tbuckley/cabot-search huggingface dataset:
Efficient Correction of a Hypertrophic Cardiomyopathy Mutation by ABEmax-NG
Authors: Shuhong Ma, Wenjian Jiang, Xujie Liu, Wen-Jing Lu, Tao Qi, Jingjing Wei, Fujian Wu, Yun Chang, Siyao Zhang, Yabing Song, Rui Bai, Jianbing Wang, Andrew S. Lee, Hongjia Zhang, Yongming Wang, Feng Lan
Journal: Circulation Research (2021)

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Thinking outside the modern capitalist logic: health-care systems based in other world views
Authors: Erika Arteaga-Cruz, Juan Cuvi
Journal: The Lancet Global Health (2021)

Latin America is home to about 800 different Indigenous Peoples and Nationalities, the equivalent to 9·8% of its population. The average infant mortality rate in Indigenous children is 60% higher than that in non-Indigenous children.1 In 2018, Ecuador reported that 50·6% of its Indigenous population lived in poverty, compared with 20·9% of the non-Indigenous population.2 Between 2014 and 2017, maternal mortality was 69% higher in Indigenous than in Mestizo women.3 Chronic malnutrition affects one in four Ecuadorian children, and the rate doubles in Indigenous children.
The consensus from The Chinese Society of Hematology on indications, conditioning regimens and donor selection for allogeneic hematopoietic stem cell transplantation: 2021 update
Authors: Xiao-hui Zhang, Jing Chen, Ming-Zhe Han, He Huang, Er-lie Jiang, Ming Jiang, Yong-rong Lai, Dai-hong Liu, Qi-Fa Liu, Ting Liu, Han-yun Ren, Yong-Ping Song, Zi-min Sun, Xiao-wen Tang, Jian-min Wang, De-pei Wu, Lan-ping Xu, Xi Zhang, Dao-bin Zhou, Xiao-jun Huang
Journal: Journal of Hematology & Oncology (2021)

Abstract The consensus recommendations in 2018 from The Chinese Society of Hematology (CSH) on indications, conditioning regimens and donor selection for allogeneic hematopoietic stem cell transplantation (allo-HSCT) facilitated the standardization of clinical practices of allo-HSCT in China and progressive integration with the world. There have been new developments since the initial publication. To integrate recent developments and further improve the consensus, a panel of experts from the CSH recently updated the consensus recommendations, which are summarized as follows: (1) there is a new algorithm for selecting appropriate donors for allo-HSCT candidates. Haploidentical donors (HIDs) are the preferred donor choice over matched sibling donors (MSDs) for patients with high-risk leukemia or elderly patients with young offspring donors in experienced centers. This replaces the previous algorithm for donor selection, which favored MSDs over HIDs. (2) Patients with refractory/relapsed lymphoblastic malignancies are now encouraged to undergo salvage treatment with novel immunotherapies prior to HSCT. (3) The consensus has been updated to reflect additional evidence for the application of allo-HSCT in specific groups of patients with hematological malignancies (intermediate-risk acute myeloid leukemia (AML), favorable-risk AML with positive minimal residual disease, and standard-risk acute lymphoblastic leukemia). (4) The consensus has been updated to reflect additional evidence for the application of HSCT in patients with nonmalignant diseases, such as severe aplastic anemia and inherited diseases. (5) The consensus has been updated to reflect additional evidence for the administration of anti-thymocyte globulin, granulocyte colony-stimulating factors and post-transplantation cyclophosphamide in HID-HSCT.
Senescent immune cells release grancalcin to promote skeletal aging
Authors: Chang-Jun Li, Ye Xiao, Yu-Chen Sun, Wen-Zhen He, Ling Liu, Mei Huang, Chen He, Min Huang, Kai-Xuan Chen, Jing Hou, Xu Feng, Tian Su, Qi Guo, Yan Huang, Hui Peng, Mi Yang, Guang-Hui Liu, Xiang-Hang Luo
Journal: Cell Metabolism (2021)
INK4 Tumor Suppressor Proteins Mediate Resistance to CDK4/6 Kinase Inhibitors
Authors: Qing Li, Baishan Jiang, Jiaye Guo, Hong Shao, Isabella S. Del Priore, Qing Chang, Rei Kudo, Zhiqiang Li, Pedram Razavi, Bo Liu, Andrew S. Boghossian, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Katherine A. Donovan, Marta Palafox, Jorge S. Reis-Filho, Elisa de Stanchina, Eric S. Fischer, Neal Rosen, Violeta Serra, Andrew Koff, John D. Chodera, Nathanael S. Gray, Sarat Chandarlapaty
Journal: Cancer Discovery (2021)

Cyclin-dependent kinases 4 and 6 (CDK4/6) represent a major therapeutic vulnerability for breast cancer. The kinases are clinically targeted via ATP competitive inhibitors (CDK4/6i); however, drug resistance commonly emerges over time. To understand CDK4/6i resistance, we surveyed over 1,300 breast cancers and identified several genetic alterations (e.g., FAT1, PTEN, or ARID1A loss) converging on upregulation of CDK6. Mechanistically, we demonstrate CDK6 causes resistance by inducing and binding CDK inhibitor INK4 proteins (e.g., p18INK4C). In vitro binding and kinase assays together with physical modeling reveal that the p18INK4C-cyclin D-CDK6 complex occludes CDK4/6i binding while only weakly suppressing ATP binding. Suppression of INK4 expression or its binding to CDK6 restores CDK4/6i sensitivity. To overcome this constraint, we developed bifunctional degraders conjugating palbociclib with E3 ligands. Two resulting lead compounds potently degraded CDK4/6, leading to substantial antitumor effects in vivo, demonstrating the promising therapeutic potential for retargeting CDK4/6 despite CDK4/6i resistance. SIGNIFICANCE: CDK4/6 kinase activation represents a common mechanism by which oncogenic signaling induces proliferation and is potentially targetable by ATP competitive inhibitors. We identify a CDK6-INK4 complex that is resilient to current-generation inhibitors and develop a new strategy for more effective inhibition of CDK4/6 kinases.This article is highlighted in the In This Issue feature, p. 275.
Plitidepsin (APL) alone or with dacarbazine (DTIC) as first-line treatment for advanced unresectable melanoma (AUM).
Authors: E. R. Plummer, P. Lorigan, L. Hayward, J. Jassem, L. Demidov, V. Moiseyenko, V. Soriano, E. Chmielowska, R. Prados, S. Szyldergemajn
Journal: Journal of Clinical Oncology (2010)

8537 Background: In patients (pts) with AUM, DTIC alone is associated with response rates (RR) 8%–15%. Aplidin, a novel cytotoxic, gave a RR of 6% as second line therapy in AUM. APL+DTIC have shown additive cytotoxicity in preclinical models. In the prior dose-finding stage of this study, 16% of 19 evaluable pts had a partial response (PR). Recommended dose (RD) was APL 2.4 mg/m2/d 1, 8 and 15 + DTIC 800 mg/m2/d1 q4w (Plummer, J Clin Oncol 27:15s, 2009; abstr 9059). Methods: A randomized 2 stage phase II study aim to determine the activity of Arm A (APL3.2 mg/m2/d 1, 8 and 15 q4w) or Arm B (APL+DTIC) at their established RD was performed. If at least 2 responses were observed per arm after 17 evaluable pts, 13 more pt would be included in the second stage. Results: 20 pts were randomized to Arm A and 38 pt (2 not treated) to Arm B (ITT population). Of these, 17 and 29 pts, respectively were evaluable for efficacy (PP population). Baseline characteristics were: 52% males; median (med) age, 53 y (range: 21–78); med ECOG, 1 (0–2); and med LDH 1.2 upper limit normal (0.4–8.2). All pts had metastases, with a med of 2 sites involved (1–6). Arm A was discontinued as no responses were seen; Arm B continued to stage 2. In arm B, relative dose intensity was 67% and 99% for APL and DTIC, respectively. Most frequent reason for missing doses was grade (G) 2/3 ALT/AST increase. Common mild toxicities included nausea, vomiting, hypersensitivity (G3/4 reactions in 9%), myalgia, diarrhea, and constipation. G1/2 anemia occurred in 61% of pts, and G3/4 neutropenia or thrombocytopenia in 6 and 8% of pts respectively, with no febrile neutropenia. Antitumor activity included 1 (3%) complete response, 6 (21%) PR and 8 (28%) stabilizations (SD); disease control rate (CR+PR+SD) was 52% (PP) and 42% (ITT). As of Dec 2009, with a med follow-up of 4 months, PFS is 3 months (95%CI: 2-5) and 96% of pts are alive at 1 year (95% CI: 89-100%). Pharmacogenomic analyses are ongoing. Conclusions: Weekly APL alone showed no activity in AUM, while combined with DTIC showed encouraging activity. Toxicity was manageable and non-life threatening, but it led to frequent APL dose omissions. A biweekly schedule should undergo clinical evaluation. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration PharmaMar PharmaMar PharmaMar
Conduct and reporting of formula milk trials: systematic review
Authors: Bartosz Helfer, Jo Leonardi-Bee, Alexandra Mundell, Callum Parr, Despo Ierodiakonou, Vanessa Garcia-Larsen, Cynthia M Kroeger, Zhaoli Dai, Amy Man, Jessica Jobson, Fatemah Dewji, Michelle Kunc, Lisa Bero, Robert J Boyle
Journal: BMJ (2021)

Abstract Objective To systematically review the conduct and reporting of formula trials. Design Systematic review. Data sources Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from 1 January 2006 to 31 December 2020. Review methods Intervention trials comparing at least two formula products in children less than three years of age were included, but not trials of human breast milk or fortifiers of breast milk. Data were extracted in duplicate and primary outcome data were synthesised for meta-analysis with a random effects model weighted by the inverse variance method. Risk of bias was evaluated with Cochrane risk of bias version 2.0, and risk of undermining breastfeeding was evaluated according to published consensus guidance. Primary outcomes of the trials included in the systematic review were identified from clinical trial registries, protocols, or trial publications. Results 22 201 titles were screened and 307 trials were identified that were published between 2006 and 2020, of which 73 (24%) trials in 13 197 children were prospectively registered. Another 111 unpublished but registered trials in 17 411 children were identified. Detailed analysis was undertaken for 125 trials (23 757 children) published since 2015. Seventeen (14%) of these recently published trials were conducted independently of formula companies, 26 (21%) were prospectively registered with a clear aim and primary outcome, and authors or sponsors shared prospective protocols for 11 (9%) trials. Risk of bias was low in five (4%) and high in 100 (80%) recently published trials, mainly because of inappropriate exclusions from analysis and selective reporting. For 68 recently published superiority trials, a pooled standardised mean difference of 0.51 (range −0.43 to 3.29) was calculated with an asymmetrical funnel plot (Egger’s test P&lt;0.001), which reduced to 0.19 after correction for asymmetry. Primary outcomes were reported by authors as favourable in 86 (69%) trials, and 115 (92%) abstract conclusions were favourable. One of 38 (3%) trials in partially breastfed infants reported adequate support for breastfeeding and 14 of 87 (16%) trials in non-breastfed infants confirmed the decision not to breastfeed was firmly established before enrolment in the trial. Conclusions The results show that formula trials lack independence or transparency, and published outcomes are biased by selective reporting. Systematic review registration PROSPERO 2018 CRD42018091928.
Antimicrobial Therapy and Respiratory Hospitalization or Death in Adults With Idiopathic Pulmonary Fibrosis—Reply
Authors: Fernando J. Martinez, Kevin J. Anstrom, Imre Noth
Journal: JAMA (2021)

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68Ga-FAPI PET/CT Imaging of Baastrup Disease in a Patient With Esophageal Cancer
Authors: Xiao Yang, Yuhong Liu, Jinping Chen, Yue Chen, Huipan Liu
Journal: Clinical Nuclear Medicine (2021)

68Ga-FAPI is a novel PET agent that has been shown to be promising for imaging tumors. Meanwhile, FAPI uptake in nonmalignant diseases has also been reported. Herein, we presented 68Ga-FAPI PET/CT findings of Baastrup disease in a patient with esophageal cancer.
OS05.5.A Methylation analysis of matched primary and recurrent <i>IDHmt</i> astrocytoma; an update from the Glioma Longitudinal Analysis NL (GLASS-NL) consortium
Authors: W R Vallentgoed, J M Niers, M J van den Bent, M C M Kouwenhoven, J M Kros, I Martin, H F van Thuijl, M A van de Wiel, P Wesseling, P J French
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The evolutionary processes that drive progression in patients with IDH-mutant astrocytoma remain unclear. The GLASS-NL consortium, as part of the larger worldwide GLASS consortium, was initiated to gain insight into the molecular mechanisms underlying glioma evolution and to identify markers of progression in IDH-mutant astrocytomas. Such markers can ultimately assist clinical decision making. Here, we present the first results of genome wide methylation profiling of samples included in the GLASS-NL study. MATERIAL AND METHODS 110 adult patients were identified with an IDH-mutant astrocytoma at first diagnosis. All patients underwent a surgical resection of the tumor at least twice, separated by at least 6 months with a median of 40.9 months (IQR: 24.0, 64.7), in 37% and 18% of the cases, patients were treated with radiotherapy or chemotherapy respectively, before surgical resection of the recurrent tumor. Methylation profiling was done on (macro dissected) DNA isolated of 235 samples from 103 patients (102 1st, 101 2nd, 29 3rd, and 3 4th resection), using the Infinium MethylationEPIC BeadChip array. Copy number variations were also derived from these data. Methylation classes were determined according to Capper et al. (2018). Overall survival (OS) was measured from date of first surgery. RESULTS Of all primary tumors, the methylation-classifier assigned 85 (87%) to the A_IDH (‘low grade’) subclass and 10 (10%) to the A_IDH_HG (‘high grade’) subclass. The relative proportion of high grade tumors increased ~three-fold at tumor recurrence (32/101, 32%) and even further in the second recurrence (15/29, 52%). The overall DNA-methylation levels of recurrent samples was lower than that of primary samples. This difference is explained by the increased number of high grade samples at recurrence, since near identical DNA-methylation levels were observed in samples that remained low grade. In an unsupervised analysis, methylation data derived from first and second resections of individual patients mostly (79%) cluster together. This indicates that variability between tumors is larger than temporal heterogeneity within tumors. Recurrent samples that do not cluster with their primary tumor, form a separate cluster and have relatively low genome-wide DNA-methylation. CONCLUSION Our data demonstrate that methylation profiling identifies a shift towards a higher grade at tumor progression coinciding with reduced genome-wide DNA-methylation levels.
Simultaneous Expression of UV and Violet SWS1 Opsins Expands the Visual Palette in a Group of Freshwater Snakes
Authors: Einat Hauzman, Michele E R Pierotti, Nihar Bhattacharyya, Juliana H Tashiro, Carola A M Yovanovich, Pollyanna F Campos, Dora F Ventura, Belinda S W Chang
Journal: Molecular Biology and Evolution (2021)

Snakes are known to express a rod visual opsin and two cone opsins, only (SWS1, LWS), a reduced palette resulting from their supposedly fossorial origins. Dipsadid snakes in the genus Helicops are highly visual predators that successfully invaded freshwater habitats from ancestral terrestrial-only habitats. Here, we report the first case of multiple SWS1 visual pigments in a vertebrate, simultaneously expressed in different photoreceptors and conferring both UV and violet sensitivity to Helicops snakes. Molecular analysis and in vitro expression confirmed the presence of two functional SWS1 opsins, likely the result of recent gene duplication. Evolutionary analyses indicate that each sws1 variant has undergone different evolutionary paths with strong purifying selection acting on the UV-sensitive copy and dN/dS ∼1 on the violet-sensitive copy. Site-directed mutagenesis points to the functional role of a single amino acid substitution, Phe86Val, in the large spectral shift between UV and violet opsins. In addition, higher densities of photoreceptors and SWS1 cones in the ventral retina suggest improved acuity in the upper visual field possibly correlated with visually guided behaviors. The expanded visual opsin repertoire and specialized retinal architecture are likely to improve photon uptake in underwater and terrestrial environments, and provide the neural substrate for a gain in chromatic discrimination, potentially conferring unique color vision in the UV-violet range. Our findings highlight the innovative solutions undertaken by a highly specialized lineage to tackle the challenges imposed by the invasion of novel photic environments and the extraordinary diversity of evolutionary trajectories taken by visual opsin-based perception in vertebrates.
Faster Rates of Molecular Sequence Evolution in Reproduction-Related Genes and in Species with Hypodermic Sperm Morphologies
Authors: R Axel W Wiberg, Jeremias N Brand, Lukas Schärer
Journal: Molecular Biology and Evolution (2021)

Sexual selection drives the evolution of many striking behaviors and morphologies and should leave signatures of selection at loci underlying these phenotypes. However, although loci thought to be under sexual selection often evolve rapidly, few studies have contrasted rates of molecular sequence evolution at such loci across lineages with different sexual selection contexts. Furthermore, work has focused on separate sexed animals, neglecting alternative sexual systems. We investigate rates of molecular sequence evolution in hermaphroditic flatworms of the genus Macrostomum. Specifically, we compare species that exhibit contrasting sperm morphologies, strongly associated with multiple convergent shifts in the mating strategy, reflecting different sexual selection contexts. Species donating and receiving sperm in every mating have sperm with bristles, likely to prevent sperm removal. Meanwhile, species that hypodermically inject sperm lack bristles, potentially as an adaptation to the environment experienced by hypodermic sperm. Combining functional annotations from the model, Macrostomum lignano, with transcriptomes from 93 congeners, we find genus-wide faster sequence evolution in reproduction-related versus ubiquitously expressed genes, consistent with stronger sexual selection on the former. Additionally, species with hypodermic sperm morphologies had elevated molecular sequence evolution, regardless of a gene's functional annotation. These genome-wide patterns suggest reduced selection efficiency following shifts to hypodermic mating, possibly due to higher selfing rates in these species. Moreover, we find little evidence for convergent amino acid changes across species. Our work not only shows that reproduction-related genes evolve rapidly also in hermaphroditic animals, but also that well-replicated contrasts of different sexual selection contexts can reveal underappreciated genome-wide effects.
Prospective analysis of different oral iron posology on clinical findings and serum iron parameters including hepcidin in patients with iron deficiency anemia
Authors: M. Yuksel, O. Dogan, M. K. Yuksel
Journal: HemaSphere (2021)

Background: Iron Deficiency Anemia (IDA) is a common health problem in daily clinical practice. A better understanding of iron metabolism in recent years;has created the need for revising treatment regimens in the treatment of IDA. Aims: Based on these data, we aimed to evaluate the effectiveness of oral ferrous sulfate treatment at different doses, and posologies in premenopausal women diagnosed with IDA, and its relationship with hepcidin, treatment compliance, and gastrointestinal side effects in this study. Methods: This is a prospective observational study including premenopausal female patients median age 36 (18-50) diagnosed with IDA. This study was approved by local ethic committe and sponsored by Ankara University School of Medicine Scientific Research Projects(BAP proje number 20L0230012) All patients recieved po ferrous sulfate (FS) 80 mg elemental iron) for three months. Patients were classified into three group according to FS dose: Group 1: 2x1/day;Group 2: 1x1/ day;Group 3: 1x1every other day. At the time of enrollment, thereafter at the second week of FS and at the third month: Hb level, transferrin saturation(%TS), total iron binding capacity were recorded. Blood was drawn and stored at -20 temperature for hepcidin analysis from patiens who signed informed consent. Results: We intent to analyse 50 patients for each group, however as a consequence of COVID-19 pandemic, neither patients could come to hospitals nor we could visit them. The patients in each group, ages and results are shown Table At the end of the second week a significant increase in Hb level was observed (p   0.05). The increase in TS% and decrease in total iron binding capacity were similar in all three group at the end of the treatment (p> 0.05). The change between the second week and the initial hepcidin was mostly observed in the second group (p= 0.024) and the change between the three group were similar (p = 0.708). Gastrointestinal side effects were observed more in the first group who received 2∗1 daily than in the second and third group (p   0.05) and there was no increase in appetite and weight in group 3. Summary/Conclusion: Hb level increase at the end of second week was ≥1 g / dl in the first and second group and <1 g / dl in the third treatment group. However, at the end of the treatment third month anemia was significantly improved in all three group and the increase in Hb level was similar. We consider, 1∗1 daily or 1∗1 every other day posology would be more appropriate instead of 2∗1 daily due to the significant gastrointestinal side effects in the first group. In addition, we believe in that, the evaluation of Hb response in the second week is too early to decide treatment outcome due to the slower Hb increase in the other day group and serial Hepcidin measurements will give a better idea to better understand the kinetics.
Elective endoscopic gallbladder treatment in patient with recurrent gallbladder colic and high surgical risk
Authors: Mario Gagliardi, Gianenrico Rizzatti, Michele Impagnatiello, Alberto Larghi
Journal: Endoscopy (2021)

An 80-year-old woman presented with a 1-year history of recurrent right upper quadrant colicky pain. Her medical history included abdominal surgery, ischemic stroke with impaired mobility, and obesity (body mass index > 30.1 kg/cm2).