancies, regardless of the number of lymph nodes examined. Consideration of other prognostic factors is critical for decisions about therapy, particularly for patients with stage II CC., (Copyright © 2013 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: Gallbladder carcinoma (GBC) is a rare disease that is often diagnosed incidentally in its early stages. Simple cholecystectomy is considered the standard treatment for stage I GBC. This study was conducted in a large cohort of patients with stage I GBC to test the hypothesis that the extent of surgery affects survival., Methods: The National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database was queried to identify patients in whom microscopically confirmed, localized (stage I) GBC was diagnosed between 1988 and 2008. Surgical treatment was categorized as cholecystectomy alone, cholecystectomy with lymph node dissection (C + LN) or radical cholecystectomy (RC). Age, gender, race, ethnicity, T1 sub-stage [T1a, T1b, T1NOS (T1 not otherwise specified)], radiation treatment, extent of surgery, cause of death and survival were assessed by log-rank and Cox's regression analyses., Results: Of 2788 patients with localized GBC, 1115 (40.0%) had pathologically confirmed T1a, T1b or T1NOS cancer. At a median follow-up of 22 months, 288 (25.8%) had died of GBC. Five-year survival rates associated with cholecystectomy, C + LN and RC were 50%, 70% and 79%, respectively (P < 0.001). Multivariate analysis showed that surgical treatment and younger age were predictive of improved disease-specific survival (P < 0.001), whereas radiation therapy portended worse survival (P = 0.013)., Conclusions: In the largest series of patients with stage I GBC to be reported, survival was significantly impacted by the extent of surgery (LN dissection and RC). Cholecystectomy alone is inadequate in stage I GBC and its use as standard treatment should be reconsidered., (© 2012 International Hepato-Pancreato-Biliary Association.)

Although multimodal treatment (surgery, chemotherapy±radiation) has improved survival in patients with rectal cancer, there are inconsistent treatment patterns in hospitals in the United States. The objective of the study was to evaluate whether treatment paradigms have changed for patients with Stage II and III rectal cancer in community hospitals compared with academic research hospitals, i.e., teaching or comprehensive hospitals engaged in research. The National Cancer Database was queried to identify all patients diagnosed with Stage II or III rectal adenocarcinoma between 2000 and 2008. The first course of treatment and patient clinicodemographic factors were evaluated. Of 70,409 patients in the study cohort, 7,235 (62.9%) at community hospitals, 24,465 (66.9%) at comprehensive hospitals, and 14,868 (66.6%) at teaching hospitals received multimodal therapy. Community hospitals were more likely to treat individuals who were older, white, and with lower income compared with the other facility types. Teaching hospitals treated a higher proportion of uninsured patients. Despite differences in patient demographics, community hospitals have increased the use of multimodal treatment for rectal cancer but continue to remain below academic research hospital standards.

Label-retaining cells (LRCs) have been proposed to represent adult tissue stem cells. LRCs are hypothesized to result from either slow cycling or asymmetric cell division (ACD). However, the stem cell nature and whether LRC undergo ACD remain controversial. Here, we demonstrate label-retaining cancer cells (LRCCs) in several gastrointestinal (GI) cancers including fresh surgical specimens. Using a novel method for isolation of live LRCC, we demonstrate that a subpopulation of LRCC is actively dividing and exhibits stem cells and pluripotency gene expression profiles. Using real-time confocal microscopic cinematography, we show live LRCC undergoing asymmetric nonrandom chromosomal cosegregation LRC division. Importantly, LRCCs have greater tumor-initiating capacity than non-LRCCs. Based on our data and that cancers develop in tissues that harbor normal-LRC, we propose that LRCC might represent a novel population of GI stem-like cancer cells. LRCC may provide novel mechanistic insights into the biology of cancer and regenerative medicine and present novel targets for cancer treatment., (Copyright © 2012 AlphaMed Press.)

Traditionally, distant metastatic melanoma has a poor prognosis owing to lack of efficacious, U.S. Food and Drug Administration-approved systemic therapy and the limited use of surgical resection as a therapeutic option. More recently, new biological therapies such as vemurafenib (Zelboraf) and ipilimumab (Yervoy) have shown strong promise and dramatically improved the landscape of stage IV melanoma therapy. Although there are numerous single-institution studies advocating the role for therapeutic surgical intervention, many remain skeptical of nonpalliative surgery for metastatic melanoma. Surgical resection of advanced melanoma has been proven to be effective as long as all disease is removed (R0). Patient selection is paramount. The combination of newer systemic therapies and surgical resection is currently under investigation. Understanding the tumor biology of melanoma and its mechanism of metastatic spread is essential to developing the most efficacious treatment strategy.

Background: We previously developed GoMiner, an application that organizes lists of 'interesting' genes (for example, under-and overexpressed genes from a microarray experiment) for biological interpretation in the context of the Gene Ontology. The original version of GoMiner was oriented toward visualization and interpretation of the results from a single microarray (or other high-throughput experimental platform), using a graphical user interface. Although that version can be used to examine the results from a number of microarrays one at a time, that is a rather tedious task, and original GoMiner includes no apparatus for obtaining a global picture of results from an experiment that consists of multiple microarrays. We wanted to provide a computational resource that automates the analysis of multiple microarrays and then integrates the results across all of them in useful exportable output files and visualizations., Results: We now introduce a new tool, High-Throughput GoMiner, that has those capabilities and a number of others: It (i) efficiently performs the computationally-intensive task of automated batch processing of an arbitrary number of microarrays, (ii) produces a human-or computer-readable report that rank-orders the multiple microarray results according to the number of significant GO categories, (iii) integrates the multiple microarray results by providing organized, global clustered image map visualizations of the relationships of significant GO categories, (iv) provides a fast form of 'false discovery rate' multiple comparisons calculation, and (v) provides annotations and visualizations for relating transcription factor binding sites to genes and GO categories., Conclusion: High-Throughput GoMiner achieves the desired goal of providing a computational resource that automates the analysis of multiple microarrays and integrates results across all of the microarrays. For illustration, we show an application of this new tool to the interpretation of altered gene expression patterns in Common Variable Immune Deficiency (CVID). High-Throughput GoMiner will be useful in a wide range of applications, including the study of time-courses, evaluation of multiple drug treatments, comparison of multiple gene knock-outs or knock-downs, and screening of large numbers of chemical derivatives generated from a promising lead compound.

An important feature of many chronic parasitic infections is the ability of the invading pathogen and host to establish a compromise, which ensures successful parasitism without killing the infected host. For many helminth infections, down-modulating the immune response is critical because persistent inflammation can become more damaging to the host than the invading pathogen itself. Such is the case with schistosomiasis mansoni, where chronic granulomatous inflammation in the liver causes portal hypertension, porto-pulmonary shunting, bleeding from collateral bypass vessels, and eventual death if not suppressed effectively. CD4(+) T helper type 2 cells (Th2) (secreting IL-4, IL-5, and IL-13) characterize the host response after Schistosoma mansoni infection, and recent studies have identified IL-13 as the principal mediator of hepatic fibrosis. Here, we show that the IL-13 receptor alpha 2 (IL-13R alpha 2) is a critical mediator of immune down-modulation, identifying the receptor as a life-sustaining off signal for chronic and pernicious inflammation in schistosomiasis.

Members of the RecA family of recombinases from bacteriophage T4, Escherichia coli, yeast, and higher eukaryotes function in recombination as higher-order oligomers assembled on tracts of single-strand DNA (ssDNA). Biochemical studies have shown that assembly of recombinase involves accessory factors. These studies have identified a class of proteins, called recombination mediator proteins, that act by promoting assembly of recombinase on ssDNA tracts that are bound by ssDNA-binding protein (ssb). In the absence of mediators, ssb inhibits recombination reactions by competing with recombinase for DNA-binding sites. Here we briefly review mediated recombinase assembly and present results of new in vivo experiments. Immuno-double-staining experiments in Saccharomyces cerevisiae suggest that Rad51, the eukaryotic recombinase, can assemble at or near sites containing ssb (replication protein A, RPA) during the response to DNA damage, consistent with a need for mediator activity. Correspondingly, mediator gene mutants display defects in Rad51 assembly after DNA damage and during meiosis, although the requirements for assembly are distinct in the two cases. In meiosis, both Rad52 and Rad55/57 are required, whereas either Rad52 or Rad55/57 is sufficient to promote assembly of Rad51 in irradiated mitotic cells. Rad52 promotes normal amounts of Rad51 assembly in the absence of Rad55 at 30 degrees C but not 20 degrees C, accounting for the cold sensitivity of rad55 null mutants. Finally, we show that assembly of Rad51 is induced by radiation during S phase but not during G(1), consistent with the role of Rad51 in repairing the spontaneous damage that occurs during DNA replication.

We examined the effects of a new antiangiogenic isocoumarin, NM-3, as a radiation modifier in vitro and in vivo. The present studies demonstrate that NM-3 is cytotoxic to human umbilical vein endothelial cells (HUVECs) but not to Lewis lung carcinoma (LLC) cells nor Seg-1, esophageal adenocarcinoma cells, in clonogenic survival assays. When HUVEC cultures are treated with NM-3 combined with ionizing radiation (IR), additive cytotoxicity is observed. In addition, the combination of NM-3 and IR inhibits HUVEC migration to a greater extent than either treatment alone. The effects of treatment with NM-3 and IR were also evaluated in tumor model systems. C57BL/6 female mice bearing LLC tumors were given injections for 4 consecutive days with NM-3 (25 mg/kg/day) and treated with IR (20 Gy) for 2 consecutive days. Combined treatment with NM-3 and IR significantly reduced mean tumor volume compared with either treatment alone. An increase in local tumor control was also observed in LLC tumors in mice receiving NM-3/IR therapy. When athymic nude mice bearing Seg-1 tumor xenografts were treated with NM-3 (100 mg/kg/day for 4 days) and 20 Gy (four 5 Gy fractions), significant tumor regression was observed after combined treatment (NM-3 and IR) compared with IR alone. Importantly, no increase in systemic or local tissue toxicity was observed after combined treatment (NM-3 and IR) when compared with IR alone. The bioavailability and nontoxic profile of NM-3 suggests that the efficacy of this agent should be tested in clinical radiotherapy.

The family of vascular endothelial growth factor (VEGF) proteins include potent and specific mitogens for vascular endothelial cells that function in the lation of angiogenesis Inhibition of VEGF-induced angiogenesis either by neutralizing antibodies or dominant-negative soluble receptor, blocks the growth of primary and metastatic experimental tumors Here we report that VEGF expression is induced in Lewis lung carcinomas (LLCs) both in vitro and vivo after exposure to ionizing radiation (IR) and in human tumor cell lines (Seg-1 esophageal adenocarcinoma, SQ20B squamous cell carcinoma, T98 and U87 glioblastomas, and U1 melanoma) in vitro. The biological significance of IR-induced VEGF production is supported by our finding that treatment of tumor-bearing mice (LLC, Seg-1, SQ20B, and U87) with a neutralizing antibody to VEGF-165 before irradiation is associated with a greater than additive antitumor effect. In vitro, the addition of VEGF decreases IR-induced killing of human umbilical vein endothelial cells, and the anti-VEGF treatment potentiates IR-induced lethality of human umbilical vein endothelial cells. Neither recombinant VEGF protein nor neutralizing antibody to VEGF affects the radiosensitivity of tumor cells These findings support a model in which induction of VEGF by IR contributes to the protection of tumor blood vessels from radiation-mediated cytotoxicity and thereby to tumor radioresistance.