National Institutes Of Health 's National Cancer Institute Research Articles

Incomplete HPV vaccination among individuals aged 27-45 years in the United States: A mixed effect analysis of individual and contextual factors.

10546 Background: In the United States, the Human papillomavirus (HPV) vaccine is approved for use up to age 45. Incomplete HPV vaccination rates among those over age 26, however, remain high. The aim of this study was to examine the independent effects of individual- and neighborhood-level factors on incomplete HPV vaccine series in the United States (US) among those aged 27-45 years. Methods: This retrospective cohort study used administrative data from Optum’s Clinformatics DataMart Database to identify individuals aged 27-45 years who received 1 or more doses of HPV vaccine between July 2019 and June 2022. Multilevel multivariable logistic regression models were applied to the data on 7,662 individuals aged 27-45 years who were fully vaccinated against HPV or not, nested within 3839 neighborhoods across the US. Results: More than half of the participants in this study (52.93%) were not completely vaccinated against HPV. About 64% of the eligible participants aged 27-30 years did not complete their HPV vaccine series. After adjusting for all other covariates in the final model, being older than 30 years old decreased the odds of incomplete HPV vaccine series. Participants living in neighborhoods of South region of the US had enhanced odds of incomplete HPV vaccine series compared to those residing in Northeast region (aOR 1.21; 95% CrI 1.03–1.42). There was significant clustering of incomplete HPV vaccine series at the neighborhood level. Conclusions: This study revealed that individual- and neighborhood-level factors significantly influence HPV vaccination incompleteness in the US. Interventions to improve HPV vaccination uptake and completion should take into consideration both individual- and contextual-level characteristics during design, planning and implementation of policies and programs to improve HPV vaccination coverage and completion in the US and other similar countries. Acknowledgement Dr. Adekanmbi is supported by a research career development award (K12HD052023: Building Interdisciplinary Research Careers in Women’s Health Program-BIRCWH; Berenson, PI) from the National Institutes of Health/Office of the Director (OD), National Institute of Allergy and Infectious Diseases (NIAID), and Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD). Dr. Guo is currently supported by an award (K07CA222343) from the National Institutes of Health, National Cancer Institute (NIH/NCI). Dr. Berenson is supported by an award (PP200048) from the Cancer Prevention and Research Institute of Texas (CPRIT). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or CPRIT. Conflict of Interest: All authors report no conflicts of interest.

MP09-17 PREDICTING INCIDENCE VERSUS MORTALITY FOR CANCERS ASSOCIATED WITH OVERDIAGNOSIS: AN OVERLOOKED ISSUE FOR POLYGENIC RISK SCORES AND CANCER SCREENING

You have accessJournal of UrologyCME1 May 2022MP09-17 PREDICTING INCIDENCE VERSUS MORTALITY FOR CANCERS ASSOCIATED WITH OVERDIAGNOSIS: AN OVERLOOKED ISSUE FOR POLYGENIC RISK SCORES AND CANCER SCREENING Andrew Vickers, Amit Sud, Jonine Bernstein, and Richard Houlston Andrew VickersAndrew Vickers More articles by this author , Amit SudAmit Sud More articles by this author , Jonine BernsteinJonine Bernstein More articles by this author , and Richard HoulstonRichard Houlston More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002531.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Population-based cancer screening programs, including prostate-specific antigen (PSA) screening for prostate cancer, are generally directed at all healthy individuals in a given age stratum. It has recently been proposed that PSA screening could be risk-stratified using polygenic risk scores (PRSs) based on panels of single-nucleotide polymorphisms (SNPs): those with high PRS would be screened whereas those with low PRS would be exempted. However, prostate cancer PRSs were generated using the endpoint of cancer incidence rather than cancer-specific mortality, and it has been demonstrated that the PRSs do not differentially predict lethal vs. indolent disease. As such, use of PRSs to risk-stratify screening will not address overdiagnosis, the major problem associated with PSA screening. METHODS: We developed a simple net benefit formulation to comparing different screening strategies, given as: deaths prevented – number screened / NWS – number diagnosed / (NWD -1), where NWS and NWD are the number of individuals we would be willing to, respectively, screen and diagnose, to prevent one death. We applied the formula to empirical data on PSA screening and varied NWS and NWD to assess the effects on our findings. RESULTS: Risk-stratifying PSA screening using a PRS that does not differentially discriminate between incident and lethal cancer did not improve screening outcomes in our model. Net benefit was 4 per 1000 for screening all eligible men. For a PRS with a C-index of 0.75 (higher than is typically found) but which did not discriminate between incidence and mortality, net benefit was 3.80, 3.36 and 1.78 for restricting screening to those with the highest 50%, 25% and 10% PRS. Net benefit was far lower for a concordance index of 0.65, closer to what is often reported. Results were robust for different choices of NWS and NWD. In contrast, risk stratifying screening based on PSA, which does predict mortality better than incidence, was associated with a net benefit up to 5.64, higher than that for screening all men. CONCLUSIONS: Using PSA levels to determine which men should continue screening will improve screening outcomes; using PRS to risk-stratify screening will do more harm than good. If PRS-based cancer screening is to be effective, research needs to focus on identifying PRSs associated with cancer mortality. Source of Funding: This work was supported in part by the National Institutes of Health/National Cancer Institute (NIH/NCI) with a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center [P30 CA008748], a SPORE grant in Prostate Cancer to Dr. H. Scher [P50-CA92629], the Sidney Kimmel Center for Prostate and Urologic Cancers. R.H. acknowledges grant support from Cancer Research UK (C1298/A8362) and the Wellcome Trust (214388). A.S. is in receipt of a National Institute for Health Research (NIHR) Academic Clinical Lectureship and funding from the Royal Marsden Biomedical Research Centre. This is a summary of independent research supported by the NIHR Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e143 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andrew Vickers More articles by this author Amit Sud More articles by this author Jonine Bernstein More articles by this author Richard Houlston More articles by this author Expand All Advertisement PDF DownloadLoading ...

MP26-06 EFFECTS OF MAGNETIC RESONANCE IMAGING TARGETING ON OVERDIAGNOSIS AND OVERTREATMENT OF PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Detection & Screening II (MP26)1 Sep 2021MP26-06 EFFECTS OF MAGNETIC RESONANCE IMAGING TARGETING ON OVERDIAGNOSIS AND OVERTREATMENT OF PROSTATE CANCER Andrew Vickers Andrew VickersAndrew Vickers More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002023.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: It has been suggested that targeting prostate lesions identified on magnetic resonance imaging (MRI) will improve the sensitivity of prostate biopsy for high-grade disease. The clinical significance of high-grade tumors found by MRI-targeting in men with benign systematic biopsy findings is open to question. We compared data from the National Cancer Institute (NCI) study of MRI-targeted biopsy with results from long-term follow-up of men who had negative sextant biopsy in the European Randomized trial of Screening for Prostate Cancer (ERSPC) METHODS: The NCI study included finding from MRI-targeted biopsy for 999 men with negative systematic biopsy. For ERSPC, 3,056 men who had negative sextant biopsy were followed for 11 years. We calculated the number of patients needing to be diagnosed (NND) and treated (NNT) following targeted biopsy in order to prevent one prostate cancer death at 11 years. We used a simple modelling approach that involved several assumptions, such as the proportion of the deaths in the ERSPC would have been prevented by earlier diagnosis had the initial biopsy been MRI-guided. We then varied these assumptions to assess the effects on the results. RESULTS: In the base scenario, which involved assumptions favorable to MRI, NND and NNT were 89 and 57 (table). Results were only more encouraging for MRI-targeting under unlikely scenarios, such as 100% sensitivity for MRI and 100% cure rates for treatment. CONCLUSIONS: Although MRI may be of benefit overall, considering decreases in overdiagnosis resulting from avoidance of biopsy in men with negative scans, targeting biopsy needles to MRI-detected lesions results in a large number of men diagnosed and treated per death prevented. Consideration should be given to changing guidelines on grading of MRI cores and those regarding treatment of high-grade prostate cancer. Source of Funding: This work was supported in part by the National Institutes of Health/National Cancer Institute (NIH/NCI) with a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center [P30 CA008748], a SPORE grant in Prostate Cancer to Dr. H. Scher [P50-CA92629], the Sidney Kimmel Center for Prostate and Urologic Cancers and David H. Koch through the Prostate Cancer Foundation. © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e464-e464 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andrew Vickers More articles by this author Expand All Advertisement Loading ...

PD48-02 DECISION-ANALYTIC MODELING STUDY OF THE PRECISION TRIAL: DOES PRE-BIOPSY MRI DO MORE GOOD THAN HARM?

You have accessJournal of UrologyProstate Cancer: Detection & Screening V (PD48)1 Apr 2020PD48-02 DECISION-ANALYTIC MODELING STUDY OF THE PRECISION TRIAL: DOES PRE-BIOPSY MRI DO MORE GOOD THAN HARM? Andrew Vickers* and Sigrid Carlsson Andrew Vickers*Andrew Vickers* More articles by this author and Sigrid CarlssonSigrid Carlsson More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000942.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Several recent studies, including the randomized PRECISION trial, have investigated whether men with elevated prostate-specific antigen (PSA) levels should undergo magnetic resonance imaging (MRI) before prostate biopsy, with targeted biopsy performed if MRI is positive and no biopsy for MRI negative patients. The finding that MRI reduces the number of low-grade and increases the number of high-grade cancers has been interpreted as supporting MRI. However, a technique that overgraded tumors would report similar findings. Study findings at the group level need to be complemented by modeling studies of individual patient counterfactuals. For instance, a patient who would have been grade Grade Group (GG) 1 by regular transrectal ultrasound (TRUS) biopsy but GG2 by MRI would only benefit if confirmatory biopsy after TRUS would show GG2 (hence MRI would avoid an additional biopsy) or if delayed treatment affected chance of cure. If neither are true, the patient would be harmed by curative treatment resulting from the increased grade. METHODS: We used the PRECISION trial results to create different scenarios for individual patient counterfactuals, varying the proportion of MRI-detected high-grade cancers that were reclassified from low-grade vs. benign TRUS biopsy. We assumed that only patients diagnosed with GG2+ would be treated curatively with active surveillance for GG1. We considered treatment to constitute high harm, active surveillance to be moderate harm and additional biopsy to constitute minor harm. As there is evidence that long-term rates of prostate cancer death are very low for both patients with negative TRUS biopsy and those with GG1 followed on active surveillance, delayed treatment was considered to be a moderate harm. We tested a range of scenarios for degree of harm. RESULTS: In most scenarios, MRI was associated with very low levels of net benefit that were highly dependent on assuming that the higher rates of GG2+ disease on MRI resulted from reclassification from benign disease on TRUS. In the base case, the highest net benefit for MRI across scenarios was the equivalent of 50 MRIs to prevent one overdiagnosis of GG1. MRI had was harmful in many scenarios. MRI had important benefit only under the scenario where MRI and TRUS tumors were, grade for grade, of similar oncologic risk, a position not supported by best evidence. CONCLUSIONS: Decision-analytic modelling of how MRI impacts the treatment of individual patients does not support the routine use of MRI before diagnostic biopsy, with biopsy only targeted to suspicious lesions and no biopsy for negative MRI. Source of Funding: This work was supported in part by the National Institutes of Health/National Cancer Institute (NIH/NCI) with a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center [P30 CA008748], and a SPORE grant in Prostate Cancer [P50-CA92629]. © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e993-e994 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andrew Vickers* More articles by this author Sigrid Carlsson More articles by this author Expand All Advertisement PDF downloadLoading ...

MLCD: A Unified Software Package for Cancer Diagnosis.

PURPOSEMachine Learning Package for Cancer Diagnosis (MLCD) is the result of a National Institutes of Health/National Cancer Institute (NIH/NCI)-sponsored project for developing a unified software package from state-of-the-art breast cancer biopsy diagnosis and machine learning algorithms that can improve the quality of both clinical practice and ongoing research.METHODSWhole-slide images of 240 well-characterized breast biopsy cases, initially assembled under R01 CA140560, were used for developing the algorithms and training the machine learning models. This software package is based on the methodology developed and published under our recent NIH/NCI-sponsored research grant (R01 CA172343) for finding regions of interest (ROIs) in whole-slide breast biopsy images, for segmenting ROIs into histopathologic tissue types and for using this segmentation in classifiers that can suggest final diagnoses.RESULTThe package provides an ROI detector for whole-slide images and modules for semantic segmentation into tissue classes and diagnostic classification into 4 classes (benign, atypia, ductal carcinoma in situ, invasive cancer) of the ROIs. It is available through the GitHub repository under the Massachusetts Institute of Technology license and will later be distributed with the Pathology Image Informatics Platform system. A Web page provides instructions for use.CONCLUSIONOur tools have the potential to provide help to other cancer researchers and, ultimately, to practicing physicians and will motivate future research in this field. This article describes the methodology behind the software development and gives sample outputs to guide those interested in using this package.

Academic Surgical Oncologists' Productivity Correlates with Gender, Grant Funding, and Institutional NCI Comprehensive Cancer Center Affiliation.

A scholar'sh-index is defined as the number of h papers published, each of which has been cited at least h times. We hypothesized that the h-index strongly correlates with the academic rank of surgical oncologists. We utilized the National Cancer Institute (NCI) website to identify NCI-designated Comprehensive Cancer Centers (CCC) and Doximity to identify the 50 highest-ranked general surgery residency programs with surgical oncology divisions. Demographic data of respective academic surgical oncologists were collected from departmental websites and Grantome. Bibliometric data were obtained from Web of Science. We identified 544 surgical oncologists from 64 programs. Increased h-index was associated with academic rank (p < 0.001), male gender (p < 0.001), number of National Institutes of Health (NIH) grants (p < 0.001), and affiliation with an NCI CCC (p = 0.018) but not number of additional degrees (p = 0.661) or Doximity ranking (p = 0.102). H-index was a stronger predictor of academic rank (r = 0.648) than total publications (r = 0.585) or citations (r = 0.450). This is the first report to assess the h-index within academic surgical oncology. H-index is a bibliometric predictor of academic rank that correlates with NIH grant funding and NCI CCC affiliation. We also highlight a previously unexpected and unappreciated gender disparity in the academic productivity of US surgical oncologists. When academic rank was accounted for, female surgical oncologists had lower h-indices compared with their male colleagues. Evaluation of the etiologies of this gender disparity is needed to address barriers to academic productivity faced by female surgical oncologists as they progress through their careers.

Communicating Science through a Novel Type of Journal.

Communicating Science through a Novel Type of Journal.

Mentoring Strategies and Outcomes of Two Federally Funded Cancer Research Training Programs for Underrepresented Students in the Biomedical Sciences.

The US is experiencing a severe shortage of underrepresented biomedical researchers. The purpose of this paper is to present two case examples of cancer research mentoring programs for underrepresented biomedical sciences students. The first case example is a National Institutes of Health/National Cancer Institute (NIH/NCI) P20 grant titled "South Carolina Cancer Disparities Research Center (SC CaDRe)" Training Program, contributing to an increase in the number of underrepresented students applying to graduate school by employing a triple-level mentoring strategy. Since 2011, three undergraduate and four graduate students have participated in the P20 SC CaDRe program. One graduate student published a peer-reviewed scientific paper. Two graduate students (50%) have completed their master's degrees, and the other two graduate students will receive their degrees in spring 2015. Two undergraduate students (67%) are enrolled in graduate or professional school (grad./prof. school), and the other graduate student is completing her final year of college. The second case example is a prostate cancer-focused Department of Defense grant titled "The SC Collaborative Undergraduate HBCU Student Summer Training Program," providing 24 students training since 2009. Additionally, 47 students made scientific presentations, and two students have published peer-reviewed scientific papers. All 24 students took a GRE test preparation course; 15 (63%) have applied to graduate school, and 11 of them (73%) are enrolled in grad./prof. school. Thirteen remaining students (54%) are applying to grad./prof. school. Leveraged funding provided research-training opportunities to an additional 201 National Conference on Health Disparities Student Forum participants and to 937 Ernest E. Just Research Symposium participants at the Medical University of South Carolina.

SU-D-BRF-07: Ultrasound and Fluoroscopy Based Intraoperative Image-Guidance System for Dynamic Dosimetry in Prostate Brachytherapy

Purpose: Prostate brachytherapy is a common treatment method for low-risk prostate cancer patients. Intraoperative treatment planning is known to improve the treatment procedure and the outcome. The current limitation of intraoperative treatment planning is the inability to localize the seeds in relation to the prostate. We developed an image-guidance system to fulfill this need to achieve intraoperative dynamic dosimetry in prostate brachytherapy. Methods: Our system is based on standard imaging equipments available in the operating room, including the transrectal ultrasound (TRUS) and the mobile C-arm. A simple fiducial is added to compute the C-arm pose. Three fluoroscopic images and an ultrasound volume of the seeds and the prostate are acquired and processed by four image processing algorithms: seed segmentation, fiducial detection with pose estimation, seed reconstruction, and seeds-to-TRUS registration. The updated seed positions allow the physician to assess the quality of implantation and dynamically adjust the treatment plan during the course of surgery to achieve improved exit dosimetry. Results: The system was tested on 10 phantoms and 37 patients. Seed segmentation resulted in a 1% false negative and 2% false positive rates. Fiducial detection with pose estimation resulted in a detection rate of 98%. Seed reconstruction had a mean reconstructionmore » error of 0.4 mm. Seeds-to-TRUS registration had a mean registration error of 1.3 mm. The total processing time from image acquisition to registration was approximately 1 minute. Conclusion: We present an image-guidance system for intraoperative dynamic dosimetry in prostate brachytherapy. Using standard imaging equipments and a simple fiducial, our system can be easily adopted in any clinics. Robust image processing algorithms enable accurate and fast computation of the delivered dose. Especially, the system enables detection of possible hot/cold spots during the surgery, allowing the physician to address these in the operating room rather than requiring additional therapy afterwards. This research was supported in part by the National Institutes of Health/National Cancer Institute (NIH/NCI) under grant 2R44CA099374 and grant 1R01CA151395, and in part by the Department of Defense (DoD) under grant W81XWH-05-1-0407.« less

Abstract B79: Assessing colorectal cancer screening behaviors and knowledge among at-risk Hispanics in southern New Mexico.

Abstract Introduction: Colorectal cancer (CRC) mortality rates in New Mexico have not decreased as much as the US national rates, and mortality rates among Hispanics in the state are higher than among this ethnic group in the US. Methods: A Colorectal Cancer Knowledge Assessment Survey (KAS) was administered in either English or Spanish to 247 individuals attending community events and health fairs throughout southern New Mexico. A subset of these individuals completed an electronic CRC risk assessment managed by National Institutes of Health (NIH) National Cancer Institute (NCI). Data analysis was performed using SPSS (Statistical Package for the Social Sciences) to test for significant differences in knowledge, and/or screening rates based on ethnicity. Results: There were significant differences among participants &amp;gt; 50 years old based on ethnicity for knowledge about CRC, physician discussions and recommendations, and screening rates. In all cases, with the exception of knowledge of CRC risk, Hispanics of CRC screening age, were less likely to be recommended for screening by their physician, less likely to discuss CRC screening, knew less about CRC and about the different types of screening modalities, and reported CRC screening in the past at about half the rate of their non-Hispanic white counterparts. Conclusions: The increased mortality rates for New Mexican Hispanics with colorectal cancer are likely due to the very low screening rates, which in turn are related to the lack of knowledge about this condition. Expanded education and outreach efforts for minority populations to increase knowledge and awareness of prevention and screening behaviors is critical. This work was supported in part by the NM AES and by grants NIH NCI 5 U54CA132383 (O'Connell) and NIH NCI 5 U54CA132381 (Thompson). Citation Format: Janet Sanchez, Vanessa Martinez, Beti Thompson, Mary O'Connell. Assessing colorectal cancer screening behaviors and knowledge among at-risk Hispanics in southern New Mexico. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B79.

Abstract ED03-03: Translating research into practice: Results of the WINCART Center Biospecimen Pilot Study and community outreach efforts.

Abstract ED03-03: Translating research into practice: Results of the WINCART Center Biospecimen Pilot Study and community outreach efforts.

Recruitment of African Americans to National Oncology Clinical Trials through a Clinical Trial Shared Resource

In 2000, using National Institutes of Health/National Cancer Institute (NIH/NCI) U54 funds, a clinical trials shared resource was established at Nashville General Hospital at Meharry to attract more African Americans to national cancer clinical trials. This Report from the Field describes the model used to achieve this end.

Structure of the Mycobacterium Tuberculosis Virulence Factor Rv0899 (ompATb)

Rv0899 (OmpATb) is a 326-residue membrane-associated virulence factor of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. It is essential for the adaptation of Mtb to acidic environments and has been identified as an outer membrane protein. The M domain (residues 1-72) contains a 20-residue hydrophobic sequence that may form a membrane-anchoring helix. The B domain (residues 73-195) has been described as pore-forming. It shares sequence homology with the “BON” domain of Bacterial Osmotic-shock-resistance, Nodulation-specificity and lipid-binding proteins. The C domain (residue 196-326) shares significance homology with other bacterial peptidoglycan-binding domains, including the C-terminus of the E. coli outer membrane protein OmpA, after which Rv0899 was originally named. Using NMR spectroscopy, we show that residues 73-326, spanning the joint B and C domains, adopt a well-defined three-dimensional structure in water solution, however, the individual B and C domains fold independently and interact with each other to a minimal extent. The B domain adopts a rigid and stable structure, that forms a six-stranded β-sheet protected on one side by three α-helices. No comparable arrangement of secondary structure elements could be found in the databases, suggesting that is a new fold. The structure of the B domain is suggestive of a lipid binding or structural function, and provides insights to the role of Rv0899 in Mtb virulence.(This research was supported by the National Institutes of Health (NIH), and utilized the Burnham Institute NMR Facility supported by the NIH National Cancer Institute).

Conformations and Interactions of BCL-2 Family Proteins: Implications For Apoptosis

The BCL-2 family proteins are major regulators of mitochondrion-dependent programmed cell death. They includes both pro-death and pro-life proteins, which exert their activities through physical interactions with each other with other non-homologous proteins, and with intracellular membranes. The BH3-only cytotoxic protein BID is activated by caspase-8 cleavage upon engagement of cell surface death receptors. The resulting C-terminal fragment, tBID, translocates to mitochondria, triggering the release of cytotoxic molecules and cell death. The activity of tBID is regulated by its interactions with pro-survival BCL-XL and pro-death BAX, both in the cytosol and at the mitochondrial membrane. Using NMR spectroscopy we show that full length BCL-XL is soluble and monomeric in aqueous solution. Its hydrophobic C-terminal tail, which is predicted to form a transmembrane helix in lipid membranes, folds back to interact with the hydrophobic pocket known to bind the BH3 domains of pro-apoptotic proteins. The presence of the C terminus reduces the binding affinity of BCL-XL for BH3 domains 4-fold, compared to the affinity of truncated BCL-XL. The activated pro-apoptotic protein tBID adopts an α-helical but dynamically disordered conformation in solution. However, its three-dimensional conformation is stabilized when tBID engages its BH3 domain in the BH3-binding hydrophobic groove of BCL-XL to form a stable heterodimeric complex. Studies in lipid micelles show that the proteins' conformations and interactions are dramatically different in the presence of lipids.[This research was supported by the National Institutes of Health (NIH), and utilized the Burnham Institute Structural Biology Facility supported by the NIH National Cancer Institute.]

Pace of Gene Therapy Picking Up

AN ADVISORY committee of the National Institutes of Health (NIH), Bethesda, Md, has given permission to investigators from the NIH's National Cancer Institute to extend their use of gene therapy in cancer. In a second action, this Recombinant Deoxyribonucleic Acid (DNA) Advisory Committee is granting permission for a clinical study that will attempt to correct the genetic defect that causes one type of excessive serum cholesterol. By a vote of 17 to zero, with one abstention, the committee thus gives permission to Steven A. Rosenberg, MD, and his associates at the National Cancer Institute to inject cancer patients with their own genetically altered malignant cells. "The goal is to manipulate the cancer cell so that it will be more susceptible to the body's natural defenses," says Rosenberg. In approving (by the same vote, 17 to zero, with one abstention) the cholesterol study, the committee also is giving permission to James

Clinical Data Release: How Soon?

WHEN publicly funded research results have immediate effect on patient care, should the funding agency announce the findings before they are published in a scientific journal? National Institutes of Health (NIH) officials in Bethesda, Md, are pondering this question and awaiting guidelines that might help with such early release clinical alerts. The NIH's National Cancer Institute was the first to grapple with the issue in May 1988, when it announced an adjuvant therapy for breast cancer. Then, in October 1989, that institute issued a clinical update on colon cancer management. This sort of decision has put the NIH at the center of discussion of whether to make early release of the information or use the traditional but usually more time-consuming route of initial publication in the scientific literature. The advice from several speakers came at a meeting called by the NIH to discuss ways in which this policy can be

Cofactor Question Divides Codiscoverers of HIV

THE CODISCOVERERS of the virus linked to acquired immunodeficiency syndrome (AIDS) are again at odds, now over the possible role of cofactors in AIDS ( JAMA . 1990;264:665-666). Robert Gallo, MD, and Luc Montagnier, MD, appeared together in Los Angeles, Calif, to receive a joint award from the American Association of Blood Banks for improving blood supply safety. Neither would comment on allegations, now under investigation by the National Institutes of Health (NIH) (Bethesda, Md), that Gallo may have misappropriated some of Montagnier's work in staking a claim to discovery of the human immunodeficiency virus (HIV). But the dispute over cofactors gave them plenty on which to disagree. Gallo, senior researcher at the NIH's National Cancer Institute, says HIV is

Preliminary Results May Open Door to Gene Therapy Just a Bit Wider

THE DOOR that leads to true gene therapy appears to have been opened a little wider by the finding that tumor-infiltrating lymphocytes armed with a marker gene can survive in a patient for at least 19 days. With this preliminary finding, the National Institutes of Health (NIH) (Bethesda, Md) investigators involved now are planning the next steps in this immunotherapeutic approach. Last May, after 16 reviews of the protocols and a lawsuit filed by a critic of genetic manipulation, Steven A. Rosenberg, MD, and Michael Blaese, MD, of the NIH's National Cancer Institute and W. French Anderson, MD, of the National Heart, Lung, and Blood Institute, received approval from James B. Wyngaarden, MD (then director of the NIH), and Frank E. Young, MD, PhD (commissioner of the Food and Drug Administration, Rockville, Md), to inject genetically altered cultures of tumor-infiltrating lymphocytes into 10 patients with advanced malignant melanomas (<i>JAMA</i>. 1989;262:16

Gene-Transfer Study Approval Awaits More Data

ABSTRACT APPROVAL of the gene-transfer study in cancer patients has been delayed.The proposal was recommended for approval by a National Institutes of Health (NIH) advisory committee, but has been put on hold by James B. Wyngaarden, MD, NIH director, pending submission in writing of further information. Some of this information, now forthcoming, had been withheld because data on preliminary studies had been submitted to peer-reviewed journals.The study involves placing the gene for neomycin-resistance into tumor-infiltrating lymphocytes as a marker. When these cells are injected into the patient, the presence of the marker should enable their fate to be studied over a prolonged period and an improved antitumor regimen could result.The use of tumor-infiltrating lymphocytes as immunotherapy has been studied for two years at the NIH's National Cancer Institute under the overall supervision of Steven A. Rosenberg, MD, chief, Surgery Branch. The patients' tumors are removed and the tumor-infiltrating