Large Outbreak of Hepatitis C Virus Associated With Drug Diversion by a Healthcare Technician.

Background: In May 2012, the New Hampshire (NH) Division of Public Health Services (DPHS) was notified of 4 persons with newly diagnosed hepatitis C virus (HCV) infection at hospital X. Initial investigation suggested a common link to the hospital cardiac catheterization laboratory (CCL) because the infected persons included 3 CCL patients and a CCL technician. NH DPHS initiated an investigation to determine the source and control the outbreak. Methods: NH DPHS conducted site visits, case patient and employee interviews, medical record and medication use review, and employee and patient HCV testing using enzyme immunoassay for anti-HCV, reverse-transcription polymerase chain reaction for HCV RNA, nonstructural 5B (NS5B) and hypervariable region 1 (HVR1) sequencing, and quasispecies analysis. Results: HCV HVR1 analysis of the first 4 cases confirmed a common source of infection. HCV testing identified 32 of 1074 CCL patients infected with the outbreak strain, including 3 patients coinfected with >1 HCV strain. The epidemiologic investigation revealed evidence of drug diversion by the HCV-infected technician, evidenced by gaps in controlled medication control, higher fentanyl use during procedures for confirmed cases, and building card key access records documenting the presence of the technician during days when transmission occurred. The employee's status as a traveling technician led to a multistate investigation, which identified additional cases at prior employment sites. Conclusions: This is the largest laboratory-confirmed drug diversion-associated HCV outbreak published to date. Recommendations to reduce drug diversion risk and to conduct outbreak investigations are provided.

Human outbreak of Salmonella Typhimurium associated with exposure to locally made chicken jerky pet treats, New Hampshire, 2013.

Pet treats and pet food can be contaminated with Salmonella and other pathogens, though they are infrequently implicated as the source of human outbreaks. In 2013, the New Hampshire Department of Health and Human Services investigated a cluster of Salmonella Typhimurium infections associated with contaminated locally made pet treats. Case-patients were interviewed with standardized questionnaires to assess food, animal, and social histories. Laboratory and environmental investigations were conducted, including testing of clinical specimens, implicated product, and environmental swabs. Between June and October 2013, a total of 43 ill persons were identified. Sixteen patients (37%) were hospitalized. Among 43 case-patients interviewed, the proportion exposed to dogs (95%) and pet treats (69%) in the 7 days prior to illness was statistically higher than among participants in a U.S. population-based telephone survey (61%, p<0.0001 and 16%, p<0.0001, respectively). On further interview, 38 (88%) reported exposure to Brand X Chicken Jerky, the maker of Brand X chicken jerky, or the facility in which it was made. Product testing isolated the outbreak strain from four of four Brand X Chicken Jerky samples, including an unopened package purchased at retail, opened packages collected from patient households, and unpackaged jerky obtained from the jerky maker. A site visit revealed inadequate processing of the chicken jerky, bare-hand contact with the finished product prior to packaging, and use of vacuum-sealed packaging, which may have enabled facultative anaerobic bacteria to proliferate. Seven (78%) of nine environmental swabs taken during the site visit also yielded the outbreak strain. Brand X Chicken Jerky was voluntarily recalled on September 9, 2013. Consumers should be made aware of the potential for locally made products to be exempt from regulation and for animals and animal food to carry pathogens that cause human illness, and be educated to perform hand hygiene after handling pet food or treats.

Evaluation of a multitarget real-time PCR assay for detection of Bordetella species during a pertussis outbreak in New Hampshire in 2011.

A multitarget real-time PCR assay with three targets, including insertion sequence 481 (IS481), IS1001, and an IS1001-like element, as well as pertussis toxin subunit S1 (ptxS1), for the detection of Bordetella species was evaluated during a pertussis outbreak. The sensitivity and specificity were 77 and 88% (PCR) and 66 and 100% (culture), respectively. All patients with an IS481 C(T) of <30 also tested positive by ptxS1 assay and were clinical pertussis cases. No patients with IS481 C(T) values of ≥40 tested positive by culture. Therefore, we recommend that culture be performed only for specimens with IS481 C(T) values of 30 ≤ CT <40.

Born digital or fossilised digitally? How born digital data systems continue the legacy of social violence towards LGBTQI + communities: a case study of experiences in the Republic of Ireland.

The AI and Society discourse has previously drawn attention to the ways that digital systems embody the values of the technology development community from which they emerge through the development and deployment process. Research shows how this effect leads to a particular treatment of gender in computer systems development, a treatment which lags far behind the rich understanding of gender that social studies scholarship reveals and people across society experience. Many people do not relate to the narrow binary gender options of male or female, and many people express their gender identity in much richer ways than the sex/gender binary female/woman and male/man Boolean terms will allow. We ask: are "born-digital" gendered datasets in digital systems experienced as marginalising by those who express their identity beyond the male/female binary? Case Study: Ireland. To answer this universal question, this paper presents the findings of an empirical case study of people in Ireland with diverse gender identities and expressions, and their experiences with public data systems and new technologies. In spite of great social changes in Ireland which have led to constitutional change in favour of LGBTQI + people, born-digital systems were experienced by respondents as embodying socio-cultural values which were no longer accepted in society at large. For many of the respondents, digital technologies routinely marginalise them in all kinds of ways. These systems keep alive violence and oppression long after civil rights have been enshrined in constitutional law. This study is just one example of the way assumptions about digital are disengaged from society-at-large. It is a call to arms to all who are passionate about socially-responsible technology.

Evaluation of the anti-tumour activity of Coriolus versicolor polysaccharopeptide (I'm-Yunity) alone or in combination with doxorubicin for canine splenic hemangiosarcoma.

Canine splenic hemangiosarcoma (HSA) is an aggressive tumour of vascular endothelium that carries a grave prognosis following standard of care treatment with surgery and doxorubicin. A previous pilot study revealed potential anti-tumour activity of I'm-Yunity polysaccharopeptide (PSP) for canine HSA. The aim of this prospective study was to assess patient outcome when treated with PSP alone or in combination with doxorubicin post-splenectomy compared to patients treated with surgery and doxorubicin that received a placebo in place of PSP. Dogs undergoing splenectomy for splenic HSA were eligible. Following splenectomy, owners were offered treatment with PSP alone or adjuvant doxorubicin chemotherapy (unblinded). Patients with owners that selected to proceed with doxorubicin chemotherapy were blindly randomized to receive placebo or PSP. Dogs were evaluated weekly for 15 weeks, then scheduled for monthly visits until death. One hundred and one dogs were included in the final analysis: 51 PSP alone, 25 doxorubicin/placebo, and 25 combination PSP/doxorubicin. On multivariate analysis, dogs treated with single agent PSP, female dogs, decreased haematocrit at diagnosis, and stage III disease were negatively significantly associated with outcome; however, an interaction between treatment group and sex was documented. Gender-specific outcomes revealed no significant difference in survival between treatment groups for male dogs, but female dogs treated with PSP alone had significantly reduced survival compared to females receiving doxorubicin/placebo (HR 0.21; p = .004). Anaemia (HR 5.28; p < .001) and stage III disease (HR 2.9; p = .014) remained negatively associated with survival when controlling for sex and treatment group. The addition of PSP to doxorubicin post-splenectomy did not improve survival in dogs with splenic HSA.

Outcome and Prognostic Factors in Cats Undergoing Resection of Intestinal Adenocarcinomas: 58 Cases (2008-2020).

The purpose of this multi-institutional retrospective study was to expand the available data pertaining to pre-operative clinical findings, progression-free and overall survival times, and potential prognostic factors for cats undergoing surgery for intestinal adenocarcinomas. Fifty-eight cats treated over a 12-year period were included in the study. Progression-free and overall survival times were estimated using Kaplan-Meier analyses. Potential prognostic variables were evaluated for associations with progression-free and overall survival using univariate Cox proportional hazards regression analyses. Prior to surgery, the intestinal mass was identified using ultrasonography in 89% of cats in which it was applied; however, imaging findings suggestive of intrathoracic metastases were observed in only 9% of cats. Among 22 cats undergoing ultrasound-guided fine needle aspiration cytology, the results agreed with the results of histopathology in only 10 cats. Discordant results were most commonly related to the presence of marked inflammation in cytology samples, which may have obscured the presence of neoplastic cells. Diffuse intestinal small cell lymphoma was identified as a comorbidity in 5 cats. Resection of the tumor with the objective of obtaining wide surgical margins was performed in each cat. On histopathology, 20 tumors were classified as mucinous adenocarcinoma and 28 were adenocarcinoma not otherwise specified. Intestinal transection site margins were complete in 94% of cats; however, complete mural margins were present in only 15% of cats. Local lymph node metastases were identified in 52% of cats and carcinomatosis was diagnosed in 81% of cats. Disease progression was documented in 32 of the 58 cats (55%). Of these 32 cats, 14 (43%) had local recurrence of the primary intestinal tumor. Median progression-free survival was 203 days (95% CI 130-299 days), and median overall survival time was 284 days (95% CI 200-363 days). Mitotic count was inversely associated with progression-free survival (HR 1.04; 95% CI 1.01-1.07, P = 0.005); however, none of the remaining potential prognostic factors, including administration of adjuvant chemotherapy, were significantly associated with progression-free or overall survival. Feline intestinal adenocarcinoma remains an aggressive and highly fatal disease. Large, randomized controlled clinical trials will be needed to improve the survival prospects for affected cats.

Radiologist Opinions of a Quality Assurance Program: The Interaction Between Error, Emotion, and Preventative Action.

RATIONALE AND OBJECTIVES: To investigate inter-relationships between radiologist opinions of a quality assurance (QA) program, QA Committee communications, negative emotions, self-identified risk factors, and preventive actions taken following major errors. MATERIALS AND METHODS: A 48 question electronic survey was distributed to all 431 radiologists within the same teleradiology organization between June 15 and July 3, 2018. Two reminders were sent during the survey time period. Descriptive statistics were generated, and comparisons were made with Fisher exact test. Significance level was set at p < 0.05. RESULTS: Response rate was 67.5% (291/431), and 72.5% of respondents completed all survey questions. A total of 64.3% of respondents were male, and the highest proportion of radiologists (28.9%, 187/291) had been in practice >20 years. Preventative actions following an error were positively correlated to a higher opinion of the QA process, self-identification of personal risk factors for error, and greater negative emotions following an error (all p < 0.05). A higher opinion of communications with the QA committee was associated with a positive opinion of the QA process (p < 0.001). An inverse relationship existed between negative emotion and opinion of QA committee communications (p < 0.05) and negative emotion and opinion of the QA process (p < 0.05). Radiologist gender and full time versus part time status had a significant effect on perception of the QA process (p < 0.05). CONCLUSION: Radiologist opinions of their institutional QA process was related to the number of negative emotions experienced and preventative actions taken following major errors. Nurturing trust and incorporating more positive feedback in the QA process may improve interactions with QA Committees and mitigate future errors.

Outcome, prognostic factors and histological characterization of canine gastrointestinal sarcomas.

Canine gastrointestinal sarcomas, a group of tumours that includes leiomyosarcomas (LMSAs), gastrointestinal stromal tumours (GISTs) and other rarer sarcomas, comprise about 10-30% of all gastrointestinal tumours. This study aims to characterize the histologic characteristics and clinical behaviour in order to identify prognostic factors predictive of outcome. A single institution database search for surgically treated gastrointestinal sarcomas yielded 47 cases with adequate tissue remaining for histologic analysis and 42 cases available for analysis of clinical outcome. Tumours were then prospectively evaluated for mitotic count, necrosis, haemorrhage and inflammation, as well as categorized via immunohistochemical (IHC) staining for smooth muscle actin, c-KIT and DOG-1. IHC analysis defined 32 tumours as GISTs, 14 as LMSAs and one as a sarcoma not otherwise specified. For both GISTs and LMSAs, the overall median survival time (MST) is 1024 days (range 31-1456), which did not differ statistically between tumour types (p = .92). The overall metastatic rate of GISTs in this study was 32.1% (n = 9) which was not significantly different to that of LMSAs at 15.3% (n = 2, p = .45). In multivariate analysis, mitotic count under 9 in GIST patients and complete surgical excision in all tumour types correlated with improved MST. For patients with GISTs, the intensity of c-KIT staining also correlated positively with survival, with an MST of 250 days in cases with weak staining and an MST of 1418 days in cases with moderate or strong c-KIT staining (p = .005).

Adjuvant Sirolimus Does Not Improve Outcome in Pet Dogs Receiving Standard-of-Care Therapy for Appendicular Osteosarcoma: A Prospective, Randomized Trial of 324 Dogs.

PURPOSE: The mTOR pathway has been identified as a key nutrient signaling hub that participates in metastatic progression of high-grade osteosarcoma. Inhibition of mTOR signaling is biologically achievable with sirolimus, and might slow the outgrowth of distant metastases. In this study, pet dogs with appendicular osteosarcoma were leveraged as high-value biologic models for pediatric osteosarcoma, to assess mTOR inhibition as a therapeutic strategy for attenuating metastatic disease progression. PATIENTS AND METHODS: A total of 324 pet dogs diagnosed with treatment-naïve appendicular osteosarcoma were randomized into a two-arm, multicenter, parallel superiority trial whereby dogs received amputation of the affected limb, followed by adjuvant carboplatin chemotherapy ± oral sirolimus therapy. The primary outcome measure was disease-free interval (DFI), as assessed by serial physical and radiologic detection of emergent macroscopic metastases; secondary outcomes included overall 1- and 2-year survival rates, and sirolimus pharmacokinetic variables and their correlative relationship to adverse events and clinical outcomes. RESULTS: There was no significant difference in the median DFI or overall survival between the two arms of this trial; the median DFI and survival for standard-of-care (SOC; defined as amputation and carboplatin therapy) dogs was 180 days [95% confidence interval (CI), 144-237] and 282 days (95% CI, 224-383) and for SOC + sirolimus dogs, it was 204 days (95% CI, 157-217) and 280 days (95% CI, 252-332), respectively. CONCLUSIONS: In a population of pet dogs nongenomically segmented for predicted mTOR inhibition response, sequentially administered adjuvant sirolimus, although well tolerated when added to a backbone of therapy, did not extend DFI or survival in dogs with appendicular osteosarcoma.

Feasibility of using gene expression analysis to study canine soft tissue sarcomas.

The prognosis given for canine soft tissue sarcomas (STSs) is based primarily on histopathologic grade. The decision to administer adjuvant chemotherapy is difficult since less than half of patients with high-grade STSs develop metastatic disease. We hypothesize that there is a gene signature that will improve our ability to predict development of metastatic disease in STS patients. The objective of this study was to determine the feasibility of using cDNA microarray and quantitative real-time PCR (qRT-PCR) analysis to determine gene expression patterns in metastatic versus nonmetastatic canine STSs, given the inherent heterogeneity of this group of tumors. Five STSs from dogs with metastatic disease were evaluated in comparison to eight STSs from dogs without metastasis. Tumor RNA was extracted, processed, and labeled for application to the Affymetrix Canine Genechip 2.0 Array. Array fluorescence was normalized using D-Chip software and data analysis was performed with JMP/Genomics. Differential gene expression was validated using qRT-PCR. Over 200 genes were differentially expressed at a false discovery rate of 5%. Differential gene expression was validated for five genes upregulated in metastatic tumors. Quantitative RT-PCR confirmed increased relative expression of all five genes of interest in the metastatic STSs. Our results demonstrate that microarray and qRT-PCR are feasible methods for comparing gene signatures in canine STSs. Further evaluation of the differences between gene expression in metastatic STSs and in nonmetastatic STSs is likely to identify genes that are important in the development of metastatic disease and improve our ability to prognosticate for individual patients.

Comparison of the pathogenic potentials of environmental and clinical vibrio parahaemolyticus strains indicates a role for temperature regulation in virulence.

Although the presence of pathogenic Vibrio spp. in estuarine environments of northern New England has been known for some time (C. H. Bartley and L. W. Slanetz, Appl. Microbiol. 21: 965-966, 1971, and K. R. O'Neil, S. H. Jones, and D. J. Grimes, FEMS Microbiol. Lett. 60:163-167, 1990), their virulence and the relative threat they may pose to human health has yet to be evaluated. In this study, the virulence potential of 33 Vibrio parahaemolyticus isolates collected from the Great Bay Estuary of New Hampshire was assessed in comparison to that of clinical strains. The environmental isolates lack thermostable direct hemolysin (TDH) and TDH-related hemolysin (TRH), which are encoded by tdh and trh, respectively. Though not hemolytic, they do possess putative virulence factors, such type III secretion system 1, and are highly cytotoxic to human gastrointestinal cells. The expression of known and putative virulence-associated traits, including hemolysin, protease, motility, biofilm formation, and cytotoxicity, by clinical reference isolates correlated with increased temperature from 28°C to 37°C. In contrast, the environmental isolates did not induce their putative virulence-associated traits in response to a temperature of 37°C. We further identified a significant correlation between hemolytic activity and growth phase among clinical strains, whereby hemolysin production decreases with increasing cell density. The introduction of a tdh::gfp promoter fusion into the environmental strains revealed that they regulate this virulence-associated gene appropriately in response to temperature, indicating that their existing regulatory mechanisms are primed to manage newly acquired virulence genes.

Ecological level analysis of primary lung tumors in dogs and cats and environmental radon activity.

BACKGROUND: Epidemiologic studies suggest residential radon exposure might increase the risk of primary lung cancer in people, but these studies are limited by subject mobility. This limitation might be overcome by evaluating the association in pets. HYPOTHESIS: Primary pulmonary neoplasia (PPN) rate is higher in dogs and cats residing in counties with a high radon exposure risk (Environmental Protection Agency [EPA] zone 1) compared to zones 2 (moderate radon exposure risk) and 3 (low radon exposure risk). ANIMALS: Six hundred ninety client-owned dogs and 205 client-owned cats with PPN. METHODS: Retrospective review of medical records at 10 veterinary colleges identified dogs and cats diagnosed with PPN between 2010 and 2015. Each patient's radon exposure was determined by matching the patient's zip code with published county radon exposure risk. County level PPN rates were calculated using the average annual county cat and dog populations. The PPN counts per 100 000 dog/cat years at risk (PPN rates) were compared across radon zones for each species. RESULTS: The PPN rate ratio in counties in high radon zone (1) was approximately 2-fold higher than in counties in lower radon zones for dogs (rate ratio zone 1 to 2, 2.49; 95% confidence interval [CI], 1.56-4.00; rate ratio zone 1 to 3, 2.29; 95% CI, 1.46-3.59) and cats (rate ratio zone 1 to 2, 2.13; 95% CI, 0.95-4.79; zone 1 to 3, 1.81; 95% CI, 0.9-3.61). CONCLUSIONS AND CLINICAL IMPORTANCE: Exposure to household radon might play a role in development of PPN in dogs and cats.

Post-chemotherapy perforation in cats with discrete intermediate- or large-cell gastrointestinal lymphoma.

Objectives Gastrointestinal (GI) perforation is a well described complication of GI lymphoma in people, commonly occurring within days of initiation of chemotherapy. There are no studies documenting the prevalence of GI perforation in cats with intermediate- or large-cell GI lymphoma or whether it is associated with induction of chemotherapy. The objectives of this study were to document the prevalence and timing of post-chemotherapy perforation in cats with discrete GI masses caused by intermediate- or large-cell lymphoma. Methods Cats with a diagnosis of intermediate- or large-cell lymphoma based on cytologic or histopathologic examination of a mass lesion of the GI tract and treated with chemotherapy were identified by searching the patient record database of three large specialty referral hospitals. Cats undergoing surgical resection of a GI mass prior to chemotherapy were excluded from the study. A clinical diagnosis of GI perforation was made using ultrasound findings and analysis of abdominal fluid. Results Twenty-three cats with intermediate- (n = 3) or large-cell (n = 20) lymphoma were included in the study. GI perforation was confirmed in 4/23 cats (17%), and occurred at 23, 56, 59 and 87 days after induction. There was no association between tumor size, the presence of hypoproteinemia or suppurative inflammation within the mass at the time of diagnosis and subsequent perforation. Post-hoc analysis revealed that the magnitude of weight loss within 15-28 days of diagnosis was greater in cats with perforation. Conclusions and relevance In this pilot study, we found that post-chemotherapy GI perforation in cats with intermediate- or large-cell GI lymphoma occurs. Acute perforation after induction of chemotherapy was not documented. Larger prospective studies are needed to determine risk factors associated with perforation and whether surgical excision would reduce the risk of subsequent GI perforation in these patients.

SD-1029 inhibits signal transducer and activator of transcription 3 nuclear translocation.

PURPOSE: Signal transducer and activator of transcription 3 (Stat3) proteins have important roles in cancer cell survival and proliferation. Recent studies show that aberrant Stat3 activation promotes tumor growth and survival in several human cancers, and thus, presents an attractive pathway for the development of targeted anticancer therapy. Stat3 is a DNA-binding transcription factor, and thus, its function depends on cytoplasmic to nuclear translocation. To discover novel inhibitors of the Stat3 signaling pathway, we designed a cell-based screening assay capable of identifying compounds that inhibit Stat3 nuclear translocation and activity. EXPERIMENTAL DESIGN: Cell-based fluorescence microscope screening and quantitative measurement of enhanced green fluorescent protein-Stat3 nuclear translocation assays were used to identify novel Stat3 inhibitors. The effects of identified Stat3 inhibitors on Janus kinase (Jak), Stat3 expression, and activation were determined by Western blotting and kinase in vitro autophosphorylation assay. The effects of identified Stat3 inhibitors on cell growth was evaluated by cell proliferation assay and apoptosis assay. RESULTS: Among the National Cancer Institute Diversity set, a 2,000-member library of bioactive small molecules, we identified SD-1029 as a micromolar inhibitor of IL-6 or oncostatin-induced Stat3 nuclear translocation. Biochemical analysis shows that SD-1029 inhibits tyrosyl phosphorylation of Stat3 implicating SD-1029 as an inhibitor of Jak. Further analysis shows that this compound inhibits tyrosyl phosphorylation of the Jak2 isoenzyme. The antiapoptotic proteins Bcl-X(L) and survivin, target proteins of activated Stat3, are down-regulated by SD-1029 resulting in the induction of apoptosis in several human breast and ovarian cancer cell lines. SD-1029 also enhances apoptosis induced by paclitaxel in ovarian cancer cells. CONCLUSIONS: These results show that SD-1029 directly abrogates the Jak-Stat3 signaling pathway in human cancer cells expressing constitutively active Stat, and add to the growing literature that validates this pathway as a viable target for further drug development. Finally, SD-1029 may represent a suitable prototype for structural optimization and exploration as a therapeutic lead.

Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer.

PURPOSE: One of the major obstacles in the treatment of ovarian cancer is the development of multidrug resistance. Recent evidence shows that high-grade ovarian cancer often shows activation of the signal transducers and activators of transcription 3 (Stat3) pathway with subsequent transcription of genes that support tumor growth and survival. Less studied is the role of the Stat3 pathway in acquired drug resistance. There is no information on Stat3 expression in chemotherapy naïve ovarian cancer as compared with tumors collected later in the natural history of the disease. To further clarify the significance of Stat3 activation in ovarian cancer, here we investigated the Stat3 expression and activation in ovarian cancer and ovarian cancer multidrug resistance cell lines. EXPERIMENTAL DESIGN: Western blotting, electrophoretic mobility shift assay, luciferase assays, ELISA assay, and real-time reverse transcription-PCR determined interleukin-6 and Stat3 pathway expression and activation in cell lines. Stat3 expression in ovarian cancer tissue microarray was evaluated by immunohistochemistry. RESULTS: Activated (phosphorylated) Stat3 is overexpressed in most paclitaxel-resistant ovarian cancer cells. Inhibition of Stat3 activation results in significant decreases in paclitaxel resistance and enhanced apoptosis. Drug-resistant recurrent tumors have significantly greater phosphorylated Stat3 (pStat3) expression as compared with matched primary tumors. Tumors with associated inflammatory cell infiltrates also have a higher proportion of cells staining intensely for nuclear phosphorylated Stat3 as compared with tumors without inflammatory infiltrates, consistent with paracrine activation of the Stat3 pathway by immune-mediated cytokines. CONCLUSIONS: These data support the hypothesis that interruption of Stat3 signaling could reverse resistance to paclitaxel and perhaps other chemotherapy agents in human cancer.

Chemosensitization to cisplatin by inhibitors of the Fanconi anemia/BRCA pathway.

Cisplatin resistance occurs, at least in part, through the function of the Fanconi anemia (FA)/BRCA pathway, a DNA-damage response pathway required for repair of cisplatin cross-links. In the current study, we designed a cell-based screening strategy to identify small-molecule inhibitors of the FA/BRCA pathway with the hypothesis that such molecules could restore sensitivity to platinum agents. We identified four inhibitors, including three protein kinase inhibitors (wortmannin, H-9, and alsterpaullone) and one natural compound (curcumin) that inhibit the FA/BRCA pathway. We show that curcumin, a compound that is generally regarded as safe, inhibits the monoubiquitination of the FANCD2 protein as predicted by the screen and consequently sensitizes ovarian and breast tumor cell lines to cisplatin through apoptotic cell death. We believe that this study shows an efficient, high-throughput method for identifying new compounds that may sensitize cancer cells to DNA-damaging chemotherapy.

8-benzyl-4-oxo-8-azabicyclo[3.2.1]oct-2-ene-6,7-dicarboxylic acid (SD-1008), a novel janus kinase 2 inhibitor, increases chemotherapy sensitivity in human ovarian cancer cells.

Interleukin 6 and the signal transducer and activator of transcription (STAT) 3 proteins have important roles in cancer cell survival and proliferation. Recent studies demonstrate that abnormal STAT3 activation promotes tumor growth and supports survival of many human cancers, and thus, this protein or the pathway responsible for its activation is a potential target for the new anticancer therapy. STAT3 is a DNA binding transcription factor, and therefore, its function depends on nuclear translocation. To discover inhibitors of the STAT3 pathway, we designed a cell-based screening assay capable of identifying small molecules that inhibit nuclear translocation. Among the 2000-compound National Cancer Institute Diversity set, we identified 8-benzyl-4-oxo-8-azabicyclo[3.2.1]oct-2-ene-6,7-dicarboxylic acid (SD-1008) as a micromolar inhibitor of interleukin-6 or oncostatin-induced STAT3 nuclear translocation. In addition, SD-1008 inhibits tyrosyl phosphorylation of STAT3, Janus kinase 2 (JAK2), and Src. SD-1008 also reduces STAT3-dependent luciferase activity. Biochemical studies with recombinant JAK2 proteins demonstrate that high concentrations of SD-1008 directly inhibit JAK2 kinase autophosphorylation. Exposure of various cell lines to SD-1008 decreases levels of the STAT3-dependent proteins, Bcl-X(L) and survivin, inducing apoptosis. SD-1008 also enhances apoptosis induced by paclitaxel in ovarian cancer cells. These results demonstrate that SD-1008 directly blocks the JAK-STAT3 signaling pathway in human cancer cells that express constitutively active Stat and add to the growing literature that identifies this pathway as a viable target for drug development. Finally, SD-1008 may be a suitable prototype for further chemical modification and exploration as a therapeutic agent.

Reclassification of a tubal leiomyosarcoma as an eGIST by molecular evaluation of c-KIT.

BACKGROUND: Extragastrointestinal stromal tumors (eGISTs) are rare mesenchymal-derived tumors arising outside of the GI tract. eGISTs are often histologically confused with leiomyosarcoma. Distinction between eGIST and leiomyosarcoma is critical because of the unique responsiveness of eGISTs to the molecularly targeted agent imatinib. CASE: A woman presented with a history of tubal spindle cell tumor that was initially diagnosed and treated as a leiomyosarcoma. Because of minimal response to sarcoma directed chemotherapy, the possibility that the tumor was in fact an eGIST was investigated and supported by immunohistochemical and mutational analyses of the c-Kit receptor tyrosine kinase. The patient currently has stable disease control on imatinib for the last 18 months. CONCLUSIONS: The possibility of eGIST should be considered in the differential diagnosis of tumors with a spindle cell morphology in the gynecologic tract especially when involving the ovary, fallopian tube, or uterine serosa.