tbuckley/cabot-search huggingface dataset:
The Drosophila Y Chromosome Affects Heterochromatin Integrity Genome-Wide
Authors: Emily J Brown, Alison H Nguyen, Doris Bachtrog
Journal: Molecular Biology and Evolution (2020)

Abstract The Drosophila Y chromosome is gene poor and mainly consists of silenced, repetitive DNA. Nonetheless, the Y influences expression of hundreds of genes genome-wide, possibly by sequestering key components of the heterochromatin machinery away from other positions in the genome. To test the influence of the Y chromosome on the genome-wide chromatin landscape, we assayed the genomic distribution of histone modifications associated with gene activation (H3K4me3) or heterochromatin (H3K9me2 and H3K9me3) in fruit flies with varying sex chromosome complements (X0, XY, and XYY males; XX and XXY females). Consistent with the general deficiency of active chromatin modifications on the Y, we find that Y gene dose has little influence on the genomic distribution of H3K4me3. In contrast, both the presence and the number of Y chromosomes strongly influence genome-wide enrichment patterns of repressive chromatin modifications. Highly repetitive regions such as the pericentromeres, the dot, and the Y chromosome (if present) are enriched for heterochromatic modifications in wildtype males and females, and even more strongly in X0 flies. In contrast, the additional Y chromosome in XYY males and XXY females diminishes the heterochromatic signal in these normally silenced, repeat-rich regions, which is accompanied by an increase in expression of Y-linked repeats. We find hundreds of genes that are expressed differentially between individuals with aberrant sex chromosome karyotypes, many of which also show sex-biased expression in wildtype Drosophila. Thus, Y chromosomes influence heterochromatin integrity genome-wide, and differences in the chromatin landscape of males and females may also contribute to sex-biased gene expression and sexual dimorphisms.
Covid-19: Use radiotherapy only if “unavoidable,” says NICE
Authors: Elisabeth Mahase
Journal: BMJ (2020)

Aim: The aim of the study was to compare two different neurotoxicity scales in grading chemotherapy-induced neurotoxicity. Patients and Methods: The study sample consisted of 114 cancer patients who started chemotherapy with vinca alcaloids, platinum derivatives or taxanes. Neurotoxicity was evaluated with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) and oxaliplatin scales at baseline and after every third chemotherapy cycle thereafter. Results: Neuropathy was detected in 60%, 55% and 75% at the second, third and fourth visits, respectively, with the NCI-CTC sensory scale and 59%, 55% and 80% with the oxalipalatin scale. Of the patients with grade 3-4 toxicity on the oxaliplatin scale, 23/53 had grade 1, 18/53 had grade 2 and 12/53 had grade 3 neurotoxicity on the NCI-CTC sensory scale. Conclusion: The oxaliplatin and NCI-CTC sensory scales were comparable in identifying chemotherapy-induced neuropathy, but the oxaliplatin scale more often detected the progression of the symptoms.
The Loss of TBK1 Kinase Activity in Motor Neurons or in All Cell Types Differentially Impacts ALS Disease Progression in SOD1 Mice
Authors: Valeria Gerbino, Esther Kaunga, Junqiang Ye, Daniele Canzio, Sean O’Keeffe, Noam D. Rudnick, Paolo Guarnieri, Cathleen M. Lutz, Tom Maniatis
Journal: Neuron (2020)
Covid-19: US gives emergency approval to hydroxychloroquine despite lack of evidence
Authors: Jeanne Lenzer
Journal: BMJ (2020)

The US Food and Drug Administration has authorized clinicians to prescribe chloroquine and hydroxychloroquine for patients admitted to hospital with covid-19, despite warnings from scientific advisers that no randomized controlled trial has been conducted to support the drugs’ safety and efficacy in this population.

In the emergency use authorization issued on 28 March,1 the agency acknowledged that the approval was based on “limited in-vitro and anecdotal clinical data.”

The FDA action followed President Trump’s statements at a press conference last week that hydroxychloroquine showed “tremendous promise” for patients with covid-19, adding, “I think it’s going to be great.”2

Trump cited a controversial French study of 20 patients published the previous day. Anthony Fauci, head of the National Institute for Allergies and Infectious Diseases at the National Institutes of Health, corrected Trump’s comments, saying that they were …
Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells
Authors: Anna Julie Peired, Giulia Antonelli, Maria Lucia Angelotti, Marco Allinovi, Francesco Guzzi, Alessandro Sisti, Roberto Semeraro, Carolina Conte, Benedetta Mazzinghi, Sara Nardi, Maria Elena Melica, Letizia De Chiara, Elena Lazzeri, Laura Lasagni, Tiziano Lottini, Samuela Landini, Sabrina Giglio, Andrea Mari, Fabrizio Di Maida, Alessandro Antonelli, Francesco Porpiglia, Riccardo Schiavina, Vincenzo Ficarra, Davide Facchiano, Mauro Gacci, Sergio Serni, Marco Carini, George J. Netto, Rosa Maria Roperto, Alberto Magi, Christian Fynbo Christiansen, Mario Rotondi, Helen Liapis, Hans-Joachim Anders, Andrea Minervini, Maria Rosaria Raspollini, Paola Romagnani
Journal: Science Translational Medicine (2020)

Acute tissue injury causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. Here, we show that acute kidney injury (AKI) increased the risk for papillary renal cell carcinoma (pRCC) development and tumor relapse in humans as confirmed by data collected from several single-center and multicentric studies. Lineage tracing of tubular epithelial cells (TECs) after AKI induction and long-term follow-up in mice showed time-dependent onset of clonal papillary tumors in an adenoma-carcinoma sequence. Among AKI-related pathways, NOTCH1 overexpression in human pRCC associated with worse outcome and was specific for type 2 pRCC. Mice overexpressing NOTCH1 in TECs developed papillary adenomas and type 2 pRCCs, and AKI accelerated this process. Lineage tracing in mice identified single renal progenitors as the cell of origin of papillary tumors. Single-cell RNA sequencing showed that human renal progenitor transcriptome showed similarities to PT1, the putative cell of origin of human pRCC. Furthermore, NOTCH1 overexpression in cultured human renal progenitor cells induced tumor-like 3D growth. Thus, AKI can drive tumorigenesis from local tissue progenitor cells. In particular, we find that AKI promotes the development of pRCC from single progenitors through a classical adenoma-carcinoma sequence.
Abstract P2-16-21: Novel use of a precision medicine tool in the neoadjuvant therapy setting
Authors: Peter Beitsch, Pat Whitworth, Laura Lee, Antonio Ruiz, Rick Brown, Linsey Gold, Paul Baron, Rakesh Patel
Journal: Cancer Research (2020)

Abstract Background: Molecular genomic profiles are increasingly used to guide treatment of refractory cancers and are on the forefront of personalized medicine for select patients. The neoadjuvant chemotherapy (NAC) setting provides a meaningful opportunity to compare genomic profiles to pathologic response. We report profiles to response in a novel multi center registry. Methods: An ongoing IRB (WIRB) approved registry at 6 community breast practices submitted tumor samples prior to treatment for genomic/proteomic analysis (Paradigm, Phoenix, AZ.) Tumor response and associated molecular profiles were analyzed. The test evaluated over 137 genomic alterations with known actionable variations including mutations, gene-fusions, copy number variations, MRNA expression and protein expression analysis by IHC. Results: 76 patients were enrolled and 42 have completed treatment including definitive surgery and have reported data as of this date. The vast majority of patients had invasive ductal carcinoma with 16% having triple negative biology and 20% having Her2 biology. Of the triple negative patients with reported surgical results, 42% had a complete response or minimal residual disease, and the remaining 58% had a partial response. Of the patients with HER2 biology, 85% had a complete response and the remaining a partial response. 17% of patients with luminal biology had a complete response; the remaining had only a partial response or progression. Overall, 15 patients had a complete response, 4 had minimal residual disease and the remaining (over 50%) had a partial response, stable or progressive disease. Patients who did not achieve a complete response had multiple molecular aberrations with unique markers not present in patients with PCR. These included markers of known or possible drug resistance (IGFR1, CAIX), poor prognostic markers (TP53, MET, PTEN), biomarkers of response to approved treatment that were not utilized and other markers of potential response and research. Conclusions: Comprehensive genomic testing may predict resistant biology and provide additional targets for treatment or clinical study. Genomic analysis earlier in the patient’s care path may improve response rates by suggesting modifications in standard protocols or identifying clinical trials as potential first line options. Repeat genomic analysis may also suggest options for targeted adjuvant therapy for residual cancer after neoadjuvant therapy. Citation Format: Peter Beitsch, Pat Whitworth, Laura Lee, Antonio Ruiz, Rick Brown, Linsey Gold, Paul Baron, Rakesh Patel. Novel use of a precision medicine tool in the neoadjuvant therapy setting [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-21.
Prevalence of risk of thrombosis and of bleeding and antithrombotic treatment in patients with heart failure
Authors: Massimo Pozzoli, Jose Gonzalez‐Costello, Antoni Bayes‐Genis, Gianfranco Sinagra, Stefan D. Anker, Andrew J.S. Coats, Marisa G. Crespo‐Leiro, Gerasimos Filippatos, Cécile Laroche, Aldo P. Maggioni, Alexandre Mebazaa, Massimo F. Piepoli, Luigi Tavazzi
Journal: European Journal of Heart Failure (2020)
Abstract OT3-12-01: Effect of home-based high-intensity interval training and behavioral modification using information and communication technology on cardiorespiratory fitness and exercise habits among sedentary breast cancer survivors: The habit-B randomized controlled trial in progress
Authors: Katsunori Tsuji, Eisuke Ochi, Yoichi Shimizu, Aya Kuchiba, Tomomi Narisawa, Yuri Ishino, Ryo Okubo, Taro Ueno, Taichi Shimazu, Takayuki Kinoshita, Naomi Sakurai, Yutaka Matsuoka
Journal: Cancer Research (2020)

Abstract Maintaining high levels of physical activity not only helps to maintain and improve physical health and quality of life, but also plays a role in reducing adverse effects due to cancer treatments. Moreover, a greater degree of cardiorespiratory fitness is associated with reduced risk of all-cause mortality in breast cancer survivors. However, there are no home-based programs for improving cardiorespiratory fitness using body weight exercises for breast cancer survivors. This study assesses the efficacy of the newly developed habit-B program (12-weeks, high-intensity interval training exercise, exercise counseling + guidance, home-based exercise support using information and communication technology, and a wearable device (fitbit versa®)) on peak oxygen uptake (VO2peak; mL/kg/min) compared with treatment as usual. This is a parallel-group, single blind, randomized controlled trial. Subjects are sedentary women aged 20 to 59 years who have received breast surgery in the past 2 to 13 months after diagnosis of invasive breast cancer (Stage I-IIa) and have never received chemo-therapy except for hormone therapy. The primary outcome is difference of change in VO2peak between the groups after 12 weeks. The planned sample size is 60 patients to detect the increase of 2.0 ml/kg/min change in VO2peak with a one-sided significance level of 2.5% and 80% power. The effects of this program on exercise habits, physical activity, physical fitness, fatigue, health-related quality of life, and psychological distress are also be investigated. We have already enrolled 6 subjects as of 2019.7.2, and study will be planned to be finished by 2020 April. Citation Format: Katsunori Tsuji, Eisuke Ochi, Yoichi Shimizu, Aya Kuchiba, Tomomi Narisawa, Yuri Ishino, Ryo Okubo, Taro Ueno, Taichi Shimazu, Takayuki Kinoshita, Naomi Sakurai, Yutaka Matsuoka. Effect of home-based high-intensity interval training and behavioral modification using information and communication technology on cardiorespiratory fitness and exercise habits among sedentary breast cancer survivors: The habit-B randomized controlled trial in progress [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-12-01.
Disease Monitoring Using Post-induction Circulating Tumor DNA Analysis Following First-Line Therapy in Patients with Metastatic Colorectal Cancer
Authors: Xiaoju Max Ma, Johanna C. Bendell, Herbert I. Hurwitz, Christine Ju, John J. Lee, Alex Lovejoy, Christoph Mancao, Alan Nicholas, Richard Price, Nicolas Sommer, Nalin Tikoo, Lijing Yao, Stephanie J. Yaung, John F. Palma
Journal: Clinical Cancer Research (2020)

We assessed plasma circulating tumor DNA (ctDNA) level as a prognostic marker for progression-free survival (PFS) following first-line metastatic colorectal cancer (mCRC) therapy.The Sequencing Triplet With Avastin and Maintenance (STEAM) was a randomized, phase II trial investigating efficacy of bevacizumab (BEV) plus 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) and 5-fluorouracil/leucovorin/irinotecan (FOLFIRI), administered concurrently or sequentially, versus FOLFOX-BEV in first-line mCRC. Evaluation of biomarkers associated with treatment outcomes was an exploratory endpoint. Patients in the biomarker-evaluable population (BEP) had 1 tissue sample, 1 pre-induction plasma sample, and 1 post-induction plasma sample collected ≤60 days of induction from last drug date.Among the 280 patients enrolled in STEAM, 183 had sequenced and evaluable tumor tissue, 118 had matched pre-induction plasma, and 54 (BEP) had ctDNA-evaluable sequencing data for pre- and post-induction plasma. The most common somatic variants in tumor tissue and pre-induction plasma were TP53, APC, and KRAS. Patients with lower-than-median versus higher-than-median post-induction mean allele fraction (mAF) levels had longer median PFS (17.7 vs. 7.5 months, HR, 0.33; 95% confidence interval, 0.17-0.63). Higher levels of post-induction mAF and post-induction mean mutant molecules per milliliter (mMMPM), and changes in ctDNA (stratified by a 10-fold or 100-fold reduction in mAF between pre- and post-induction plasma), were associated with shorter PFS. Post-induction mAF and mMMPM generally correlated with each other (ρ = 0.987, P < 0.0001).ctDNA quantification in post-induction plasma may serve as a prognostic biomarker for mCRC post-treatment outcomes.
miR-4651 inhibits cell proliferation of gingival mesenchymal stem cells by inhibiting HMGA2 under nifedipine treatment
Authors: Xiao Han, Ruzhuang Yang, Haoqing Yang, Yangyang Cao, Nannan Han, Chen Zhang, Ruitang Shi, Zhengting Zhang, Zhipeng Fan
Journal: International Journal of Oral Science (2020)

Abstract Drug-induced gingival overgrowth (DIGO) is recognized as a side effect of nifedipine (NIF); however, the underlying molecular mechanisms remain unknown. In this study, we found that overexpressed miR-4651 inhibits cell proliferation and induces G0/G1-phase arrest in gingival mesenchymal stem cells (GMSCs) with or without NIF treatment. Furthermore, sequential window acquisition of all theoretical mass spectra (SWATH-MS) analysis, bioinformatics analysis, and dual-luciferase report assay results confirmed that high-mobility group AT-hook 2 (HMGA2) is the downstream target gene of miR-4651. Overexpression of HMGA2 enhanced GMSC proliferation and accelerated the cell cycle with or without NIF treatment. The present study demonstrates that miR-4651 inhibits the proliferation of GMSCs and arrests the cell cycle at the G0/G1 phase by upregulating cyclin D and CDK2 while downregulating cyclin E through inhibition of HMGA2 under NIF stimulation. These findings reveal a novel mechanism regulating DIGO progression and suggest the potential of miR-4651 and HMGA2 as therapeutic targets.
Reaction to Letter from Zhang et al.
Authors: Peter D. Siersema
Journal: Endoscopy (2020)

See also: Suggestions for infection prevention and control in digestive endoscopy during current 2019-nCoV pneumonia outbreak in Wuhan, Hubei province, ChinaEndoscopy 2020; 52(04): 312-314DOI: 10.1055/a-1128-4313
Abstract P6-16-03: Surgical management of DCIS during the UK Sloane audit project
Authors: Cliona Clare Kirwan, Sheila Stallard, Senthurun Mylvaganam, Bridget Hilton, Karen Clements, Shan Cheung, Alistair Thompson
Journal: Cancer Research (2020)

Abstract Introduction The Sloane Project is a prospective cohort study, including 50% of United Kingdom screen detected ductal carcinoma in situ (DCIS) (2003-2012). We sought to examine the trends in surgical management over time for screen detected DCIS. Methods Trends in type of breast surgery were compared with DCIS radiology, pathology and breast size. Results Of 9945 patients with complete data undergoing surgical excision, 2274 (22.9%) underwent mastectomy as their first procedure, of whom 1581 (69.5%) had a simple mastectomy. Among 7877 undergoing attempted breast conserving surgery (BCS), 83 (1%) had therapeutic mammoplasty (TM). The 4:1 attempted BCS:mastectomy ratio remained consistent over time. Of attempted BCS, 882 (11.2%) were ultimately converted to mastectomy (28.9% reconstructed). Over the decade, preoperative radiological estimation of DCIS remained constant at 26mm, however pathological DCIS size steadily increased from 22.4mm (2003-4) to 25.3 (2011-12). There was no corresponding increase in mastectomy, completion mastectomy or re-excision rates. Mean tumour size excised at BCS was 19.3mm (mean), at TM was 32.4mm and at mastectomy was 39.8mm. The rates of simple mastectomy (vs reconstruction) decreased from 77.7% to 61.2% while there was a small increase in TMs (from 0.2% (2 patients) [2003-4] to 1.7% (15 patients) [2011-12]). There was a statistically (but small [8%] clinically) significant difference in mean breast volume for BCS compared to mastectomy patients (1068ml vs 988ml respectively, Student’s t-test p&amp;lt;0.0001). Mean breast volume (determined from mammography measurements) increased by 16% over the 9 years (from 1013ml to 1171ml), in parallel with increasing national BMI figures for these age groups. Conclusion Breast size and pathological size, but not radiological size of screen detected DCIS increased between 2003 and 2012, but BCS rates remained consistent. Interestingly, breast size had no apparent influence on type of surgery, although the decrease in simple mastectomy suggests breast reconstruction increased over time. Citation Format: Cliona Clare Kirwan, Sheila Stallard, Senthurun Mylvaganam, Bridget Hilton, Karen Clements, Shan Cheung, Alistair Thompson. Surgical management of DCIS during the UK Sloane audit project [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-16-03.
Helen Salisbury: Fear in the time of covid
Authors: Helen Salisbury
Journal: BMJ (2020)

While London’s hospitals are already nearing capacity, many other areas are still in the “phoney war” stage of this pandemic. Never has so much work been done, so quickly, in so many hospitals. New critical care wards have been created, operating suites repurposed, and emergency departments completely reorganised to try to concentrate infective patients in one place. Changes that would usually have taken years of wrangling about money have happened in the space of a week, with superhuman efforts from healthcare workers and managers alike. I am in awe.

Our academic colleagues are also working in overdrive, rapidly synthesising evidence and getting it out to clinicians who need …
A Cas12a ortholog with stringent PAM recognition followed by low off-target editing rates for genome editing
Authors: Peng Chen, Jin Zhou, Yibin Wan, Huan Liu, Yongzheng Li, Zhaoxin Liu, Hongjian Wang, Jun Lei, Kai Zhao, Yiliang Zhang, Yan Wang, Xinghua Zhang, Lei Yin
Journal: Genome biology (2020)

Abstract Background AsCas12a and LbCas12a nucleases are reported to be promising tools for genome engineering with protospacer adjacent motif (PAM) TTTV as the optimal. However, the C-containing PAM (CTTV, TCTV, TTCV, etc.) recognition by Cas12a might induce extra off-target edits at these non-canonical PAM sites. Results Here, we identify a novel Cas12a nuclease CeCas12a from Coprococcus eutactus , which is a programmable nuclease with genome-editing efficiencies comparable to AsCas12a and LbCas12a in human cells. Moreover, CeCas12a is revealed to be more stringent for PAM recognition in vitro and in vivo followed by very low off-target editing rates in cells. Notably, CeCas12a renders less off-target edits located at C-containing PAM at multiple sites compared to LbCas12a and AsCas12a, as assessed by targeted sequencing methods. Conclusions Our study shows that CeCas12a nuclease is active in human cells and the stringency of PAM recognition could be an important factor shaping off-target editing in gene editing. Thus, CeCas12a provides a promising candidate with distinctive characteristics for research and therapeutic applications.