tbuckley/cabot-search huggingface dataset:
Ductal carcinoma in situ and <i>BRCA</i> mutations: Association and risk factors
Authors: K. L. Smith, M. Adank, N. Kauff, K. Lafaro, J. Boyd, J. Lee, C. Hudis, K. Offit, M. Robson
Journal: Journal of Clinical Oncology (2006)

10016 Introduction: Ductal carcinoma in situ (DCIS) has been associated with BRCA mutations. Factors associated with the presence of mutations are not well defined. Methods: BRCA founder mutation status was determined in 3 groups of women with DCIS: 1) a prevalent convenience sample of Ashkenazi Jewish (AJ) women (Sukumvanich SSO 2005), 2) an incident cohort of AJ women ascertained before breast surgery and 3) a clinical ascertainment of probands (P) with DCIS (53 AJ and 38 non-AJ) presenting to a cancer risk assessment service. For women in groups 1 and 2, BRCA founder mutation status was also determined in age-matched controls with invasive breast cancer (BC). Results: Within the prevalent ascertainment, 3/62 (4.8%) women with DCIS and 15/130 (11.5%) controls with invasive BC had BRCA mutations. In the incident cohort, 0/58 (0%) women with DCIS and 6/116 (5.2%) controls with invasive BC had BRCA mutations (combined OR 3.6, 95% CI 1.1–12.5, p 0.04). In the clinical ascertainment of AJ women with DCIS, mutations were identified in 4/35 (11.4%) P ≤ 50 yrs at dx and in 2/18 (11.1%) P &gt; 50 yrs. The proportion of AJ P with mutations based on family history (FH) of BC and ovarian cancer (OC) is shown in the table. In AJ P with DCIS, FH of OC is strongly associated with BRCA mutations (adjusted OR 10.0, 95% CI 1.1–89.3, p 0.04). Among non-AJ P, no mutations were identified without a FH of OC or BC ≤ 50 yrs at dx. Conclusions: DCIS is associated with BRCA mutations in AJ women, but the prevalence is lower than in women with invasive cancer. FH of OC is a strong risk factor. [Table: see text] No significant financial relationships to disclose.
Elevated Levels of p53 Antigen in Cultured Skin Fibroblasts From Patients With Hereditary Adenocarcinoma of the Colon and Rectum and Its Relevance to Oncogenic Mechanisms<xref ref-type="fn" rid="FN2">2</xref>
Authors: L Kopelovich, A B DeLeo
Journal: JNCI Journal of the National Cancer Institute (1986)

Skin fibroblasts (SFs) from patients with adenomatosis of the colon and rectum (ACR) were shown, in general, to express elevated amounts of the p53 antigen as determined by immunoprecipitation with the monoclonal antibody PAb421. Infection with simian virus 40 (SV40) induced expression of the p53 antigen in SFs from normal individuals and further amplified its expression in ACR cells. The half-lives of the p53 antigen in mock-infected ACR cells and in SV40-transformed normal or ACR cells were about 2 and 15 hours, respectively. No immediate differences were detected in the coding segment of the human p53 gene between normal and ACR cells by either Southern or Northern blot analysis. These results suggest that over-expression of the p53 antigen is due, in part, to the increased stability of the p53 antigen in ACR cells. Over-expression represents an early event that is possibly associated with initiation and promotion of inherited colon cancer.
The novel flightless-I gene brings together two gene families, actin-binding proteins related to gelsolin and leucine-rich-repeat proteins involved in Ras signal transduction.
Authors: C Claudianos, H D Campbell
Journal: Molecular Biology and Evolution (1995)

The Drosophila melanogaster gene flightless-I, involved in gastrulation and muscle degeneration, has Caenorhabditis elegans and human homologues. In these highly conserved genes, two previously known gene families have been brought together, families encoding the actin-binding proteins related to gelsolin and the leucine-rich-repeat (LRR) group of proteins involved in protein-protein interactions. Both these gene families exhibit characteristics of molecular changes involving replication slippage and exon shuffling. Phylogenetic analyses of 19 amino acid sequences of 6 related protein types indicate that actin-associated proteins related to gelsolin are monophyletic to a common ancestor and include flightless proteins. Conversely, comparison of 24 amino acid sequences of LRR proteins including the flightless proteins indicates that flightless proteins are members of a structurally related subgroup. Included in the flightless cluster are human and mouse rsp-1 proteins involved in suppressing v-Ras transformation of cells and the membrane-associated yeast (Saccharomyces cerevisae) adenylate cyclase whose analogous LRRs are required for interaction with Ras proteins. There is a strong possibility that ligands for this group could be related and that flightless may have a similar role in Ras signal transduction. It is hypothesized that an ancestral monomeric gelsolin precursor protein has undergone at least four independent gene reorganization events to account for the structural diversity of the extant family of gelsolin-related proteins and that gene duplication and exon shuffling events occurred prior to or at the beginning of multicellular life, resulting in the evolution of some members of the family soon after the appearance of actin-type proteins.
Lysis of Feline Lymphoma Cells by Complement-Dependent Antibodies in Feline Leukemia Virus Contact Cats. Correlation of Lysis and Antibodies to Feline Oncornavirus-Associated Cell Membrane Antigen 2
Authors: Chris K. Grant, M. Essex, N. C. Pedersen, W. D. Hardy, J. R. Stephenson, S. M. Cotter, G. H. Theilen
Journal: JNCI Journal of the National Cancer Institute (1978)

Sera were collected from normal cats, from cats exposed to feline leukemia virus (FeLV) infection, and from sick animals including many with leukemias and lymphomas. In blind studies, the sera (346 samples) were tested 1) for lytic antibodies, with the use of cat complement in a 20-hour 51Cr-release test, and 2) for antibodies to feline oncornavirus-associated cell membrane antigen (FOCMA) by the membrane immunofluorescence test. In both assays the target cells were FL74, a cat lymphoblastoid line which replicates FeLV. Correlation of presence or absence of antibodies detected by both tests was 91% overall and 100% for the 93 samples that contained lytic antibody predominantly at a titer of ≥1:25 and anti-FOCMA antibody at a titer of ≥1:16. Complement-dependent and anti-FOCMA antibodies were detected in sera from viremic cats; by radioimmunoprecipitation, these sera did not contain detectable antibodies to either the major envelope or core proteins of FeLV (gp70 and p30), nor did they contain antibodies to the endogenous cat “oncornavirus” RD114. Immune sera that lysed FL74 target cells, which replicate A-, B-, and C-virus subgroups, also lysed F422 cells, which replicate only A-subgroup virus. Complement-dependent antibodies were detected in sera from laboratory-bred normal cats only after contact exposure to cats infected with FeLV; lytic antibodies appeared between 8 and 32 weeks after exposure commenced. Appearance of lytic antibody coincided with first evidence in blood smears of virus infection, and prolonged high antibody titers were maintained, whether or not the leukemia virus infection persisted. The incidence of detection of complement-dependent antibodies was ≤2% in sera from cats maintained in controlled FeLV-free environments, 25% in sera from a randomized sampling of privately owned cats, 36–45% in sera from virus-infected cats of leukemia-cluster households, and 8% in sera from cats with leukemia or lymphoma. Exposure of cats to horizontal FeLV infection induced antibodies that lysed cat lymphoma cells slowly with cat complement; these antibodies were similar to anti-FOCMA antibodies, which have a proved antitumor and immune surveillance function in vivo.
Content and method of parental disclosure of genetic risk to young adult and minor children in <i>BRCA</i> families
Authors: K. Pawlowski, L. Patrick-Miller, C. K. Daugherty, O. I. Olopade, J. J. Dignam, C. N. Ibe, F. J. Hlubocky, S. A. Cummings, M. A. White, L. Dudlicek, A. R. Bradbury
Journal: Journal of Clinical Oncology (2007)

1536 Background: Prior research has found that many BRCA mutation carriers report discussing their genetic test results with their minor children. The content, method and process of this communication have not been previously described. Methods: 20 parents (yielding 42 parent-offspring pairs, POP) have completed a 62-item questionnaire regarding the content and methods of communication of genetic risk to offspring. Results: Of 19 (45%) POP where parents reported disclosure of their BRCA mutation to offspring in response to a binary (yes/no) question, all reported telling their children about the genetic mutation itself, as well as the parents’ risk for cancer. In 74% of POP the offspring’s chance of inheriting the mutation or risk for cancer were said to have been communicated. In 53% of POP parents reported discussion of parental risk reduction measures, and in only 37% of POP parents reported communication of offspring risk reduction measures. Of the POP where parents reported some communication of cancer risk, 22% described incorporating written materials. In 75% of POP parents reported communication through multiple conversations over time (1 -20 conversations, up to 4 years). Conclusions: Although many BRCA carriers report discussing their genetic mutation with offspring, the content and extent of parental communication is variable, often including information regarding the genetic mutation, but less frequently the offspring’s risk of inheriting the gene and infrequently communication regarding risk reduction measures. Further research on this expanding cohort will allow for analyses of parent and child factors associated with disclosure content in order to guide the development of interventions to facilitate age and content-appropriate communication of genetic risk to at-risk offspring. No significant financial relationships to disclose.
Lymphokine-activated human blood monocytes destroy tumor cells but not normal cells under cocultivation conditions.
Authors: I J Fidler, E S Kleinerman
Journal: Journal of Clinical Oncology (1984)

The possibility that tumoricidal human blood monocytes would recognize and destroy tumorigenic targets but leave bystander nontumorigenic cells unharmed was investigated. Highly purified preparations of peripheral blood monocytes isolated from normal human donors were activated in vitro by incubation with human lymphokines encapsulated in multilamellar liposomes. The cytotoxic properties of these monocytes against several tumorigenic and nontumorigenic allogeneic target cell populations were assessed by an in vitro radioisotope-release assay. Various combinations of three tumorigenic and three nontumorigenic target-cell populations, labeled with either [3H]thymidine or [14C]thymidine, were mixed and plated onto monolayers of blood monocytes. In all combinations used, activated monocytes specifically lysed only allogeneic neoplastic cells. At least in vitro, activated human blood monocytes can recognize and selectively destroy neoplastic cells.
Poisoning from OEnanthe Crocata
Authors: J. G. Appleton
Journal: BMJ (1861)

Over a 1-month period all patients arriving in the accident and emergency department by ambulance following a 99999 call were questioned using a standard proforma. They were assessed as to whether their medical condition warranted ambulance transfer. A number of social and practical points were analyzed to see whether they would identify any group of patients who used the emergency service without medical need. Overall 289 patients were questioned. Of these 178 (62%) were considered to have medically warranted an ambulance call whereas 111 (38%) did not. A number of features which were more likely to result in an unjustified call were identified. These would suggest that basic knowledge of first aid by the public is poor and should be improved.
Three pairs of alkaloid enantiomers from the root of Isatis indigotica
Authors: Yufeng Liu, Xiaoliang Wang, Minghua Chen, Sheng Lin, Li Li, Jiangong Shi
Journal: Acta Pharmaceutica Sinica B (2016)

Three pairs of enantiomerically pure alkaloids with diverse structure features, named isatindigoticoic acid A and epiisatindigoticoic acid A [(−)-1 and (+)-1], phaitanthrin A and epiphaitanthrin A [(−)-2 and (+)-2], and isatindopyrromizol A and epiisatindopyrromizol A [(−)-3 and (+)-3], respectively, were isolated from an aqueous extract of the roots of Isatis indigotica. Racemic and scalemic mixtures of these enantiomers were separated by HPLC on a chiral semi-preparative column. Their structures including absolute configurations were determined by extensive spectroscopic analysis in conjunction with the calculation of electronic circular dichroism (ECD) spectra. The enantiomer pairs possess parent structures of 2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylic acid, indolo[2,1-b]quinazolinone, and 3-thioxohexahydro-1H-pyrrolo[1,2-c]imidazol-1-one, respectively. Except for phaitanthrin A [(−)-2] which the configuration was previously undetermined, these compounds are new enantiomeric natural products.
Double combination therapy in patients with pulmonary arterial hypertension associated with connective tissue disease
Authors: Enrico Gotti, Enri Leci, Alessandra Manes, Massimiliano Palazzini, Elena Beciani, Elisa Conficoni, Nicole Rizzo, Francesca Terzi, Gaia Mazzanti, Francesca Sciarra, Nazzareno Galiè
Journal: European Respiratory Journal (2011)

Background: Pulmonary arterial hypertension associated with connective tissue disease (PAH-CTD) is a severe and progressive condition despite the availability of 3 specific classes of drugs: prostanoids (PROST), endothelin receptor antagonists (ERA) and phosphodiesterase-5 inhibitors (PDE5-I). Combination therapy (CT) has been proposed for patients with unsatisfactory response to monotherapy.

Aim: To examine the effect of double CT in patients with PAH -CTD who do not achieve an adequate clinical response on monotherapy.

Methods: Between October 1999 and December 2010, 48 PAH-CTD patients in WHO functional class III treated with monotherapy were included. At baseline and after 5±5 months on CT, all patients underwent 6-minute walk test (6MWT) and right-heart catheterization.

Results: Mean age was 58±14 years, 85% females. Mean time from initiation of monotherapy to initiation of CT was 18±20 months. Forty (83%) patients received ERA+PDE5-I, 5 (10%) received PDE5-I+PROST and 3 (7%) received ERA+PROST. Four (8%) patients died before CT assessment. The table shows the haemodynamic and functional changes after CT.

View this table:



Conclusions: CT in CTD-PAH patients improves exercise capacity and haemodynamics. However 8% of patient die after an average of 3.2±1.5 months of CT testifying the persistent severity of the condition.
Dasatinib and docetaxel combination treatment for patients with castration-resistant progressive prostate cancer: A phase I/II study (CA180086)
Authors: J. Araujo, A. J. Armstrong, E. L. Braud, E. Posadas, M. Lonberg, G. E. Gallick, G. C. Trudel, P. Paliwal, S. Agrawal, C. J. Logothetis
Journal: Journal of Clinical Oncology (2009)

5061 Background: Dasatinib, a potent inhibitor of SRC family kinases, inhibits in vitro prostate cancer cell proliferation and migration. Consistent with those findings are the clinical observations that osteoclast activity and bone turnover are downregulated in patients treated with dasatinib. We report promising preliminary results of dasatinib in combination with docetaxel (D) for treatment of metastatic castration-resistant prostate cancer (CRPC). Methods: Male pts with progressive CRPC and castrate levels of testosterone (≤50 ng/dL) requiring chemotherapy were enrolled. Escalating doses of dasatinib (50–120 mg QD) and D (60–75 mg/m 2 Q 21 days) were evaluated (n = 16) followed by enrollment of 30 pts at the phase 2-selected dose (100 mg dasatinib QD + D at 75 mg/m 2 Q 21 days). Continuation of bisphosphonates was permitted; anti-androgens were discontinued. Primary endpoint (Ph. 2) was to determine drug-drug interactions. Secondary endpoints were: changes in PSA, bone scans and tumor size, bone metabolism [urinary N-telopeptide (uNTX) and bone alkaline phosphatase (BAP)] and PK. Results: 46 pts were treated with 28 pts still on therapy. Median treatment duration (n = 18, pts off study) was 4.2 months (0.13–9.63). Preliminary analysis showed no interaction between dasatinib and D. PSA response was seen in 13/32 (41%) pts, clinical benefit (PR + SD) for RECIST-evaluable pts was 21/21, [7 PR, 5 uPR and 4 SD (at ≥21 wks) and 5 SD at ≥6 wk)]. Of 31 pts with bone scans, 30 patients had a best response of either improved (32%) or stable (65%) at ≥6 weeks. For pts with measurable bone markers levels, 12/26 (46%) had a ≥35% decrease in uNTX and 17/24 (71%) had a decrease in BAP from baseline. 6 of 42 pts experienced ≥ grade 3 adverse events (AEs), including fatigue, myelosuppression and pleural effusion (n = 1). Most common grade 1/2 AEs were fatigue, dysgeusia, GI, and skin disorders. Conclusions: Dasatinib and D at doses up to 120 mg QD and 75 mg/m 2 are safe with manageable toxicities and no drug-drug interactions. These data confirm the antitumor and antiosteoclast activity of dasatinib in combination with D and serve as the basis for the ongoing phase III study of this combination. [Table: see text]
The Spectrum of Neurogenic Tumors of the Sympathetic Nervous System: Maturation and Adrenergic Function
Authors: Lazar J. Greenfield, William M. Shelley
Journal: JNCI Journal of the National Cancer Institute (1965)

The spontaneous maturation of fully malignant neuroblastomas to benign ganglioneuromas has been observed sporadically since the now famous case of Gushing and Wolbach reported in 1927. More recently, tumors of the neuroblastoma family have been observed to produce significant amounts of catechol amines resulting in hypertensive or diarrheal syndromes. The present study reviews all the cases belonging to this group of tumors seen at The Johns Hopkins Hospital and selected only on the basis of availability of histologic material and follow-up information. Of the 66 cases, 30 showed clear evidence of maturation. Of these 30, 11 had completed the maturation to the structure of benign ganglioneuroma. The maturation phenomenon is judged to be the single most important factor influencing the clinical behavior of the tumor. Maturation correlates directly with surgical resectability and eventual salvage. Examples of dramatic responses to X ray and/or nitrogen mustard therapy in the immature and clinically inoperable group are cited. Maturation to ganglioneuroma is observed at the sites of metastasis. The observations correlate very well with recently reported in vitro studies. Ten of the 66 cases showed clinical evidence of significant catechol amine production. This phenomenon is observed in the entire spectrum of tumors and does not correlate apparently with morphologic maturity.
A randomized crossover trial of venlafaxine (V) versus gabapentin (G) for hot flashes (HF) in breast cancer survivors.
Authors: L. Bordeleau, O. Jugovic, M. Ennis, K. I. Pritchard, D. Warr, R. Haq, C. L. Loprinzi, P. J. Goodwin
Journal: Journal of Clinical Oncology (2010)

9023 Background: Nonhormonal pharmacologic interventions are recommended for the treatment of HF in breast cancer survivors. Antidepressants (SSRI/SNRI) and G have been shown to be effective, however, it is still unclear which agent is best. Methods: A randomized crossover trial compared 4 weeks of V (37.5 mg × 7 days followed by 75 mg/day) and G (300 mg daily × 3 days, 300 mg BID × 3 days then 300 mg TID). Eligibility included postmenopausal women with at least 14 bothersome HF per week for the prior month. A 2-week baseline period was followed by the first treatment period. Crossover to the alternative treatment occurred following a 2 week dose tapering/wash out period. The primary endpoint was patient preference. Secondary endpoints included change from baseline in HF score (frequency × severity) per a prospective daily HF diary, change in HF frequency, QOL, mood and toxicity. Toxicities were evaluated with a self-report questionnaire and NCI common terminology criteria. A two-stage group sequential design was used with the first analysis pre-planned at 66 patients and the second (if needed) at 131, allowing for drop out/indecision rate of 25%. The design had 80% power to detect a shift from equal preference of ≥ 15 % (2 sided type 1 error at 5%). Results: Data analysis after 66 patients showed the pre-defined stopping rule was satisfied. The study arms were well balanced. Of 56 patients with a preference (8 dropped out and 2 had no preference), 18 preferred G and 38 preferred V (32% and 68% respectively; p = 0.01). Both V and G reduced HF scores (66% reduction) and frequency (55% reduction) similarly and significantly. Satisfaction with the preferred treatment was high. V was associated with more appetite loss, nausea and constipation, and less sleeplessness, nervousness, and negative mood changes than at baseline (all p ≤ 0.03) whereas G was associated with more dizziness and increased appetite, and less sleeplessness (all p ≤ 0.004). Conclusions: Breast cancer survivors prefer V over G for the treatment of HF. Both agents are effective in the management of HF based on recorded diary experience. Preference appears to be driven by the balance between effectiveness and tolerance. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, GlaxoSmithKline, Novartis, Roche Amgen, AstraZeneca, GlaxoSmithKline, Novartis, Roche AstraZeneca
Expression of EGFR, VEGF, and K-ras mutation as predictors for response of cetuximab in colorectal cancer patients
Authors: D. Hwang, E. Jung, S. Cho
Journal: Journal of Clinical Oncology (2009)

e15147 Background: Cetuximab has been effective in metastatic colorectal cancer (CRC) patients. EGFR is involved in CRC through its downstream signaling pathways, including RAS and MAKP pathway and angiogenesis. We evaluated the predictive value of EGFR and VEGF expressions and K-ras mutation status in colorectal cancer patients treated with cetuximab in combination with chemotherapy Methods: Our study included 29 CRC patients treated with cetuximab in combination with chemotherapy (20 patients with FOLFIRI and 5 patients with FOLFOX, and 4 patients with monotherapy). Paraffin blocked tumor tissues were analyzed for EGFR and VEGF expression using quantitative real time PCR and K-ras mutation status (codons 12 and 13) using direct sequencing. Results: 12 patients (43%) had a partial response (PR) and 6 patients (21%) with stable disease (SD) and 11 patients (38%) with progressive disease (PD). EGFR expression was not correlated with the response of cetuximab (p=0.60) The median EGFR expression level was 0.30 x 10 -3 in PR and 0.25 x 10 -3 in SD and 0.26 x 10 -3 in PD. High VEGF expression was associated with the response of cetuximab (p=0.03). The mean VEGF expression level was 4.3 x 10 -3 in PR and 1.64 x 10 -3 in SD and 1.72 x 10 -3 in PD. A K-ras mutation was present in 45 % (13/29) and did not significantly correlated with non-response of cetuximab (p=0.05). A K-ras mutation was detected 33% (4/12) in PR and 33% (2/6) in SD and 70 % (7/10) in PD. Conclusions: VEGF expression in tumor may be a potential predictor for the response of cetuximab. But EGFR expression and K-ras mutation status is not significantly correlated with clinical outcome of cetuximab. And a K-ras mutation is found in the response group. [Table: see text]