tbuckley/cabot-search huggingface dataset:
David Dunger: paediatric endocrinologist and clinical scientist
Authors: Rebecca Wallersteiner
Journal: BMJ (2021)

David Dunger was born in Southend on Sea to Brian Dunger who was an army officer in the second world war and later worked for Standard Chartered Bank. His mother, Jean, was a corporal in Bomber Command and later worked for Southend Football Club. Dunger attended Westcliff Grammar School for Boys, where he shone at biology and art. He later confessed to family and friends that he spent his youth in the seaside resort’s amusement arcades, carousing (and smoking) with his lifelong friend, Emmanuel. As a teenager, he decided to become a physician and resorted to buying How to be a Doctor , a slim book from WH Smith, in the absence of other career advice.

It helped—Dunger scraped into Charing Cross Medical School to read medicine through clearing. He was an unconventional medical student who spent much of his time putting on esoteric foreign films—but his passions became medicine and biology.

A research fellowship at University College London (UCL) in physiology followed. Dunger later recalled “hairy times,” struggling to shepherd recalcitrant sheep used in the laboratory (and unharmed) into and out of the lifts at UCL to the amazement of passers-by. He then spent a year in Zimbabwe working as medical officer, where he turned his hand to surgery, adult medicine, obstetrics, paediatrics—whatever was needed in Wankie, a black mining community. This presaged his later …
Recent Advances in AIEgen‐Based Photodynamic Therapy and Immunotherapy
Authors: Menglei Zha, Guang Yang, Yaxi Li, Chen Zhang, Bo Li, Kai Li
Journal: Advanced Healthcare Materials (2021)

Abstract Cancer, one of the leading causes of death, has seriously threatened public health. However, there is still a lack of effective treatments. Nowadays, photodynamic therapy (PDT), relying on photosensitizers to trigger the generation of reactive oxygen species (ROS) for killing cancer cells, has been emerging as a noninvasive anti‐cancer strategy. To enhance the overall anti‐cancer efficacy of PDT, various approaches including molecular design and combination with other therapeutic techniques have been proposed and implemented. Especially, photodynamic immunotherapy that can effectively evoke the body's immune response has attracted much attention. Recently, a class of photosensitizers with aggregation‐induced emission (AIE) character have shown unique promises, taking advantage of their profound fluorescence and ROS‐generating ability in the aggregation state. Despite the promising results demonstrated by several groups, the associated studies are few and the mechanism of such AIEgen‐based photodynamic immunotherapy has not been fully understood. This review discusses the recent advances in the AIEgen‐based enhanced PDT with a special focus on the AIE photosensitizers for photodynamic immunotherapy, aiming to inspire more opportunities for in‐depth investigation of the working principles in this emerging anti‐cancer approach.
Impact of decreasing the proportion of higher energy foods and reducing portion sizes on food purchased in worksite cafeterias: A stepped-wedge randomised controlled trial
Authors: James P. Reynolds, Minna Ventsel, Daina Kosīte, Brier Rigby Dames, Laura Brocklebank, Sarah Masterton, Emily Pechey, Mark Pilling, Rachel Pechey, Gareth J. Hollands, Theresa M. Marteau
Journal: PLoS Medicine (2021)

Background Overconsumption of energy from food is a major contributor to the high rates of overweight and obesity in many populations. There is growing evidence that interventions that target the food environment may be effective at reducing energy intake. The current study aimed to estimate the effect of decreasing the proportion of higher energy (kcal) foods, with and without reducing portion size, on energy purchased in worksite cafeterias. Methods and findings This stepped-wedge randomised controlled trial (RCT) evaluated 2 interventions: (i) availability: replacing higher energy products with lower energy products; and (ii) size: reducing the portion size of higher energy products. A total of 19 cafeterias were randomised to the order in which they introduced the 2 interventions. Availability was implemented first and maintained. Size was added to the availability intervention. Intervention categories included main meals, sides, cold drinks, snacks, and desserts. The study setting was worksite cafeterias located in distribution centres for a major United Kingdom supermarket and lasted for 25 weeks (May to November 2019). These cafeterias were used by 20,327 employees, mainly (96%) in manual occupations. The primary outcome was total energy (kcal) purchased from intervention categories per day. The secondary outcomes were energy (kcal) purchased from nonintervention categories per day, total energy purchased per day, and revenue. Regression models showed an overall reduction in energy purchased from intervention categories of −4.8% (95% CI −7.0% to −2.7%), p &lt; 0.001 during the availability intervention period and a reduction of −11.5% (95% CI −13.7% to −9.3%), p &lt; 0.001 during the availability plus size intervention period, relative to the baseline. There was a reduction in energy purchased of −6.6% (95% CI −7.9% to −5.4%), p &lt; 0.001 during the availability plus size period, relative to availability alone. Study limitations include using energy purchased as the primary outcome (and not energy consumed) and the availability only of transaction-level sales data per site (and not individual-level data). Conclusions Decreasing the proportion of higher energy foods in cafeterias reduced the energy purchased. Decreasing portion sizes reduced this further. These interventions, particularly in combination, may be effective as part of broader strategies to reduce overconsumption of energy from food in out-of-home settings. Trial registration ISRCTN registry ISRCTN87225572 .
P13.14 Inhibition of extracellular carbonic anhydrases reduces glioblastoma cell invasion
Authors: M Proescholdt, Z Qiu, J Falter, N Schmidt
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Malignant gliomas metabolize glucose preferably by glycolysis which is in accordance with the Warburg effect. This induces a high demand of glucose combined with a significant lactic acid load. The hypoxia-inducible carbonic anhydrase (CA) IX has been shown to moderate the extrusion of hydrogen ions into the extracellular space. Since the acidification of the extracellular environment contributes to host tissue invasion due to activation of proteolytic enzymes, we hypothesized that CA IX plays an important role in malignant glioma Recently, specific small molecule inhibitors of this enzyme have been developed and may provide an innovative strategy for anti - invasive treatment. MATERIAL AND METHODS Two established and 4 primary GBM cell lines (2 with mesenchymal and 2 with proneural transcriptional profile) were exposed to the CAIX inhibitor U104 under normoxic and hypoxic conditions. Cell toxicity was measured by ATP and crystal violet assay. For invasion assessment, a matrigel invasion chamber system with 8 µm pore size polycarbonate filter was used. CAIX expression was analyzed by quantitative RTPCR and Western Blot. RESULTS Hypoxia significantly induced CAIX expression in all cell lines. Invasiveness increased significantly under hypoxic conditions in the mesenchymal cells (p &amp;lt; 0.01). Regardless of oxygenation status, the mesenchymal group displayed significantly higher invasiveness compared to the proneural group (p = 0.006). Looking at all cell lines, invasion is significantly inhibited by U104, both under normoxic and hypoxic conditions (p &amp;lt; 0.01). However, while the mesenchymal group showed the highest susceptibility to CAIX inhibition followed by the proneurally differentiated group, the established cell lines were entirely refractory to CAIX inhibition. CONCLUSION Our data demonstrate that CAIX inhibition can effectively inhibit invasion in malignant glioma cells independent from oxygenation status, however the effects are significantly influenced by cell type specific biological features.
Prospective analysis of newly diagnosed autoimmune hemolytic anemia: A single center study
Authors: D. Pulanic, M. Raos, G. Salai, M. Vodanovic, A. Boban, M. Mikulic, S. B. Kinda, D. Dujmovic, P. Roncevic, J. Batinic, A. Ostojic, L. Desnica, I. Radman, R. Vrhovac, B. G. Cepulic, I. Aurer
Journal: HemaSphere (2021)

Background: Autoimmune hemolytic anemia (AIHA) is an autoimmune- mediated disease in which erythrocytes are destroyed through (auto)antibodies against their surface antigens, resulting in premature lysis. It is a rare disorder and data about characteristics of AIHA from clinical practice are rare, especially if collected prospectively. Aims: This prospective study was conducted in order to analyze characteristics of patients with newly diagnosed AIHA. Methods: A single-center prospective study was performed at the University Hospital Center Zagreb (UHC), a tertiary center and the largest Croatian hospital, which included all consecutive patients with a newly diagnosed direct antiglobulin test positive AIHA from 1st Jan 2019 to 31th Dec 2020. Study was approved by UHC Ethical Committee. Descriptive statistics were performed and results are reported as frequencies (percentage) for categorical and as means (±standard deviation) or medians (minimum-maximum), as appropriate, for continuous values. Results: Data includes 17 patients (41% men), median age at diagnosis 52 (5-76) years. Majority of patients had secondary AIHA (14/17, 82%), mostly due to underlying lymphoproliferative malignant disease (7/14 patients, 50%). 4 had underlying autoimmune disorders, 1 solid cancer, 1 developed AIHA after allogeneic bone marrow transplantation, and 1 after M. pneumoniae infection. Median hemoglobin (Hb) at diagnosis was 74 (39-124) g/L;12 (71%) patients required hospital care with admission Hb of 58 (39-124) g/L, and 10 (59%) received erythrocyte transfusion. 15 (88%) patients required therapy with corticosteroids, and 6 (35%) received rituximab (as the first line therapy in 3/6 (50%) of patients). Patients were followed with a median time of 474 (22-648) days during which 13 (76%) achieved complete remission (CR) without signs of hemolysis or anemia, 1 showed improvement but failed to achieve normal Hb levels, 1 was refractory to therapy, and 2 were lost to follow-up. Median time from diagnosis to best response was 137 (43- 606) days. Of 13 patients in CR, 2 (15%) relapsed which was observed 260 and 363 days after remission. During follow up 2 patients suffered from COVID-19 infection, but neither showed signs of AIHA relapse. 2 patients died during follow-up due to AIHA-unrelated causes. Summary/Conclusion: Although with relatively small number of patients, this prospective study of newly diagnosed AIHA patients showed increased percentage of rituximab administration (from 17.6% to 35%) comparing to our previous retrospective single-center analysis from 2014 to 2018 (EHA library: Pulanic D, et al. 2019;PB 1963.). This is probably due to the increase of rituximab availability due to lower costs and more experience with this treatment modality.
Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer
Authors: Nicoletta Colombo, Coraline Dubot, Domenica Lorusso, M Valeria Caceres, Kosei Hasegawa, Ronnie Shapira-Frommer, Krishnansu S Tewari, Pamela Salman, Edwin Hoyos Usta, Eduardo Yañez, Mahmut Gümüş, Mivael Olivera Hurtado de Mendoza, Vanessa Samouëlian, Vincent Castonguay, Alexander Arkhipov, Sarper Toker, Kan Li, Stephen M Keefe, Bradley J Monk
Journal: New England Journal of Medicine (2021)

Pembrolizumab has efficacy in programmed death ligand 1 (PD-L1)–positive metastatic or unresectable cervical cancer that has progressed during chemotherapy. We assessed the relative benefit of adding pembrolizumab to chemotherapy with or without bevacizumab.
Society for the Study of Celiac Disease position statement on gaps and opportunities in coeliac disease
Authors: M. Ines Pinto-Sanchez, Jocelyn A. Silvester, Benjamin Lebwohl, Daniel A. Leffler, Robert P. Anderson, Amelie Therrien, Ciaran P. Kelly, Elena F. Verdu
Journal: Nature Reviews Gastroenterology & Hepatology (2021)
Covid-19: How Native Americans led the way in the US vaccination effort
Authors: Joanne Silberner
Journal: BMJ (2021)

Data from the US Centers for Disease Control and Prevention (CDC) show that Native American groups-American Indians and Alaska Natives-have consistently had the best vaccination records since covid-19 vaccination in the US began in early 2021.The CDC's daily tracker for 13 September showed that 47.5% of American Indians and Alaska Natives were fully vaccinated. 1 This compared with 41.8% of Asians, 37.8% of white Americans, and 29.9% of African Americans.The American Indian/Alaska Native group has maintained its lead since the beginning of vaccination in the first dose category as well.Community leaders ascribe this success to two things: first, the US government's decision to allow Native American communities to control vaccine distribution; and second, traditional ethnic values including respect for elders, "community first" philosophies, and a willingness to trust science-so long as it's presented by community members themselves.
Sequence-dependent synergistic antitumor interaction of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA, Vorinostat) in combination with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in non-small cell lung cancer cells
Authors: Alfredo Budillon, Francesca Bruzzese, Elena Di Gennaro, Massimiliano Barbieri, Alessandra Leone, Michele Caraglia
Journal: Cancer Research (2006)

2425  In this study we analyzed the antitumor effect of the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA, Vorinostat) in combination with gefitinib (‘Iressa’, ZD1839), an orally active EGFR-TKI (EGFR tyrosine kinase inhibitor) on A549 non-small cell lung cancer cells. Simultaneous exposure of A549 cells to gefitinib and SAHA, resulted in strong synergistic antiproliferative effect as demonstrated by median drug effect analysis calculating a combination index (CI) according to the method of Chou and Talalay. Dose reduction indexes (DRI) which represent the order of magnitude (fold) of dose reduction obtained in combination setting compared to each drug alone, resulted in a 5 to 21 fold-reduction in the IC50 values for SAHA and gefitinib, respectively. Moreover, the antitumor effects of SAHA in combination with gefitinib was sequence-dependent with strong synergistic effect achieved when SAHA was applied simultaneously or 24 hours before gefitinib. An antagonistic effect was observed when gefitinib was applied before SAHA. The molecular mechanisms underlying the interaction between SAHA and gefitinib could be ascribed to the time and dose dependent down-regulation of EGFR induced by SAHA within 24 hours from the beginning of treatment. Interestingly, SAHA was also able to down-regulate the expression of phospho-AKT after 24 hours while phospho-ERK1/2 were not affected. Moreover, in order to investigate the mechanism of the synergistic interaction observed we have performed high-sensitive two-dimensional difference in gel electrophoresis (2D-DIGE) and identified several proteins differentially expressed in SAHA/Gefitinib combination as compared with control cells. Furthermore, matrix-assisted laser desorption/ionization-time of fight (MALDI-TOF) mass spectrometry (MS) and ESI-Ion trap MS/MS were performed to identify the protein spots whose abundance changed significantly between the different conditions. Several proteins regulating mitochondrial homeostasis where identified and their role in the synergistic effect observed are currently under investigation. Overall, these results demonstrated that the combination of SAHA with specific inhibitors of EGFR such as gefitinib may improve the efficacy of treatment of non small cell lung cancer and should be clinically explored.‘Iressa’ is a trademark of AstraZeneca
Racial and ethnic disparities in nasopharyngeal cancer with an emphasis among Asian Americans.
Authors: Qian Wang, Hui Xie, Changchuan Jiang, Yaning Zhang, Yannan Li, Nicholas Theodoropoulos, Paolo Boffetta
Journal: Journal of Clinical Oncology (2021)

118 Background: Nasopharyngeal cancer (NPC) is characterized by a distinct geographic distribution which reflects genetic predispositions, with highest incidence in Southeastern Asia and Southern China. It continues to cause a significant health burden among Asian Americans (AAs), which is a fast growing but understudied racial group. Prior studies investigating NPC combined all AA groups which may mask heterogeneities among AA subgroups. We aimed to examine the disparities in NPC by dividing AAs into four major ethnic groups - Chinese, Filipinos, Vietnamese, and Japanese Americans. Methods: NPC cases were identified from the Surveillance, Epidemiology, and End Result (SEER) 18 database from 1975-2016. Information regarding age, sex, race/ethnicity, education, income, % of foreign born, marital status, region of SEER registry, stage, histology, grade, surgery, chemotherapy, and radiation therapy were extracted. Multivariate-adjusted Cox proportional hazard regression and Fine-Gray sub-distribution hazard models were used to calculate overall and cause-specific mortality. SEER*Stat was used to calculated age-adjusted incidence. Results: Among a total of 11,737 NPC patients, 42.2% were non-Hispanic White (NHW), 10.7% non-Hispanic Black (NHB), 7.1% Hispanics, 18.9% Chinese, 7.6% Filipinos, 4.8% Vietnamese, 1.0% Japanese and 7.7% other Asians. AAs continue to have the highest NPC incidence among all racial groups despite of an overall decreasing trend. Japanese were significantly more likely to be diagnosed at localized stage, having low grade tumor and having keratinizing squamous cell carcinoma histology compared to other AAs. Compared to NHW, Filipino Americans had decreased mortality (HR = 0.90; 95%CI:0.84-0.98). Chinese (HR = 0.95; 95%CI: 0.90-1.01), and Vietnamese (HR = 0.94; 95%CI: 0.86-1.03) also observed marginally reduced mortality but not Japanese Americans (HR = 1.09; 95%CI: 0.90-1.32). No differences in NPC-specific mortality by race/ethnicity groups were found. In addition, Chinese, Filipino and Vietnamese Americans with NPC were less likely to die of other cancer and cardiovascular disease than NHW, but no such differences were observed among NHB, Hispanics or Japanese Americans. Conclusions: Asian Americans have been historically studied as one single racial group mostly due to limited sample size, despite that it is consistent of a diverse population with different genetic makeup, socioeconomic status, cultural background, health behaviors, and health care access. Our novel finding that significant disparities exist within AA NPC patients in regard to demographic and clinical features, overall and cause-specific mortality underlines the importance of adequate AA-subgroup specific sample size in future studies in order to understand the prognostic role of ethnicity in NPC, and advocates more ethnically and culturally tailored cancer care delivery.
Response to: Correspondence on “European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) SLE classification criteria item performance” by Bossuyt<i>et al</i>
Authors: Martin Aringer, Karen Costenbader, Nicolai Leuchten, Thomas Dörner, Sindhu R Johnson
Journal: Annals of the Rheumatic Diseases (2021)

In their letter, 1 Drs Bossuyt and Meroni have used an elegant and creative approach to make use of the data on antinuclear antibodies (ANAs) of the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria project for systemic lupus erythematosus (SLE) . 2 They point out that the individual ANA titre has implications for the likelihood ratio (LR) of a diagnosis of SLE.This interpretation concludes that the LR for 1:160 is just below 1 (0.94) and drops to clearly below 1 with lower titres, that is, 0.17 at 1:80, 0.08 at 1:40 and 0.02 if negative.This means that lower titre ANA actually decreases the pretest probability of SLE, important information for diagnostic considerations.These findings also reiterate important differences between classification and diagnosis.For the EULAR/ACR SLE classification criteria, 3 4 the criterion, ANA of ≥1:80 ever, is used as a dichotomous entry criterion.This means that individuals who are always ANA negative are not considered for SLE classification.This is based on the low likelihood of SLE being truly ANA negative, in line with the actual performance in the EULAR/ ACR SLE criteria cohort. 5For ANA-positive patients, however, the low titre was chosen to not lose sensitivity.Specificity in the range of the other specific items 5 cannot be reached by ANA, even under the best of circumstances.Diagnosis is not the same as classification but looks at the individual patient rather than combing a cohort for study purposes.What Drs Bossuyt and Meroni now point out with their analysis is that low-titre ANAs by themselves are not a sufficient argument for SLE.While ANAs of at least 1:80 are sufficient for classifying SLE, low-titre ANA by itself, without relevant clinical arguments, is not a sufficient reason to suspect SLE.
P-selectin targeted RAGE-shRNA lipoplexes alleviate atherosclerosis-associated inflammation
Authors: Cristina Ana Mocanu, Elena Valeria Fuior, Geanina Voicu, Daniela Rebleanu, Florentina Safciuc, Mariana Deleanu, Ioana Madalina Fenyo, Virginie Escriou, Ileana Manduteanu, Maya Simionescu, Manuela Calin
Journal: Journal of Controlled Release (2021)

The receptor for advanced glycation end products (RAGE) plays a central role in the chronic inflammatory process associated with atherosclerosis development. We aimed to develop lipoplexes carrying RAGE-short hairpin (sh) RNA, targeted to the adhesion molecule P-selectin, selectively expressed on the surface of activated endothelium (Psel-lipo/shRAGE) to down-regulate RAGE expression as a therapeutic strategy for atherosclerosis. In vitro, Psel-lipo/shRAGE lipoplexes were efficiently taken up by activated endothelial cells (EC), decreased the expression of RAGE protein, and proved to be functional by reducing the monocyte adhesion to activated EC. In ApoE-deficient mice, the targeted lipoplexes accumulated specifically and efficiently transfected the aorta. The repeated administration of Psel-lipo/shRAGE lipoplexes, twice per week for one month: i) reduced the expression of RAGE protein in the aorta by decreasing the expression of NF-kB and TNF-α; ii) diminished the plasma levels of TNF-α, IL6, IL-1β, and MCP-1; iii) inhibited the atherosclerotic plaque development and iv) had no significant adverse effects. In conclusion, the newly developed Psel-lipo/shRAGE lipoplexes reduce the inflammatory processes associated with RAGE signaling and the progression of atherosclerosis in ApoE-deficient mice. Downregulation of RAGE employing these lipoplexes may represent a promising new targeted therapy to block atherosclerosis progression.