tbuckley/cabot-search huggingface dataset:
Phase I study of sequential targeted gene delivery: Intravenous infusions of Rexin-G followed by Reximmune-C induce tumor necrosis and recruitment of tumor infiltrating lymphocytes in cancerous lesions
Authors: G. H. Cornelio, C. C. Lorenzo, F. F. Lopez, F. L. Hall, E. M. Gordon
Journal: Journal of Clinical Oncology (2008)

3077 Background: Rexin-G and Reximmune-C are pathotropic nanoparticles bearing a cytocidal cyclin G1 gene and a granulocyte- macrophage colony stimulating factor (GM-CSF) gene respectively. The purpose of the Phase I study is to evaluate the safety and therapeutic potential of i.v. infusions of Rexin-G followed by Reximmune-C, in an effort to achieve a personalized cancer vaccination in vivo in patients with chemo-resistant solid tumors. Methods: Seven patients received Rexin-G i.v. at a dose of 4 x 10e10 cfu per day for 2 -6 weeks followed by Reximmune-C i.v. at 2.5 x 10e9 cfu or 5 x 10e10 cfu per day for 2 to 5 days (Cumulative Dose: 1.00 -1.25 x 10e10 cfu). Results: There was no dose-limiting toxicity noted and GM-CSF protein was NOT detected in serum samples obtained during and after treatment with Reximmune-C. Immunologic reactions consisted of flu-like symptoms in two patients, redness and swelling of tumor-infiltrated cervical lymph node and metastatic chest nodule in two patients, swelling and acute left-sided flank pain in one patient with adrenal gland metastasis. In 2 cases, GM-CSF-expressing cancer cells were detected, by immunohistochemical staining, in tumors indicating successful targeted delivery in vivo of the GM-CSF gene. In one patient, the GM-CSF-positive cancer cells were surrounded by tumor-infiltrating lymphocytes (TILs), in addition to extensive tumor necrosis. Evaluation of the complement of recruited TILs by selective immunostaining showed significant numbers of both immunoreactive CD8+ killer T cells and CD68+ macrophages. Further, one patient‘s biopsied tumor showed 100% tumor necrosis associated with TILs consisting of CD35+ dendritic cells, CD8+ killer T cells, and CD138+ plasma B cells suggesting a relatively mature immune response. The median progression-free survival was 2 months and the median over-all survival was 5 months. Conclusions: These studies demonstrate that (1) the functionality of the targeted gene delivery platform is profound, (2) the genetic constructs are relatively safe and (3) the potential for a personalized cancer vaccination in vivo using this sequential gene transfer approach is a realistic goal. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Epeius Biotechnologies Corporation Epeius Biotechnologies Corporation Epeius Biotechnologies Corporation
TAP-ing into TIEPPs for cancer immunotherapy
Authors: Rolf Kiessling
Journal: Journal of Clinical Investigation (2016)

Cancer immunotherapy in which cytotoxic T cells (CTLs) target tumor-specific antigens complexed to MHC-I molecules has been used successfully for several types of cancer; however, MHC-I is frequently downregulated in tumors, resulting in CTL evasion. Recently, it has been shown that MHC-Ilo tumors produce a set of T cell epitopes associated with impaired peptide processing (TEIPP) that have potential to be exploited for immunotherapy. TEIPP-specific CTLs recognize tumors defective in antigen presentation machinery (APM) but not those with intact APM. In this issue of the JCI, Doorduljn et al. evaluated thymus selection and peripheral behavior of TEIPP-specific T cells, using a unique T cell receptor (TCR) transgenic mouse model. They demonstrated that TEIPP-specific T cells in TAP-deficient mice have largely been deleted by central tolerance, while the same T cells in WT mice are naive and sustained. The results of this study suggest that TIEPPs have potential to be successful targets for elimination of MHC-Ilo tumors.
Use of Enzyme-Labeled Antibody for Electron Microscope Localization of Lymphocytic Choriomeningitis Virus Antigens in Infected Cell Cultures
Authors: Herbert T. Abelson, Gilbert H. Smith, Harold A. Hoffman, Wallace P. Rowe
Journal: JNCI Journal of the National Cancer Institute (1969)

Horseradish peroxidase-labeled antibody in combination with an in situ fixation and embedding procedure was used to locate viral antigens in infected tissue culture cells. The cytochemical reaction product mediated by the peroxidase-conjugated antibody allowed observation of antigen-antibody sites at both the light and electron microscope levels in the same preparation. Lymphocytic choriomeningitis (LCM) virus-infected 3T3 cells were studied. The electron microscope studies confirmed the morphology of the LCM virion as previously reported and showed that the extracellular virions were intensely stained by the enzyme-labeled guinea pig anti-LCM antibody conjugates. In addition, large cytoplasmic ribosomal aggregates were observed in the LCM-infected cells, and virus-specific antigens were demonstrated to be associated with these structures. Neither the cytoplasmic ribosomal aggregates nor the extracellular virions were stained with normal guinea-pig serum conjugated to horseradish peroxidase. The applicability of this technique for the study of in vitro virus-cell interactions is discussed.
Bexarotene prevents and reverses gemcitabine resistance in non-small-cell lung cancer cells by affecting gene amplification
Authors: T. W. Hermann, W. Yen, P. Tooker, S. Ng, A. Negro-Vilar, W. W. Lamph
Journal: Journal of Clinical Oncology (2006)

2057 Background: Bexarotene (BEX) is a retinoid X receptor selective drug approved for treatment of CTCL and has activity in various cancers. Here we evaluate its effect on acquired drug resistance towards gemcitabine (GEM) in Calu3 NSCLC models. Methods: Parental or GEM-resistant Calu3 NSCLC cells were treated with BEX and GEM as single agents or in combination. Over the treatment course the cells were evaluated for molecular changes (RNA expression and DNA amplification), which were associated with resistance status. Results: Calu3 cells treated with repeated cycles of GEM alone gradually developed resistance to this drug. However, inclusion of BEX prevented the development of resistance and cells remained chemosensitive. Microarray analysis showed a strong increase of rrm1 (ribonucleotide reductase M1) expression in the resistant cells (Calu3-GemR), a gene known to be involved in GEM resistance. In addition, the expression of genes surrounding the chromosomal location of rrm1 was increased suggesting that resistance was due to gene amplification at the 11p15 locus. This was confirmed by analysis of genomic DNA, indicating a 20-fold increase of rrm1 gene copy number. To evaluate BEX’s activity on pre-existing GEM-resistance, Calu3-GemR cells were treated with ten 10-day cycles of vehicle, GEM, BEX, or GEM plus BEX. After 4 treatment cycles the cultures treated with the combination regimen showed a loss in cell numbers, which continued until the end of the 10 th cycle. This indicated a re-sensitization of the Calu3-GemR cells to treatment. The cultures treated with the single drug regimens expanded as the vehicle controls. However, analysis of RNA and DNA samples collected over the treatment course revealed that rrm1 gene amplification was gradually reduced even in the cultures treated with BEX alone, reaching parental levels at the end of the study. As expected from these data, the BEX-treated Calu3-GemR cells were again sensitive to GEM. Conclusions: The data indicate that bexarotene can re-sensitize GEM-resistant tumor cells by reversing gene amplification. This suggests that bexarotene may have general clinical utility in cancers where drug-resistance by gene amplification is a major obstacle to successful therapy. [Table: see text]
A Y-chromosomal DNA fragment is conserved in human and chimpanzee.
Authors: B K Rasheed, E C Whisenant, R Fernandez, H Ostrer, Y M Bhatnagar
Journal: Molecular Biology and Evolution (1991)

A human male-specific Y-chromosomal DNA fragment (lambda YH2D6) has been isolated. By deletion-mapping analysis, 2D6 has been localized to the euchromatic portion of the long arm (Yq11) of the human Y chromosome. Among great apes, this fragment was found to be conserved in male chimpanzee but was lacking in male gorilla and male orangutan. No homologous fragments were detected in females of orangutan, gorilla, chimpanzee, or human. Nucleotide sequence analysis indicated the presence of partial-Alu-elements and of sequences similar to the GATA repeats of the snake Bkm sequence.
Pulmonary embolism after thrombolysis of hemodialysis grafts.
Authors: H F Smits, P P Van Rijk, J W Van Isselt, W P Mali, H A Koomans, P J Blankestijn
Journal: Journal of the American Society of Nephrology (1997)

The aim of this study was to determine the incidence of pulmonary embolization occurring after mechanical or pharmacomechanical percutaneous intravascular thrombolysis in 23 patients with occluded hemodialysis grafts. In all patients, pulmonary perfusion scintigraphy was performed before and immediately after thrombolysis. In eight (35%) of the patients, there was evidence of pulmonary embolism resulting from the interventional procedure; however, in only one was there clinical symptoms. It is concluded that there is substantial risk of pulmonary embolism in patients undergoing percutaneous intravascular thrombolysis for an occluded hemodialysis graft.
Women who regret sterilisation (Letter)
Authors: Alderman B
Journal: BMJ (1977)

In an attempt to compensate for a lack of a control group in R.M.L. Winstons paper concerning women who regret sterilization data are presented from the information gathered on a total of 1081 women sterilized consecutively at the Womens  Hospital at Liverpool.  614 of the 1081 were traced 24-42 months later.  8.8% of the women indicated that they regretted having been sterilized.  The most common reason for regretting the sterilization was a desire to bear children with a new partner.  The age distribution at the time of  the sterilization of patients who subsequently regretted the procedure suggests that sterilization performed at a young age is more likely to lead to regret.  These regrets did not all result in requests for reversal of the procedure which is in accord with Winstons findings.  The association between parity and subsequent regret of the procedure was not as clear.  It would not be wise to refuse young women sterilization although patients sterilized at a young age appear to run an increased risk of regretting their sterilization.  Instead there should be careful counseling of the very young prior to sterilization particularly with a view to predicting the likely divorce.
Macrophages and Dendritic Cells
Authors: Myron I. Cybulsky, Cheolho Cheong, Clinton S. Robbins
Journal: Circulation Research (2016)

Atherosclerosis is a complex chronic disease. The accumulation of myeloid cells in the arterial intima, including macrophages and dendritic cells (DCs), is a feature of early stages of disease. For decades, it has been known that monocyte recruitment to the intima contributes to the burden of lesion macrophages. Yet, this paradigm may require reevaluation in light of recent advances in understanding of tissue macrophage ontogeny, their capacity for self-renewal, as well as observations that macrophages proliferate throughout atherogenesis and that self-renewal is critical for maintenance of macrophages in advanced lesions. The rate of atherosclerotic lesion formation is profoundly influenced by innate and adaptive immunity, which can be regulated locally within atherosclerotic lesions, as well as in secondary lymphoid organs, the bone marrow and the blood. DCs are important modulators of immunity. Advances in the past decade have cemented our understanding of DC subsets, functions, hematopoietic origin, gene expression patterns, transcription factors critical for differentiation, and provided new tools for study of DC biology. The functions of macrophages and DCs overlap to some extent, thus it is important to reassess the contributions of each of these myeloid cells taking into account strict criteria of cell identification, ontogeny, and determine whether their key roles are within atherosclerotic lesions or secondary lymphoid organs. This review will highlight key aspect of macrophage and DC biology, summarize how these cells participate in different stages of atherogenesis and comment on complexities, controversies, and gaps in knowledge in the field.
Understanding decision supports (DS) for women with breast cancer eligible for clinical trials (CT)
Authors: J. Wright, S. Dimitry, J. Sussman, T. J. Whelan
Journal: Journal of Clinical Oncology (2006)

10534 Background: CTs are vital to the development of treatments for patients with cancer, but a low proportion of patients participate in trials, resulting in decreased access to new options. Methods: The study purpose was to explore DS for CT participation decision-making with women diagnosed with breast cancer who were offered a CT. 31 women took part in 6 focus groups - 3 groups of women who consented to a CT, 3 groups who declined a CT. Open-ended questions were asked about specific DS and ideas for new ones. Information rich cases were selected for the sample. Data analyses were conducted by 2 independent coders using a line-by-line, open coding process. Reliability was checked by a 3rd coder. Data was organized with template and editing approaches. Results were compared by group type (declined/consented to CT). Results: Common themes emerged from both group types: too much information is given at the first oncology consult; patients prefer to get CT information from the cancer centre, after their surgery, but prior to their oncology consult; no strong preference about who acts as a DS—family doctor, surgeon, other—as long as good relationship exists; oncologist (to lesser degree surgeon) is seen as most informed about their case; preference for oncologist vs trials nurse to describe CT concept, answer questions, direct them to other information sources; patients doubt family doctors or surgeons have detailed knowledge of CTs, know specific trial data; patients want to feel prepared, know what may happen before they come to oncologist - consult process, CT may be option - to avoid surprise; helpful to know that there is time to make CT decision; other patients are a good source of DS and information. Conclusions: Patients had strong preference to receive information about CTs prior to their consultation with an oncologist; this timing was seen as helpful for decision-making about a CT by both group types. No significant financial relationships to disclose.
Higher versus lower blood pressure targets for vasopressor therapy in shock: a multicentre pilot randomized controlled trial
Authors: François Lamontagne, Maureen O. Meade, Paul C. Hébert, Pierre Asfar, François Lauzier, Andrew J.E. Seely, Andrew G. Day, Sangeeta Mehta, John Muscedere, Sean M. Bagshaw, Niall D. Ferguson, Deborah J. Cook, Salmaan Kanji, Alexis F. Turgeon, Margaret S. Herridge, Sanjay Subramanian, Jacques Lacroix, Neill K.J. Adhikari, Damon C. Scales, Alison Fox-Robichaud, Yoanna Skrobik, Richard P. Whitlock, Robert S. Green, Karen K.Y. Koo, Teddie Tanguay, Sheldon Magder, Daren K. Heyland
Journal: Intensive Care Medicine (2016)
Melatonin to Improve Skin and Sleep in Pediatric Dermatitis
Authors: Anita Slomski
Journal: JAMA (2016)

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Rescue with recombinant Carboxypeptidase G2 (CPG2) in high-dose methotrexate (HD-MTX) induced renal failure: Results in 42 patients from a German emergency protocol
Authors: S. Schwartz, K. Borner, K. Müller, L. Fischer, A. Korfel, T. Atkinson, R. Melton, E. Thiel
Journal: Journal of Clinical Oncology (2004)

8067 Background: Accumulation of MTX in patients (pts.) with renal failure after HD-MTX is a rare, but life-threatening complication. Recombinant CPG2 cleaves MTX into the less toxic metabolite 2,4-diamino-N-pteroic acid (DAMPA) and glutamate. We have conducted an emergency use protocol using CPG2 in pts. with delayed MTX-elimination/renal failure after HD-MTX. Methods: Pts. with MTX serum levels of >5μmol/l at 42h, >1μmol/l at 42h* or >0.4μmol/l at 48h* (* + renal insufficiency: creatinine >1.5 upper limit of normal) after start of HD-MTX (>1g/m2 MTX) were eligible. Pts. with renal insufficiency were also eligible at <42h. Concentrations of MTX and metabolites were measured by high-performance-liquid-chromatography (HPLC) in acidified serum samples. Results: 42 pts. (age: 10–78 years) with lymphoma (29), acute lymphoblastic leukemia (12) or germ cell tumor (1) were enroled. MTX serum levels at registration ranged from 1.01 - 1187.42μmol/l (median: 9.8). CPG2 was given at dosages ranging from 10–58units/kg i.v. at median 55h (range: 27–176h) after start of HD-MTX. Except for skin reaction grade III and fever grade II in one pt. each, CPG2 was well tolerated. Serial serum samples were available for HPLC analysis in 24 pts.. MTX serum levels rapidly declined from a median of 5.11μmol/l (range: 0.35–165.86) to 1μmol/l or less within 7–50 minutes after CPG2 administration. Serum creatinine levels remained normal in 2 pts. and returned to normal values in 21 pts. after a median of 17 days (range: 4–127). The remaining 19 pts. had median peak serum creatinine levels of 283μmol/l which subsequently declined to a median of 150μmol/l by days 1–58 after CPG2. Conclusions: CPG2 is a safe and effective antidote in HD-MTX treated pts. with delayed MTX-clearance/renal failure. Further studies are needed to evaluate the efficacy of CPG2 with respect to clinical endpoints, as well as the role of this novel drug as a standard rescue agent. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Protherics Plc Protherics Plc Enact Pharma PLC and Protherics PLC
Contrasting Frequencies and Effects of<i>cis</i>- and<i>trans</i>-Regulatory Mutations Affecting Gene Expression
Authors: Brian P. H. Metzger, Fabien Duveau, David C. Yuan, Stephen Tryban, Bing Yang, Patricia J. Wittkopp
Journal: Molecular Biology and Evolution (2016)

Heritable differences in gene expression are caused by mutations in DNA sequences encoding cis-regulatory elements and trans-regulatory factors. These two classes of regulatory change differ in their relative contributions to expression differences in natural populations because of the combined effects of mutation and natural selection. Here, we investigate how new mutations create the regulatory variation upon which natural selection acts by quantifying the frequencies and effects of hundreds of new cis- and trans-acting mutations altering activity of the TDH3 promoter in the yeast Saccharomyces cerevisiae in the absence of natural selection. We find that cis-regulatory mutations have larger effects on expression than trans-regulatory mutations and that while trans-regulatory mutations are more common overall, cis- and trans-regulatory changes in expression are equally abundant when only the largest changes in expression are considered. In addition, we find that cis-regulatory mutations are skewed toward decreased expression while trans-regulatory mutations are skewed toward increased expression. We also measure the effects of cis- and trans-regulatory mutations on the variability in gene expression among genetically identical cells, a property of gene expression known as expression noise, finding that trans-regulatory mutations are much more likely to decrease expression noise than cis-regulatory mutations. Because new mutations are the raw material upon which natural selection acts, these differences in the frequencies and effects of cis- and trans-regulatory mutations should be considered in models of regulatory evolution.
A prospective study of non-coplanar conformal radiotherapy for stage I NSCLC using middle-sized fractions
Authors: K. Karasawa, N. Hanyu, M. Kawakami, K. Harada
Journal: Journal of Clinical Oncology (2005)

7280 Background: Recently steretactic radiotherapy for small lung tumors using hypofractionation of 10–20Gy fractions has become very popular throughout the world and the results are very promising. But it has some contraindications for those tumors locating near certain critical organs such as large vessels, esophagus, main bronchus, heart, etc. We have been treating those tumors with relatively low fraction size (3–4Gy/fr) without fixation of the patient. In order to prove the safety and efficacy of non-coplanar 3DCRT for stage I NSCLC with middle fraction size, we analized our data. Methods: Eligibility criteria is as follows; tumor size: 5cm or smaller, V20: 20% or less, PS: 3 or better, and no limitation according to age and respiration status.Between September 1999 and June 2004, 35 patients were treated with this method. Age ranged from 53 to 90 (average 77.3). The sex ratio was 26 to 9. There were 17 patients (18 sites) with T1 tumors and 19 patients (19 sites) with T2 tumors. Seven tumors were SqCCa, 23 were adenoca, and 7 others. The patients were treated with 6 to 10 fixed non-coplanar 6MV photon beam. Average total dose 69.4Gy (range: 59.5 -75Gy). Average overall treatment time was 32.8days (range: 26 - 38). Median follow-up period was 29months (range: 6 - 62 months). Results: Average V20 was 12% (range: 6–20%). Overall 1 and 3-year survival and local control rates were 91%, 75%, 100% and 84% respectively. In patients with T1 tumors, 1 and 3-year survival and local control rates were 87%, 59%, 100% and 91% respectively. In patients with T2 tumors, 1 and 3-yesr survival and local control rates were 94%, 80%, 100% and 79% respectively. Only 3 patients (9%) had grade 2 lung toxicity according to NCI-CTCv2.0. Conclusions: Concerning the status of our patients, non-coplanar 3DCRT for stage I NSCLC is promising with fairly good local control and survival and with acceptable toxicity. Longer follow-up with larger number of patients is necessary. No significant financial relationships to disclose.