tbuckley/cabot-search huggingface dataset:
Advances in targeted alpha therapy for prostate cancer
Authors: G. De Vincentis, W. Gerritsen, J.E. Gschwend, M. Hacker, V. Lewington, J.M. O’Sullivan, M. Oya, M. Pacilio, C. Parker, N. Shore, O. Sartor
Journal: Annals of Oncology (2019)

Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment.
Detection of bcl-2 gene rearrangement in MALT lymphomas from HCV-infected patients
Authors: Massimo Libra, Valli De Re, Annunziata Gloghini, Patrick M. Navolanic, Manuela Indelicato, Maria C. Mazzarino, Anna L. Zignego, Franca Stivala, Antonino Carbone, Mauro Boiocchi
Journal: Cancer Research (2004)

2693  Previously, t(14;18)(q32;q21) has been associated primarily with follicular lymphomas (FLs) whereas t(11;18)(q21;q21) has been associated primarily with MALT lymphomas. However, a novel form of t(14;18)(q32;q21) has been recently reported to occur frequently in MALT lymphomas. This novel translocation differs from t(14;18)(q32;q21) classically associated with FLs in that it fuses IGH with MALT1 instead of bcl-2. It was detected most frequently in MALT lymphomas of the liver, skin, salivary gland, and conjunctiva. Interestingly, each of these anatomical sites are susceptible to hepatitis C virus (HCV) infection. Previous studies have suggested a role for bcl-2 rearrangement in development of lymphoproliferative disorders among patients infected with HCV. However, it remains unclear whether the classical form of t(14;18)(q32;q21) involving fusion of IGH with bcl-2 contributes to development of MALT lymphomas in HCV-infected patients. Tumor biopsy specimens from HCV-infected and HCV-negative MALT lymphoma patients were analyzed by PCR for the presence of bcl-2 rearrangement. Rearrangement of bcl-2 was detected in 4 of 11 (36%) MALT lymphomas from HCV-infected patients, but in only 1 of 9 (11%) MALT lymphomas from HCV-negative patients. All 4 instances of bcl-2 rearrangement detected in tumor biopsy specimens from HCV-infected patients occurred at the MBR. In contrast, the single instance of bcl-2 rearrangement detected among HCV-negative patients occurred at the mcr. Rearrangement of bcl-2 was also detected in 15 of 15 (100%) HCV-negative FL patients, which is consistent with previous studies indicating that bcl-2 rearrangement is present in the majority of FLs. Notably, FLs are infrequent among HCV-infected patients. To investigate whether MALT lymphoma biopsy specimens positive for bcl-2 rearrangement might have had follicular origins, CD10 expression was analyzed. CD10 is usually expressed in FLs both within and between follicles. All MALT lymphomas available for analysis were negative for CD10 expression, which excluded the possibility these tumors were of follicular origin. These data indicate that, in addition to t(11;18)(q21;q21) and t(14;18)(q32;q21) translocations involving MALT1, bcl-2 rearrangement is detectable in MALT lymphomas. Furthermore, MALT lymphomas from HCV-infected patients were more likely to exhibit bcl-2 rearrangement than MALT lymphomas from HCV-negative patients.
Abstract #3958: Role of epidermal growth factor receptor-induced cell cycle progression in radiation sensitization
Authors: Susan Hiniker, Aarif Ahsan, Theodore Lawrence, Mukesh Nyati
Journal: Cancer Research (2009)

Sensitivity of tumor cells to radiation therapy is a critical determinant of outcome in the treatment of many cancers. Recent advances in the field of signal transduction have suggested a key role for the epidermal growth factor receptor (EGFR) in radiation sensitivity. It is a widely accepted principle in radiation biology that there is phase-specific variability in radiation sensitivity; since both EGFR inhibitors and radiation can induce cell cycle arrest, cell cycle status deserves careful consideration in the optimization of combined treatment with EGFR inhibitors with radiation. Furthermore, it is known that even within a single tumor there are areas of proliferating cells as well as resting cells, and their respective responses to EGFR inhibition combined with radiation is unknown. We sought to determine the effects of radiation on resting and logarithmically proliferating cultured cells and found that resting cells are significantly more sensitive to ionizing radiation than logarithmically proliferating cells in culture. We performed cell cycle analysis before and after irradiation in both culture conditions and found that a significantly greater number of G1 cells in confluence-arrested culture progressed through the cell cycle after irradiation than proliferating cells. Because EGFR-ERK signaling has been implicated in G1\#8594;S transition, we analyzed the role of EGFR and extracellular regulated kinase (ERK) in radiation-induced activation of cell cycle progression in confluence-arrested cells. We found that in confluence-arrested cells, EGFR and ERK activation resulted in progression to S-phase. Inhibition of this activation blocked S-phase progression and protected cells from radiation-induced death, the effects being especially pronounced for EGFR inhibition. In a control system using Chinese hamster ovary (CHO) cells, which lack endogenous EGFR expression, exogenously expressed EGFR also became activated in confluence-arrested cells, which led to radiation-induced cell death. Collectively, our data demonstrate a novel phenomenon of radiation-induced increase in cell death in confluence-arrested cells involving the EGFR and ERK pathways. This work may have important implications for the rational design of clinical trials optimizing treatment schedule in the combination of EGFR inhibitors with chemotherapy and radiation therapy.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3958.
Medical Use of Cannabis in 2019
Authors: Kevin P. Hill
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Impact of antithymocyte globulin on new HLA groups for unrelated donor allogeneic stem cell transplantation.
Authors: Yoo Jin Lee, Jong Gwang Kim, Soo Jung Lee, Byung Woog Kang, Yee Soo Chae, Joon Ho Moon, Sang Kyun Sohn
Journal: Journal of Clinical Oncology (2013)

e18017 Background: The outcomes of unrelated donor transplantation have improved with refinements in HLA testing. Recently, grouping of HLA matching for unrelated donor was suggested, defining by well-matched, partially-matched, and mismatched. In the current study, the role of anti-thymocyte globulin (ATG) for each group was evaluated. Methods: A total of 120 patients diagnosed as hematologic diseases and received allogeneic stem cell transplantation (SCT) from unrelated donor were retrospectively analyzed. Results: 28 patients were classified as well-matched, 52 as partially-matched, and 40 as mismatched. Among them, 73 patients received ATG as graft-versus-host disease (GVHD) prophylaxis. The overall survival (OS) rate was higher for well-matched group (82%) compared to partially-matched (53%) and mismatched (34%, p=0.076). For partially-matched group, the OS was significantly improved with ATG (83.3% vs. 38.6%, p=0.018). But, the OS was not different between groups with or without ATG for well-matched (87.5% vs. 66.7%, p=0.487) and mismatched (32.4% vs. 41.7%, p=0.215). ATG decreased the cumulative incidence of grade 3-4 acute GVHD (10% vs. 40.2%, p=0.068) and severe chronic GVHD (21.2% vs. 52.2%, p=0.037). The use of ATG (HR=0.248, p=0.029) was related with favorable OS for partially-matched group. However, the favorable effect of ATG was not observed in well-matched and mismatched groups. Conclusions: ATG effectively improved survival rate for partially-matched group in unrelated donor transplantation. However, the positive effect of ATG was not observed in well-matched and mismatched group.
Transcription is required for active DNA demethylation
Authors: Ana D'Alessio, Ian Weaver, Shelley Brown, Moshe Szyf
Journal: Cancer Research (2007)

1052  A hallmark of vertebrate genes is that actively transcribed genes are hypomethylated in critical regulatory sequences. However the mechanisms that link gene transcription and DNA hypomethylation are unclear. Using a trichostatin A (TSA) induced replication-independent demethylation assay in HEK 293 cells and chromatin immuno-precipitation assays with pertinent histone modification antibodies and bisulfite mapping, we study the temporal and causal relationship between chromatin and active DNA demethylation. We show that RNA transcription is required for DNA demethylation. Histone acetylation precedes but is not sufficient to trigger DNA demethylation. Following histone acetylation, RNA polymerase II (RNAP II) interacts with the methylated promoter. Inhibition of RNAP II transcription with actinomycin D, a-amanitin, or CDK7 siRNA inhibits DNA demethylation. H3 trimethyl lysine 4 methylation, a marker of actively transcribed genes, was associated with the CMV promoter only after demethylation. TSA induced demethylation of the endogenous cancer testis gene GAGE follows a similar sequence of events and is dependent on RNA transcription as well. These data suggest that DNA demethylation follows rather than precedes early transcription and points towards a novel function for DNA demethylation - a memory of actively transcribed genes. We are currently investigating if SWI/SNF chromatin remodeling factors associated with transcription, which have been shown to set a platform for histone eviction by allowing a more open configuration of the chromatin, may favor DNA demethylase access to the DNA.  Supported by a grant from the National Cancer Institute of Canada to MS. Shelley E. Brown is supported by a CIHR fellowship.
Reasons to strike first
Authors: William Buckner, Luke Glowacki
Journal: Behavioral and Brain Sciences (2019)

De Dreu and Gross predict that attackers will have more difficulty winning conflicts than defenders. As their analysis is presumed to capture the dynamics of decentralized conflict, we consider how their framework compares with ethnographic evidence from small-scale societies, as well as chimpanzee patterns of intergroup conflict. In these contexts, attackers have significantly more success in conflict than predicted by De Dreu and Gross's model. We discuss the possible reasons for this disparity.
Reproductive (In)justice — Two Patients with Avoidable Poor Reproductive Outcomes
Authors: Kelly R. Knight, Laura G. Duncan, Marek Szilvasi, Ashish Premkumar, Margareta Matache, Andrea Jackson
Journal: New England Journal of Medicine (2019)

Interview with Dr. Kelly Knight on reproductive injustice and actions clinicians can take to prevent disparities in reproductive health outcomes. (15:58)Download After a stillbirth, a California woman with an opioid use disorder hears clinicians questioning her fitness for reproduction. During a cesarean delivery, a Romani woman in Czechoslovakia is unwittingly sterilized. What can be done to correct such reproductive injustice?
XPO1 Inhibitor Selinexor Overcomes Ibrutinib Resistance in Mantle Cell Lymphoma Via Nuclear Retention of IκB
Authors: Y. Lynn Wang, Mei Ming, Bingqing Xie, Madina Sukhanova, Weige Wang, Sabah Kadri, Shruti Sharma, Jimmy Lee, Sharon Shacham, Yosef Landesman, Natalia Maltsev, Pin Lu
Journal: Blood (2017)
SP0043 Epidemiology of cardiovascular complications in systemic lupus erythematosus
Authors: M Petri
Journal: Annals of the Rheumatic Diseases (2001)

<h3></h3> Cardiovascular complications are increasingly recognised as a major cause of morbidity and mortality in SLE. The incidence of myocardial infarction is elevated 8 to 50-fold compared to age and gender matched controls. Traditional cardiovascular risk factors are increased in SLE, and are associated with both preclinical and clinical atherosclerosis. However, even after adjustment for traditional risk factors, a large difference in the frequency of cardiovascular disease exists between SLE patients and controls. In the general population, atherosclerosis is now recognised as a chronic inflammatory condition, with elevations of C-reactive protein and IL-6. TNF has a role in the pathogenesis of congestive heart failure. These and other inflammatory cytokines likely play a role in SLE. Furthermore, SLE patients are hypercoagulable secondary to antiphospholipid antibodies and other factors. Thus, the pathogenesis of cardiovascular complications in SLE is likely multifactorial, with both SLE and traditional risk factors playing a role.
Individualizing the interval between neoadjuvant chemoradiation with uracil-tegafur (UFT) and total mesorectal excision in magnetic resonance imaging (MRI) defined poor-risk rectal cancer
Authors: B. Sizer, T. Arulampalam, R. Austin, D. Basu, N. Lacey, D. Menzies, R. Motson
Journal: Journal of Clinical Oncology (2007)

14557 Background: The importance of achieving negative circumferential resection margins (CRM) for patients (pts) with MRI - defined poor - risk rectal cancer (PRRC) has led to an increase in the use of pre-operative chemoradiotherapy (CRT) employing long fractionation schedules, usually with an interval of 4 to 6 weeks before surgery. We report our experience of using serial MRI post CRT to optimise the timing of total mesorectal excision (TME) surgery at maximal radiological response for each pt. Methods: Data was collected prospectively from 4/03 to 10/06 on toxicity and response for 50 consecutive patients ( 36 male; median age 64 years, range 39 - 76 years), 47 with biopsy - proven PRRC by MRI criteria (threatened / definite CRM involvement, T3 &gt; 5mm into perirectal fat, T4 tumours, and / or multiple nodes) and 3 pts with localised recurrence after previous anterior resection. Pts received 2 phase, conformal external beam radiotherapy ( 45 - 50.4 Gy / 25 - 28 fractions / 5 weeks), concurrently with their choice of either oral UFT (n = 44, 88%), 240mg/m2/d d 1 - 28 with Leucovorin (LV) 90mg/d or iv bolus 5 FU (n= 6) 300mg/m2 d 1,8,15,22,29 with LV 20 mg/m2). Clinical re-assessment q 2 wkly from 4 weeks post CRT, with serial MRIs 4-weekly, from 6 wks. Results: 48 pts (96%) completed CRT, worst toxicity, diarrhoea Grade 3, 6%. Mean number of MRI scans per pt post CRT 1.48, with response seen in 46 pts (92%), of whom 43 (86%) underwent resection, 27 (63%) of which were performed laparoscopically. Median time to surgery was 11 weeks (range 8 to 15 wks). 37pts (86% of those undergoing surgery) achieved R0 resection, mean CRM 6.1mm, mean no. of identifiable lymph nodes 6.4, most frequent pathology ypT3 pN0 26%, pCR 16%, Tmic, 21%. Surgical morbidities included small bowel adhesions requiring laparotomy 8%, infection/abscess 14%. Post-operative mortality 5%. 1 PRRC pt developed liver metastases prior to surgery. Conclusions: CRT with UFT/LV is well tolerated and effective in achieving substantial tumour regression pre-operatively for PRRC. The optimal timing of surgery post CRT at maximal response can be documented with serial MRI, resulting in a high rate of R0 resections. Laparoscopic TME is feasible in this group of pts. [Table: see text]
The novel lupus antigen protein Acheron promotes breast cancer progression
Authors: Rong Shao, Steven Scully, Wei Yan, Brook Bentley, James Mueller, Lawrence Schwartz
Journal: Cancer Research (2008)

4141  Gene microarray databases have shown that the newly described La protein family member Acheron (Achn) is up-regulated in basal-like breast cancers relative to normal mammary tissue. We sought to determine if Achn expression could exacerbate the malignant properties of breast cancer cells in human. Retroviral constructs were created that encoded wild-type Achn (AchnWT), as well as Achn lacking either its nuclear localization signal (AchnNLS) or its nuclear export signal (AchnNES), fused in frame with enhanced GFP. These constructs were subsequently introduced into a breast cancer line, MDA-MB-231, through retroviral infection. Both AchnWT and AchnNES enhanced cell proliferation and the invasive activity of the engineered cells relative to controls, while ectopic AchnNLS did not have ability to alter these activities. Consistent with the increased invasive behavior, cells expressing either AchnWT or AchnNES expressed elevated levels of active MMP-9 and VEGF. Using an MMP-9 promoter-luciferase reporter system, we found that both AchnWT and AchnNES but not AchnNLS were able to drive luciferase expression, suggesting that nuclear Achn plays a role in MMP-9 transcription. Achn-engineered MDA-MB-231 cells were then injected into 4-week old SCID/Beige mice and the resulting tumors examined over a 7 week period. AchnWT and AchnNES expressing tumors were five-fold larger than those generated from control or AchnNLS expressing cells. Concomitantly, an immunohistological analysis displayed an approximately five-fold increase in expression levels of VEGF in both the AchnWT and AchnNES expressing tumors relative to that seen in the control or AchnNLS tumors. Taken together, these data suggest that nuclear Achn can enhance the metastatic behavior of breast cancer cells in part by altering proliferation, invasion, and angiogenesis at several levels.
A prospective study of BRAF and K-ras mutations in colorectal polyps: location, histologic subtype and clinical relevance
Authors: Kevin J. Spring, Rozemary Karamatic, Michael D. Walsh, Kazutomo Togashi, Mark Appleyard, Tanya Pike, Lisa A. Simms, Joanne Young, Vicki L. Whitehall, Jeremy R. Jass, Barbara A. Leggett
Journal: Cancer Research (2006)

388  Colorectal cancer (CRC) is a leading cause of cancer mortality and is considered a heterogenous disease. The majority of CRCs arise sporadically through the accumulation of genetic alterations and clonal expansion. Approximately 15% of sporadic CRC exhibit high-level microsatellite instability (MSI-H) and are frequently associated with the CpG island methylation phenotype (CIMP). The initiation and progression of sporadic MSI-H cancers is less well understood and may evolve from hyperplastic polyps (HPs). Previously, hyperplastic polyps as opposed to adenomas were considered to have little or no malignant potential, but this view is being increasingly challenged. It has been proposed that a subset of HPs predispose to sporadic MSI-H cancers and progress through an alternate serrated neoplastic pathway involving oncogenic BRAF (V600E) mutation. Recently oncogenic BRAF mutations have been identified in hyperplastic polyps, serrated adenomas (SA) and carcinomas of the colorectum. Both BRAF and K-ras are involved in the MAP kinase signalling pathway, which influences cell differentiation, proliferation, survival and apoptosis. Activation of this pathway may be an early event in the development of sporadic MSI-H cancers from a specific subset of HPs. In this study we investigated prevalence, location, size, and mutation of BRAF and K-ras in all colorectal polyps obtained from an unselected series of colonoscopies. Two hundred patients were recruited for this study and of these 151 had polyps. All polyps were removed and 99% were retrieved for histology and further analysis. 449 polyps from 146 patients were classified by a single pathologist and further analysed for BRAF and K-ras mutations. Polyps were classified as HPs either of goblet cell (GC) or microvesicular (MV) sub-type, serrated adenomas (SAs), sessile serrated adenomas (SSAs), mixed polyps (MPs), tubular adenomas (TAs) and tubulovillous adenomas (TVAs). Polyps were screened for A1796 activating BRAF mutations (V600E) and K-ras codon 12 and 13 mutations using both an allele-specific real-time PCR assay and Sequenom MassARRAY assay. Of these 32% were HPs (consisting of 19% GC and 13% MV sub-type), 1% SAs, 1.5% MPs, 12% SSAs, 50 % TAs and 4% TVAs. The majority of GC- and MV- HPs were distal in location compared with SSAs, SAs and MPs which were mainly proximally located. In SSAs, SAs and MPs BRAF mutations were more highly represented (79%), whereas K-ras mutations were uncommoon (8%). Conversely, BRAF mutation was extremely rare in TAs and TVAs (0.6%). In conclusion the high prevalence of BRAF mutation in proximal serrated polyps (SSAs, SAs and MPs) provides further support for the serrated neoplastic pathway in the development of sporadic MSI-H colorectal cancer.
Disrupted hippocampal growth hormone secretagogue receptor 1α interaction with dopamine receptor D1 plays a role in Alzheimer′s disease
Authors: Jing Tian, Lan Guo, Shaomei Sui, Christopher Driskill, Aarron Phensy, Qi Wang, Esha Gauba, Jeffrey M. Zigman, Russell H. Swerdlow, Sven Kroener, Heng Du
Journal: Science Translational Medicine (2019)

GHSR1α and DRD1 coactivation preserves the integrity of hippocampal synapses in Alzheimer’s disease.