tbuckley/cabot-search huggingface dataset:
Dopamine D1 and D2 receptors are distinctly associated with rest-activity rhythms and drug reward
Authors: Rui Zhang, Peter Manza, Dardo Tomasi, Sung Won Kim, Ehsan Shokri-Kojori, Sukru B. Demiral, Danielle S. Kroll, Dana E. Feldman, Katherine L. McPherson, Catherine L. Biesecker, Gene-Jack Wang, Nora D. Volkow
Journal: Journal of Clinical Investigation (2021)

BACKGROUNDCertain components of rest-activity rhythms such as greater eveningness (delayed phase), physical inactivity (blunted amplitude), and shift work (irregularity) are associated with increased risk for drug use. Dopaminergic (DA) signaling has been hypothesized to mediate the associations, though clinical evidence is lacking.METHODSWe examined associations between rhythm components and striatal D1 (D1R) and D2/3 receptor (D2/3R) availability in 32 healthy adults (12 female, 20 male; age 42.40 ± 12.22 years) and its relationship to drug reward. Rest-activity rhythms were assessed by 1-week actigraphy combined with self-reports. [11C]NNC112 and [11C]raclopride positron emission tomography (PET) scans were conducted to measure D1R and D2/3R availability, respectively. Additionally, self-reported drug-rewarding effects of 60 mg oral methylphenidate were assessed.RESULTSWe found that delayed rhythm was associated with higher D1R availability in caudate, which was not attributable to sleep loss or so-called social jet lag, whereas physical inactivity was associated with higher D2/3R availability in nucleus accumbens (NAc). Delayed rest-activity rhythm, higher caudate D1R, and NAc D2/3R availability were associated with greater sensitivity to the rewarding effects of methylphenidate.CONCLUSIONThese findings reveal specific components of rest-activity rhythms associated with striatal D1R, D2/3R availability, and drug-rewarding effects. Personalized interventions that target rest-activity rhythms may help prevent and treat substance use disorders.TRIAL REGISTRATIONClinicalTrials.gov: NCT03190954.FUNDINGNational Institute on Alcohol Abuse and Alcoholism (ZIAAA000550).
Five versus seven days of nitrofurantoin for urinary tract infections in women with diabetes: a retrospective cohort study
Authors: Kelly D. Hendriks-Spoor, Floor L. Wille, Thijs ten Doesschate, Julia W. Dorigo-Zetsma, Theo J.M. Verheij, Cornelis H. van Werkhoven
Journal: Clinical Microbiology and Infection (2021)

To compare the effectiveness of 5 versus 7 days of nitrofurantoin treatment for urinary tract infection (UTI) in women with diabetes.Data were collected retrospectively from Dutch general practitioners between 2013 and 2020. Nitrofurantoin prescriptions with a duration of 5 days (5DN) or 7 days (7DN) in women with diabetes were included. Inverse propensity weighting was performed to calculate adjusted risk differences (RD) for treatment failure within 28 days. Secondary outcomes were 14-day treatment failure, severe treatment failure and 28-day treatment failure in defined risk groups.Nitrofurantoin was prescribed in 6866 episodes, 3247 (47.3%) episodes with 5DN and 3619 (52.7%) episodes with 7DN. Patients in the 7DN group had more co-morbidities, more diabetes-related complications and were more insulin-dependent. There were 517/3247 (15.9%) failures in the 5DN group versus 520/3619 (14.4%) in the 7DN group. The adjusted RD for failure within 28 days was 1.4% (95% CI -0.6 to 3.4).We found no clinically significant difference in treatment failure in women with diabetes with UTI treated with either 5DN or 7DN within 28 days. A 5-day treatment should be considered to reduce cumulative nitrofurantoin exposure in DM patients.
Abstract 2643: Human and mouse reconstructed plate-based 3-dimensional culture assays that mimic the tumor microenvironment
Authors: Michael E. Steffey, Ying Qu, Andrew Karalewitz, Sumithra Urs, Julia Kirshner, Scott Wise
Journal: Cancer Research (2021)

Abstract In order to predict efficacy and toxicity of compounds advancing in the oncology drug discovery pipeline, and to minimize requirements for multiple animal studies, the development of in vitro assays that recapitulate in vivo conditions is increasingly important. While high throughput screening favors 2D assays, both for cost and relative speed in culturing and plating, they do not recapitulate the tumor architecture and the microenvironment that is more comparable to in vivo models. We now report this has been accomplished using zPREDICTA's organ-specific three-dimensional (3D) culture models which support long-term culture of carcinoma cells. Physiologic extracellular matrix (ECM) components are critical in maintaining the physical and spatial microenvironment as well as tumor phenotypes in reconstructed bone marrow (r-Bone) and mouse breast (r-mBreast) models. The r-Bone ECM allows for co-culture of tumor cells with mesenchymal stem cells, fibroblasts, lymphoid, myeloid, and CAR-T cells. The data here describes clear differences in the in vitro pharmacology of several standard of care agents in 2D, in adherent or suspension cultures, compared to the recapitulated 3D tumor microenvironment of the human hematopoietic compartment or the mouse breast ductal epithelium. For example, we find that cisplatin has a 10-30 fold higher IC50 in 4 different murine cell lines (MMTV-PyMT, 4T1, EMT6, and E0771) when cultured in the r-mBreast model than when those cells are adhered to the polystyrene in a 2D culture. Cytotoxicity assays such as CellTiter-Glo® can also be performed in a high throughput format in both 96 and 384-well 3D assay formats and we demonstrate equivalent bortezomib IC50 values in RPMI 8226 cell r-Bone cultures in both plate types. Additionally, cells can be isolated from the matrix after test agent exposure and analyzed by an appropriate downstream application, such as flow cytometry, where we show anti-CD19 CAR-T cell killing of CD19+ NALM6 cells in r-Bone cultures. These 3D models represent new early opportunities to screen test agents in a platform that is designed to more closely mimic in vivo tissue microenvironments and serve as a more relevant tool for multi drug screening and as a prerequisite to animal studies. Citation Format: Michael E. Steffey, Ying Qu, Andrew Karalewitz, Sumithra Urs, Julia Kirshner, Scott Wise. Human and mouse reconstructed plate-based 3-dimensional culture assays that mimic the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2643.
Protecting olympic participants from COVID-19: the trialled and tested process
Authors: Fabio Pigozzi, Bernd Wolfarth, Ana Cintron Rodriguez, Juergen Michael Steinacker, Victoriya Badtieva, James Lee John Bilzon, Christian Schneider, William O Roberts, Jeroen Swart, Demitri Constantinou, Michiko Dohi, Theodora Papadopoulou, Mark Hutchinson, Luigi Di Luigi, Maher Zahar, Raymond So, Fergus M Guppy, Jean-François Kaux, Upul Madahapola, Sandra Rozenstoka, Pedro Manonelles Marqueta, Jose Antonio Casajús, Sebastien Racinais, Konstantinos Natsis, Irina Zelenkova, Bulent Ulkar, Elif Ozdemir, Francisco Arroyo, André Pedrinelli, Mike Miller, Norbert Bachl, Michael Geistlinger, Yannis P Pitsiladis
Journal: British Journal of Sports Medicine (2021)

Diagnosis is one of the most important tasks performed by primary care physicians. The World Health Organization (WHO) recently prioritized patient safety areas in primary care, and included diagnostic errors as a high-priority problem. In addition, a recent report from the Institute of Medicine in the USA, <i>‘Improving Diagnosis in Health Care</i>’, concluded that most people will likely experience a diagnostic error in their lifetime. In this narrative review, we discuss the global significance, burden and contributory factors related to diagnostic errors in primary care. We synthesize available literature to discuss the types of presenting symptoms and conditions most commonly affected. We then summarize interventions based on available data and suggest next steps to reduce the global burden of diagnostic errors. Research suggests that we are unlikely to find a ‘magic bullet’ and confirms the need for a multifaceted approach to understand and address the many systems and cognitive issues involved in diagnostic error. Because errors involve many common conditions and are prevalent across all countries, the WHO’s leadership at a global level will be instrumental to address the problem. Based on our review, we recommend that the WHO consider bringing together primary care leaders, practicing frontline clinicians, safety experts, policymakers, the health IT community, medical education and accreditation organizations, researchers from multiple disciplines, patient advocates, and funding bodies among others, to address the many common challenges and opportunities to reduce diagnostic error. This could lead to prioritization of practice changes needed to improve primary care as well as setting research priorities for intervention development to reduce diagnostic error.
Abstract 1886: Anti -GPRC5D/CD3 T cell-redirecting bispecific antibody with potent in vitro and in vivo antitumor efficacy against multiple myeloma
Authors: Tatsushi Kodama, Yu Kochi, Waka Nakai, Hideaki Mizuno, Takeshi Baba, Kiyoshi Habu, Noriaki Sawada, Hiroyuki Tsunoda, Takahiro Shima, Kohta Miyawaki, Yoshikane Kikushige, Yasuo Mori, Toshihiro Miyamoto, Takahiro Maeda, Koichi Akashi
Journal: Cancer Research (2021)

Abstract Background: Although treatment advances over recent decades have significantly improved survival of patients with multiple myeloma, there is still an unmet medical need for more effective treatments. The orphan G protein-coupled receptor, class C group 5 member D (GPRC5D), was previously identified as expressed by mRNA in patients with multiple myeloma with only low expression detected in normal tissues, but confirmation of protein expression remained elusive. In this study, we determined the cell surface expression of GPRC5D on malignant and normal hematological cells. In addition, we evaluated the antitumor activity and mechanism of GPRC5D TRABs in in vitro and in vivo mouse models. Method &amp; Results: We established specific monoclonal antibodies against human GPRC5D and identified its expression on the surface of malignant cells involved in multiple myeloma, but except for plasma cells and B cells, did not find it at appreciable levels on normal hematopoietic cells and bone marrow progenitors, including hematopoietic stem cells. To investigate whether GPRC5D could be therapeutic target, we generated IgG-based anti-GPRC5D/CD3 bispecific T-cell-redirecting antibodies (GPRC5D TRABs). GPRC5D TRABs induced T cell activation and the killing of a wide variety of GPRC5D expressing tumor cells in vitro. In mouse models with reconstituted human immune cells, GPRC5D TRABs showed strong antitumor efficacy against GPRC5D-positive tumors through the activation of T cells. Conclusion: These findings suggest that GPRC5D is an antigen specific to multiple myeloma and a potential target of TRAB therapy. Citation Format: Tatsushi Kodama, Yu Kochi, Waka Nakai, Hideaki Mizuno, Takeshi Baba, Kiyoshi Habu, Noriaki Sawada, Hiroyuki Tsunoda, Takahiro Shima, Kohta Miyawaki, Yoshikane Kikushige, Yasuo Mori, Toshihiro Miyamoto, Takahiro Maeda, Koichi Akashi. Anti -GPRC5D/CD3 T cell-redirecting bispecific antibody with potent in vitro and in vivo antitumor efficacy against multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1886.
Abstract 9250: Endocardial Electrogram Characteristics Indicating an Epicardial Origin of Focal Ventricular Arrhythmias
Authors: William H Sauer, Wendy Tzou, Joseph L Schuller, Russell Heath, David Katz, Duy T Nguyen, Ryan G Aleong, Paul D Varosy
Journal: Circulation (2011)

Introduction: While most ventricular arrhythmias (VA) can be ablated successfully using an endocardial (ENDO) approach, epicardial (EPI) mapping and ablation is sometimes required. There may be clues on the surface electrocardiogram related to intrinsicoid deflection and QRS width; however, identification of an EPI origin of VA with certainty remains problematic, and there are no reported ENDO electrogram (EGM) characteristics that may direct ablation strategy. Methods: All patients referred for ablation of ventricular tachycardia or frequent ventricular ectopy from June 2006 through July 2010 were evaluated. Only patients with completed electroanatomical activation maps of a focal VA from ENDO and EPI were included. EGMs recorded by a bipolar mapping catheter in the area of earliest ENDO activation were analyzed and compared to the area of early EPI activation. Results: There were 17 patients with completed ENDO and EPI electroanatomical maps of a focal VA identified. We identified 3 characteristics from ENDO mapping that consistently indicated an EPI VA origin: 1) Diffusely early activation (&gt; 2cm2 region of sites with equally earliest activation within 10 msec; figure); 2) Sequence of a far-field EGM followed by a near-field EGM in the region of earliest ENDO activation; and 3) Inability to capture the far-field component of the earliest ENDO EGM (stimulus-QRS &lt; egm-QRS time) or reproduce the PVC or VT QRS complex morphology with pacing at the earliest ENDO activation site. Conclusions: The presence of a diffuse area of early activation and inability to capture a far-field electrogram from the endocardium indicates an epicardial origin of a focal ventricular arrhythmia.
Bringing Gene Therapy to the Clinic
Authors: B G Ball, W F Anderson
Journal: JAMA (2000)

DERIVATIVES TO TREAT syphilis at the turn of the 20th century has been viewed as the dawn of the age of chemotherapy and rational drug design. 1When Ehrlich's personal secretary, Martha Marquardt, commented on his life, she reserved her most heartfelt praise not for his brilliance as a chemist but for his mission."Nothing on earth mattered to him except scientific research aimed to overcome suffering and disease." 1 These noble aims, however, were subject to priorities and agendas over which he had no control.English clinic staff viewed patients with syphilis as depraved sexual offenders, which adversely affected their compliance with treatment.In English colonies such as Uganda, eradicating syphilis was not a economic priority. 2,3 For these reasons, syphilis remained an explosive epidemic.Today, it is exciting to imagine the possibilities of biotechnological wonders like the human genome project, stem cells, and microarrays.But the priorities driving these efforts may be leading us astray.Michael R. Reich recently declared that the current drug development system, despite its "extraordinary research and development capacity," has led to "global inequities in health care." 4 He argued that the dependence on large profits from affluent countries created restrictively high drug prices and a penchant for developing drugs that target only the health problems of the wealthy.The solution, according to Reich, is the creation of incentives and reforms to refocus the global pharmaceutical industry on curing the most serious diseases rather than merely the most profitable ones.Articles in this issue explore how existing health management systems and technologies could be optimized "to overcome suffering and disease," often despite severe financial and logistical challenges.June Dahl argues for systematic changes to improve the medical management of pain-one of the most undertreated conditions for which highly effective drugs are readily available.Amit Etkin explains how the human genome data can be made clinically useful.Bret Ball and French Anderson outline how to overcome the major barriers that impede the application of gene therapy in the clinic.David Walton and Paul Farmer call for an end to the policies of negligence that have governed the treatment of multidrug-resistant tuberculosis in third world countries.Since Ehrlich's time, few of the principles of disease management seem to have changed."Rational drug design" still occurs largely through a process of large-scale screening techniques, moments of serendipity, and years of targeted research.Effective use of available therapies remains hampered by physicians who fail to prescribe drugs rationally.Pathogens may evolve to evade our therapies.But, at the current rate of progress in biotechnology, we may soon have the tools with which to address most of the world's diseases.However, how will we employ these tools and would Martha Marquardt approve?
Reply to Eugenio Ventimiglia, Edoardo Pozzi, Massimo Alfano, Francesco Montorsi, and Andrea Salonia’s Letter to the Editor re: Scott D. Lundy, Naseer Sangwan, Neel V. Parekh, et al. Functional and Taxonomic Dysbiosis of the Gut, Urine, and Semen Microbiomes in Male Infertility. Eur Urol 2021;79:826–36
Authors: Scott D. Lundy, Sarah C. Vij, Charis Eng
Journal: European Urology (2021)
Abstract 1627: Preclinical characterization of a novel CTLA-4-targeted ETB for direct Treg depletion
Authors: Swati Khanna, Caleigh Howard, Lilia A. Rabia, Alvaro Aldana, Jay Zhao, Betty Chang, Hilario J. Ramos, Aimee Iberg
Journal: Cancer Research (2021)

Abstract Regulatory T cell (Treg) depletion enhances the anti-tumor efficacy of CTLA-4 targeted mAbs in preclinical models, and is a mechanism supported by retrospective clinical data analysis. In response to these findings, many next-generation CTLA-4 targeting therapeutics have been designed to increase Fc-mediated Treg depletion in the tumor microenvironment. CTLA-4-targeted engineered toxin bodies (ETBs) are designed to deplete Tregs in the tumor microenvironment (TME) directly and in a manner independent of Fc-mediated effector functions, offering a unique approach to CTLA-4 targeted therapy. ETBs, or engineered toxin bodies, are large molecule proteins consisting of an antibody fragment genetically fused to a proprietary de-immunized (DI) form of the Shiga-like toxin A subunit (SLTA). Once engaged to the specific cell surface target of interest, in this case CTLA-4, ETBs internalize, route to the cytosol, and permanently inactivate ribosomes through an irreversible enzymatic process. This results in cell death via apoptotic mechanisms.Here we describe the preclinical characterization of a lead candidate CTLA-4-targeted ETB. CTLA-4-ETB-A directly binds and specifically kills CTLA-4 positive cells in vitro and induces apoptosis of ex-vivo expanded Tregs. CTLA-4-ETB-A is designed to bind CTLA-4 in a manner unique from classic blocking antibodies and is not expected to have sustained blocking ability in vivo due to the relatively short half-life of an ETB compared to a neutralizing mAb. We predict this will allow for focused Treg depletion in the TME based on target expression levels, while sparing autoreactive T cell activation in the periphery. Utilizing human CTLA-4 knock in mouse syngeneic tumor models, we show that CTLA-4-ETB-A can reduce the % Tregs and increase the CD8/Treg ratio in the TME. Preclinical assessment of safety and pharmacodynamic signals are underway in cynomolgus studies. Citation Format: Swati Khanna, Caleigh Howard, Lilia A. Rabia, Alvaro Aldana, Jay Zhao, Betty Chang, Hilario J. Ramos, Aimee Iberg. Preclinical characterization of a novel CTLA-4-targeted ETB for direct Treg depletion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1627.
Body-mass index and diabetes risk in 57 low-income and middle-income countries: a cross-sectional study of nationally representative, individual-level data in 685 616 adults
Authors: Felix Teufel, Jacqueline A Seiglie, Pascal Geldsetzer, Michaela Theilmann, Maja E Marcus, Cara Ebert, William Andres Lopez Arboleda, Kokou Agoudavi, Glennis Andall-Brereton, Krishna K Aryal, Brice Wilfried Bicaba, Garry Brian, Pascal Bovet, Maria Dorobantu, Mongal Singh Gurung, David Guwatudde, Corine Houehanou, Dismand Houinato, Jutta M Adelin Jorgensen, Gibson B Kagaruki, Khem B Karki, Demetre Labadarios, Joao S Martins, Mary T Mayige, Roy Wong McClure, Joseph Kibachio Mwangi, Omar Mwalim, Bolormaa Norov, Sarah Crooks, Farshad Farzadfar, Sahar Saeedi Moghaddam, Bahendeka K Silver, Lela Sturua, Chea Stanford Wesseh, Andrew C Stokes, Utibe R Essien, Jan-Walter De Neve, Rifat Atun, Justine I Davies, Sebastian Vollmer, Till W Bärnighausen, Mohammed K Ali, James B Meigs, Deborah J Wexler, Jennifer Manne-Goehler
Journal: The Lancet (2021)
Rapamycin Pretreatment Rescues the Bone Marrow AML Cell Elimination Capacity of CAR-T Cells
Authors: Zhigang Nian, Xiaohu Zheng, Yingchao Dou, Xianghui Du, Li Zhou, Binqing Fu, Rui Sun, Zhigang Tian, Haiming Wei
Journal: Clinical Cancer Research (2021)

Ongoing clinical trials show limited efficacy for Chimeric antigen receptor (CAR) T treatment for acute myeloid leukemia (AML). The aim of this study was to identify potential causes of the reported limited efficacy from CAR-T therapies against AML.We generated CAR-T cells targeting Epithelial cell adhesion molecule (EpCAM) and evaluated their killing activity against AML cells. We examined the impacts of modulating mTORC1 and mTORC2 signaling in CAR-T cells in terms of CXCR4 levels. We examined the effects of a rapamycin pretreatment of EpCAM CAR-T cells (during ex vivo expansion) and assessed the in vivo antitumor efficacy of rapamycin-pretreated EpCAM CAR-T cells (including CXCR4 knockdown cells) and CD33 CAR-T cells in leukemia xenograft mouse models.EpCAM CAR-T exhibited killing activity against AML cells but failed to eliminate AML cells in bone marrow. Subsequent investigations revealed that aberrantly activated mTORC1 signaling in CAR-T cells results in decreased bone marrow infiltration and decreased the levels of the rapamycin target CXCR4. Attenuating mTORC1 activity with the rapamycin pretreatment increased the capacity of CAR-T cells to infiltrate bone marrow and enhanced the extent of bone marrow AML cell elimination in leukemia xenograft mouse models. CXCR4 knockdown experiments showed that CXCR4 contributes to the enhanced bone marrow infiltration capacity of EpCAM CAR-T cells and the observed reduction in bone marrow AML cells.Our study reveals a potential cause for the limited efficacy of CAR-T reported from current AML clinical trials and illustrates an easy-to-implement pretreatment strategy, which enhances the anti-AML efficacy of CAR-T cells.See related commentary by Maiti and Daver, p. 5739.
Covid-19: Failings in imaging services have put cancer patients at risk, watchdog says
Authors: Shaun Griffin
Journal: BMJ (2021)

The government should urgently prioritise improving NHS imaging services in England, which are too often failing to detect cancer in scans and radiography, the Parliamentary and Health Service Ombudsman service has recommended.

The watchdog body has written letters to the patient safety minister, Nadine Dorries, and others to highlight findings from its report, published this week,1 that show recurring failings in the way x ray and scan results are reported on and followed up across the NHS. Rapid improvements in diagnosis will be crucial to tackle the backlog of care caused by the covid-19 pandemic, it said.

The ombudsman, Rob Behrens, said, “X ray and scan results are key to diagnosis and treatment for many people. Yet the failings outlined in this report show that, without a concerted effort …