tbuckley/cabot-search huggingface dataset:
Mouse visual cortex areas represent perceptual and semantic features of learned visual categories
Authors: Pieter M. Goltstein, Sandra Reinert, Tobias Bonhoeffer, Mark Hübener
Journal: Nature Neuroscience (2021)

Abstract Associative memories are stored in distributed networks extending across multiple brain regions. However, it is unclear to what extent sensory cortical areas are part of these networks. Using a paradigm for visual category learning in mice, we investigated whether perceptual and semantic features of learned category associations are already represented at the first stages of visual information processing in the neocortex. Mice learned categorizing visual stimuli, discriminating between categories and generalizing within categories. Inactivation experiments showed that categorization performance was contingent on neuronal activity in the visual cortex. Long-term calcium imaging in nine areas of the visual cortex identified changes in feature tuning and category tuning that occurred during this learning process, most prominently in the postrhinal area (POR). These results provide evidence for the view that associative memories form a brain-wide distributed network, with learning in early stages shaping perceptual representations and supporting semantic content downstream.
Optogenetic therapy restores retinal activity in primate for at least a year following photoreceptor ablation
Authors: Juliette E. McGregor, Karteek Kunala, Zhengyang Xu, Peter J. Murphy, Tyler Godat, Jennifer M. Strazzeri, Brittany A. Bateman, William S. Fischer, Keith Parkins, Colin J. Chu, Teresa Puthussery, David R. Williams, William H. Merigan
Journal: Molecular Therapy (2021)

All retina-based vision restoration approaches rely on the assumption that photoreceptor loss does not preclude reactivation of the remaining retinal architecture. Whether extended periods of vision loss limit the efficacy of restorative therapies at the retinal level is unknown. We examined long-term changes in optogenetic responsivity of foveal retinal ganglion cells (RGCs) in non-human primates following localized photoreceptor ablation by high-intensity laser exposure. By performing fluorescence adaptive optics scanning light ophthalmoscopy (AOSLO) of RGCs expressing both the calcium indicator GCaMP6s and the optogenetic actuator ChrimsonR, it was possible to track optogenetic-mediated calcium responses in deafferented RGCs over time. Fluorescence fundus photography revealed a 40% reduction in ChrimsonR fluorescence from RGCs lacking photoreceptor input over the 3 weeks following photoreceptor ablation. Despite this, in vivo imaging revealed good cellular preservation of RGCs 3 months after the loss of photoreceptor input, and histology confirmed good structural preservation at 2 years. Optogenetic responses of RGCs in primate persisted for at least 1 year after the loss of photoreceptor input, with a sensitivity index similar to optogenetic responses recorded in intact retina. These results are promising for all potential therapeutic approaches to vision restoration that rely on preservation and reactivation of RGCs.
Safety, immunogenicity and efficacy of PfSPZ Vaccine against malaria in infants in western Kenya: a double-blind, randomized, placebo-controlled phase 2 trial
Authors: Martina Oneko, Laura C. Steinhardt, Reuben Yego, Ryan E. Wiegand, Phillip A. Swanson, Natasha KC, Dorcas Akach, Tony Sang, Julie R. Gutman, Elizabeth L. Nzuu, Allan Dungani, B. Kim Lee Sim, Paul Ndaya Oloo, Kephas Otieno, Dennis K. Bii, Peter F. Billingsley, Eric R. James, Simon Kariuki, Aaron M. Samuels, Said Jongo, Winnie Chebore, Salim Abdulla, Claudia Daubenberger, Maxmillian Mpina, David Styers, Gail E. Potter, Ginnie Abarbanell, Thomas L. Richie, Stephen L. Hoffman, Robert A. Seder
Journal: Nature Medicine (2021)
Endoscopic tissue sampling – Part 1: Upper gastrointestinal and hepatopancreatobiliary tracts. European Society of Gastrointestinal Endoscopy (ESGE) Guideline
Authors: Roos E. Pouw, Maximilien Barret, Katharina Biermann, Raf Bisschops, László Czakó, Krisztina B. Gecse, Gert de Hertogh, Tomas Hucl, Marietta Iacucci, Marnix Jansen, Matthew Rutter, Edoardo Savarino, Manon C. W. Spaander, Peter T. Schmidt, Michael Vieth, Mário Dinis-Ribeiro, Jeanin E. van Hooft
Journal: Endoscopy (2021)

1: ESGE recommends that, where there is a suspicion of eosinophilic esophagitis, at least six biopsies should be taken, two to four biopsies from the distal esophagus and two to four biopsies from the proximal esophagus, targeting areas with endoscopic mucosal abnormalities. Distal and proximal biopsies should be placed in separate containers.Strong recommendation, low quality of evidence. 2: ESGE recommends obtaining six biopsies, including from the base and edge of the esophageal ulcers, for histologic analysis in patients with suspected viral esophagitis.Strong recommendation, low quality of evidence. 3: ESGE recommends at least six biopsies are taken in cases of suspected advanced esophageal cancer and suspected advanced gastric cancer.Strong recommendation, moderate quality of evidence. 4: ESGE recommends taking only one to two targeted biopsies for lesions in the esophagus or stomach that are potentially amenable to endoscopic resection (Paris classification 0-I, 0-II) in order to confirm the diagnosis and not compromise subsequent endoscopic resection.Strong recommendation, low quality of evidence. 5: ESGE recommends obtaining two biopsies from the antrum and two from the corpus in patients with suspected Helicobacter pylori infection and for gastritis staging.Strong recommendation, low quality of evidence. 6: ESGE recommends biopsies from or, if endoscopically resectable, resection of gastric adenomas.Strong recommendation, moderate quality of evidence. 7: ESGE recommends fine-needle aspiration (FNA) and fine-needle biopsy (FNB) needles equally for sampling of solid pancreatic masses.Strong recommendation, high quality evidence. 8: ESGE suggests performing peroral cholangioscopy (POC) and/or endoscopic ultrasound (EUS)-guided tissue acquisition in indeterminate biliary strictures. For proximal and intrinsic strictures, POC is preferred. For distal and extrinsic strictures, EUS-guided sampling is preferred, with POC where this is not diagnostic.Weak recommendation, low quality evidence. 9: ESGE suggests obtaining possible non-neoplastic biopsies before sampling suspected malignant lesions to prevent intraluminal spread of malignant disease.Weak recommendation, low quality of evidence. 10: ESGE suggests dividing EUS-FNA material into smears (two per pass) and liquid-based cytology (LBC), or the whole of the EUS-FNA material can be processed as LBC, depending on local experience.Weak recommendation, low quality evidence.
Mapping the evolving landscape of super-enhancers during cell differentiation
Authors: Yan Kai, Bin E. Li, Ming Zhu, Grace Y. Li, Fei Chen, Yingli Han, Hye Ji Cha, Stuart H. Orkin, Wenqing Cai, Jialiang Huang, Guo-Cheng Yuan
Journal: Genome biology (2021)

Abstract Background Super-enhancers are clusters of enhancer elements that play critical roles in the maintenance of cell identity. Current investigations on super-enhancers are centered on the established ones in static cell types. How super-enhancers are established during cell differentiation remains obscure. Results Here, by developing an unbiased approach to systematically analyze the evolving landscape of super-enhancers during cell differentiation in multiple lineages, we discover a general trend where super-enhancers emerge through three distinct temporal patterns: conserved, temporally hierarchical, and de novo. The three types of super-enhancers differ further in association patterns in target gene expression, functional enrichment, and 3D chromatin organization, suggesting they may represent distinct structural and functional subtypes. Furthermore, we dissect the enhancer repertoire within temporally hierarchical super-enhancers, and find enhancers that emerge at early and late stages are enriched with distinct transcription factors, suggesting that the temporal order of establishment of elements within super-enhancers may be directed by underlying DNA sequence. CRISPR-mediated deletion of individual enhancers in differentiated cells shows that both the early- and late-emerged enhancers are indispensable for target gene expression, while in undifferentiated cells early enhancers are involved in the regulation of target genes. Conclusions In summary, our analysis highlights the heterogeneity of the super-enhancer population and provides new insights to enhancer functions within super-enhancers.
P09.05 Treatment strategy of MRI postcontrast non-enhanced gliomas
Authors: O Kalita, L Hrabalek, V Jan, M Slachta, Y Klementová, M Dolezel, E Cechakova, J Drabek, M Hajduch, P Hok, P Hlustik, L Tuckova, M Halaj, J Vrbkova
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND MRI postcontrast nonenhanced brain tumors are found benign biologic entities with the better prognosis. The aim of this paper is to evaluate predictive features on MRI considered definite diagnosis occurrence, tumor progression, upgrading and postcontrast enhancement evolution on follow-up serial MRI. MATERIAL AND METHODS We retrospectively collected patients with the initially MRI postcontrast nonenhanced brain tumors, treated in our hospital from January 2009 to June 1, 2006. All tumors were converted into WHO 2016 IDH status classifications in accordance with current recommendations. Information about surgeries, patient clinical condition, MRI, and results of histological, immunohistochemical, molecular genetic, and cytogenetic investigations were gathered. Semiautomatic segmentations were performed using FSLeyes software (part of FSL package) on preoperative and followed-up 3D T1-w MPRAGE, T2-w or FLAIR scans. We focused on residual tumor volume, and time distribution of T2/FLAIR changes and T1-w postcontrast enhancement evolution. RESULTS Seventy-eight patients were enrolled in this study. There were 47 gliomas grade II 22 grade III and 9 grade IV. Glioma II comprised 35 diffuse astrocytomas (23 patients had IDH1 mutation). Nine gliomas grade III and 6 gliomas grade IV had IDH1 mutation. Overall survival in glioma group grade II, grade III, grade IV was 187.9 months, 71.1 months and 25.2 months, respectively. Oncotherapy underwent 14 gliomas grade II after first surgery, 13 patients had radiotherapy a 1 patient had neoadjuvant chemotherapy. Seventeen gliomas grade III were indicated to oncotherapy, 5 patients had radiotherapy and 12 had chemoradiotherapy. All patients with glioma grade IV experienced oncotherapy. Time to progression of non-contrast enhanced brain tumor was 5.8 years. Time to up-grading of non-contrast enhanced brain tumor was 16.8 months. Detailed time relations of glioma subgroup will be displayed in tables. CONCLUSION Regarding MRI postcontrast non-enhanced tumors, predominantly low grade gliomas (LGG), aggressive oncotherapy are reluctant to use but they are prone to repeat surgeries. Decision making issues are age, clinical patient status, histologic and genetic tumor characteristics, residual tumor volume, published guidelines for brain tumor treatment, and patient′s willing. Generally, hyposignal on the T1 postcontrast scans strictly relate to the better prognosis, even in HGG. Longer survival expectancy increases quality of life awareness. Prior to MRI postcontrast enhanced evolution and up-grading, T2/FLAIR changes have been demonstrated. T2/FLAIR scans considered also main role in LGG follow-up strategy. Individual tailored therapy is principal strategy. Supported by Ministry of Health of the Czech Republic, grant nr. NV19-04-00281 and grant nr. NU21-03-00195
Acoustic Droplet Printing Tumor Organoids for Modeling Bladder Tumor Immune Microenvironment within a Week
Authors: Zhiyi Gong, Lanxiang Huang, Xuan Tang, Keke Chen, Zhuhao Wu, Lingling Zhang, Yue Sun, Yu Xia, Hui Chen, Yongchang Wei, Fubing Wang, Shishang Guo
Journal: Advanced Healthcare Materials (2021)

Abstract Current organoid models are limited by the incapability of rapidly fabricating organoids that can mimic the immune microenvironment for a short term. Here, an acoustic droplet‐based platform is presented to facilitate the rapid formation of tumor organoids, which retains the original tumor immune microenvironment and establishes a personalized bladder cancer tumor immunotherapy model. In combination with a hydrophobic substrate, the acoustic droplet printer can yield a large number of homogeneous and highly viable bladder tumor organoids in vitro within a week. The generated organoids consist of all components of bladder tumor, including diverse immune elements and tumor cells. By coculturing tumor organoids with autologous immune cells for 2 days, tumor reactive T cells are induced in vitro. Furthermore, it is also demonstrated that these tumor‐reactive T cells can also enhance the killing efficiency of matched organoids. Because of the easy operation, repeatability, and stability, the proposed acoustic droplet platform will provide a reliable approach for personalized tumor immunotherapy.
MG53 suppresses tumor progression and stress granule formation by modulating G3BP2 activity in non-small cell lung cancer
Authors: Haichang Li, Pei-Hui Lin, Pranav Gupta, Xiangguang Li, Serena Li Zhao, Xinyu Zhou, Zhongguang Li, Shengcai Wei, Li Xu, Renzhi Han, Jing Lu, Tao Tan, Dong-Hua Yang, Zhe-Sheng Chen, Timothy M. Pawlik, Robert E. Merritt, Jianjie Ma
Journal: Molecular Cancer (2021)

Cancer cells develop resistance to chemotherapeutic intervention by excessive formation of stress granules (SGs), which are modulated by an oncogenic protein G3BP2. Selective control of G3BP2/SG signaling is a potential means to treat non-small cell lung cancer (NSCLC).Co-immunoprecipitation was conducted to identify the interaction of MG53 and G3BP2. Immunohistochemistry and live cell imaging were performed to visualize the subcellular expression or co-localization. We used shRNA to knock-down the expression MG53 or G3BP2 to test the cell migration and colony formation. The expression level of MG53 and G3BP2 in human NSCLC tissues was tested by western blot analysis. The ATO-induced oxidative stress model was used to examine the effect of rhMG53 on SG formation. Moue NSCLC allograft experiments were performed on wild type and transgenic mice with either knockout of MG53, or overexpression of MG53. Human NSCLC xenograft model in mice was used to evaluate the effect of MG53 overexpression on tumorigenesis.We show that MG53, a member of the TRIM protein family (TRIM72), modulates G3BP2 activity to control lung cancer progression. Loss of MG53 results in the progressive development of lung cancer in mg53-/- mice. Transgenic mice with sustained elevation of MG53 in the bloodstream demonstrate reduced tumor growth following allograft transplantation of mouse NSCLC cells. Biochemical assay reveals physical interaction between G3BP2 and MG53 through the TRIM domain of MG53. Knockdown of MG53 enhances proliferation and migration of NSCLC cells, whereas reduced tumorigenicity is seen in NSCLC cells with knockdown of G3BP2 expression. The recombinant human MG53 (rhMG53) protein can enter the NSCLC cells to induce nuclear translation of G3BP2 and block arsenic trioxide-induced SG formation. The anti-proliferative effect of rhMG53 on NSCLC cells was abolished with knockout of G3BP2. rhMG53 can enhance sensitivity of NSCLC cells to undergo cell death upon treatment with cisplatin. Tailored induction of MG53 expression in NSCLC cells suppresses lung cancer growth via reduced SG formation in a xenograft model.Overall, these findings support the notion that MG53 functions as a tumor suppressor by targeting G3BP2/SG activity in NSCLCs.
P14.02 The Natural History of a Residual Intracranial Meningioma- Volumetric Growth and Predictors of Progression
Authors: C S Gillespie, G E Richardson, M A Mustafa, A I Islim, S M Keshwara, B A Taweel, A Bakhsh, S Kumar, C P Millward, S Mehta, N Rathi, E Chavredakis, A R Brodbelt, S J Mills, M D Jenkinson
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Resection of meningioma leaves residual solid tumour in ~25% of patients. Selection for further treatment and follow-up strategy may benefit from knowledge of volumetric growth and associated prognostic factors. MATERIAL AND METHODS Growth rates were assessed using a linear mixed effects model, in a retrospective adult cohort that underwent subtotal resection of meningioma (2004–2018). Endpoints were re-treatment, end of follow-up or death. Cox regression analysis was used to identify prognostic factors for progression, defined using the Response Assessment in Neuro-Oncology (RANO) volumetric criteria. RESULTS 236 patients were included. Mean age at surgery was 56.3 years (SD=13.7) and 73.7% were female. WHO grades were 1 (n=195, 82.6%), 2 (n=40, 16.9%) and 3 (n=1, 0.5%). Adjuvant fractionated radiotherapy (fRT) was administered to 34 patients (14.4%), with no propensity towards higher WHO grade or residual volume. Median pre-operative meningioma and post-operative residual volumes were 34.0cm3 (IQR 16.0–63.0) and 2.0cm3 (IQR 0.8–5.2), respectively. Median follow-up was 64 months (IQR 42–104). Median absolute growth rate (AGR) and relative growth rate (RGR) were 0.1cm3/year and 4.3%/year, respectively. According to RANO criteria, 132 (55.9%) patients progressed, of which 13 (9.8%) developed symptoms. Median progression-free survival was 56 months (95% CI 43.1–69.0). Multivariable analysis identified adjuvant fRT (HR 1.7, [95% CI 1.0–2.8], P=0.046), skull base location (HR 1.5, [95% CI 1.0–2.4], P=0.047) and Ki-67 index (HR 3.7 [95% CI 1.3–10.8], P=0.017) as prognostic factors for volumetric progression. WHO grade was not significant (HR 1.0, [95% CI 0.5–1.7], P=0.905). Forty-nine patients who progressed (37.1%) underwent further treatment: fRT (n=19), re-operation (n=15), Stereotactic radiosurgery (SRS) (n=10) and surgery+adjuvant fRT (n=5). Of those, 8 (16.3%) progressed further (after re-operation [n=6] and SRS [n=2]). Seven were treated with a 2nd re-operation (n=3), fRT (n=3), and SRS (n=1). One patient progressed after a 2nd reoperation and was treated with SRS, after which they remained stable. Median survival was not reached. 5- and 10-year overall survival (OS) was 96% and 86% respectively. CONCLUSION Growth rates of a residual meningioma vary with a dichotomy observed in progression rates. Half of patients with a residual meningioma showed radiological progression requiring multiple treatment to control the tumour. The other half demonstrate a more indolent course. Skull base location and higher Ki67 are important prognostic factors for progression and therefore, should be considered to stratify patients for adjuvant radiotherapy.
The micrornas mir-373 and mir-520c promote tumor migration, invasion and metastasis
Authors: Qihong Huang, Kiranmai Gumireddy, Mariette Schrier, Carlos le Sage, Remco Nagel, Suresh Nair, David Egan, Anping Li, Guanghua Huang, Andres Klein-Szanto, Gimotty Phyllis, Dionyssios Katsaros, George Coukos, Lin Zhang, Ellen Pure, Reuven Agami
Journal: Cancer Research (2008)

5015  MicroRNAs (miRNAs) are single-stranded noncoding RNAs that play important roles in many biological processes. Although the oncogenic and tumor suppressive functions of several miRNAs have been characterized, the role of miRNAs in mediating tumor metastasis was only recently addressed and still remained largely unexplored. To identify potential metastasis-promoting miRNAs, we set up a genetic screen using a non-metastatic human breast tumor cell-line that was transduced with a miRNA-expression library and subjected to a trans-well migration assay. We found human miR-373 and 520C to stimulate cancer cell migration as well as tumor cell invasion in vitro and in vivo, and that certain cancer cell lines depend on endogenous miR-373 activity to migrate efficiently. Mechanistically, the migration phenotype of miR-373 and miR-520C can be explained by their suppression of CD44 expression. Finally, we found significant up-regulation of miR-373 expression in clinical breast cancer primary and metastasis samples that inversely correlated with CD44 expression. Taken together, our study indicates that miRNAs are involved in tumor migration and invasion and implicates miR-373 and conceivably 520C as metastasis-promoting miRNAs.
A Clinical Conundrum: Intensifying Glycemic Control in the Presence of Advanced Diabetic Retinopathy
Authors: Eli Ipp, Monisha Kumar
Journal: Diabetes Care (2021)

Diabetic retinopathy (DR) is a potentially devastating complication of diabetes because of the risk of developing blindness. While therapies to prevent blindness are improving, in much of the world visual impairment continues to occur and impact on the lives of people with diabetes and the societies they live in (1,2). Glycemic control has been shown to provide protection from progression of DR (3–5), but there appear to be limits to that protection. Lowering A1C with a goal of achieving A1C <7% was no better than using a goal slightly above that (6.8% vs. 7.3%) when baseline A1C was ∼7.5% at the outset; this small decrement and small continued difference did not further protect the retina (6). Furthermore, if duration of diabetes is sufficiently long, even relatively tight control is eventually associated with development of DR (3–5), suggesting that there are other factors that mediate DR besides glycemia (7,8).

Another factor that might limit the effect of improving glycemia to prevent progression is the presence of advanced DR at the time of initiating a glycemic control trial (9). The Veterans Affairs Diabetes Trial (VADT) did not show evidence of protection against DR progression, explained by the severity level of DR at the start of the trial (9), which was greater than in other comparable large trials (3–5).

This month's issue of Diabetes Care contains another publication from the VADT with the major outcome focused on eye procedures that were performed subsequent to entry into …
Mass Shootings in the US During the COVID-19 Pandemic
Authors: Pablo A. Peña, Anupam Jena
Journal: JAMA Network Open (2021)

Mass shootings are rare events with causes that are not well understood, particularly, the extent to which they are responses to social and economic circumstances.The COVID-19 pandemic imposed sudden and additional psychological and financial strains across society through fear of death, social isolation, economic hardship, and general uncertainty.Although several studies have examined how gun violence, homicides, and other crimes have responded to the pandemic, these analyses have focused on small groups of cities and have not considered mass shootings, which are an extreme form of violence whose causes may not be the same. 1-4This cross-sectional study analyzes changes in mass shootings in the US during the COVID-19 pandemic. MethodsThis cross-sectional study used publicly available, aggregated data and was exempt from informed consent and human subjects review at Harvard Medical School.This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.This cross-sectional study analyzed changes in mass shootings during the COVID-19 pandemic by examining publicly available information about mass shootings in the US between January 1, 2014, and June 30, 2021, from the Gun Violence Archive, a repository of gun violence incidents collected from over 7500 law enforcement, media, government, and commercial sources. 5In the data, mass shootings are defined as shootings in which 4 or more people were killed or injured, not counting the perpetrator (eMethods in the Supplement).We downloaded the data between April 14, 2021, to July 2, 2021, and analyzed the data from April 14, 2021, to July 3, 2021.We plotted 28-day moving means of the count of mass shootings in each year between 2014 and 2020, with partial data from January to June 2021.We focused on the period from mid-April 2020 onward and compared the data with the trends in the years prior to account for any seasonal variation in mass shootings.In addition, we conducted an event study Figure.