PNAS Research Articles

Molecular signature for senile and complicated cataracts derived from analysis of sumoylation enzymes and their substrates in human cataract lenses.

Sumoylation is one of the key regulatory mechanisms in eukaryotes. Our previous studies reveal that sumoylation plays indispensable roles during lens differentiation (Yan et al. 2010. Proc Natl Acad Sci USA. 107:21034–21039; Gong et al. 2014. Proc Natl Acad Sci USA. 111:5574–5579). Whether sumoylation is implicated in cataractogenesis, a disease largely derived from aging, remains elusive. In the present study, we have examined the changing patterns of the sumoylation ligases and de‐sumoylation enzymes (SENPs) and their substrates including Pax6 and other proteins in cataractous lenses of different age groups from 50 to 90 years old. It is found that compared with normal lenses, sumoylation ligases 1 and 3, de‐sumoylation enzymes SENP3/7/8, and p46 Pax6 are clearly increased. In contrast, Ubc9 is significantly decreased. Among different cataract patients from 50s to 70s, male patients express more sumoylation enzymes and p46 Pax6. Ubc9 and SENP6 display age‐dependent increase. The p46 Pax6 displays age‐dependent decrease in normal lens, remains relatively stable in senile cataracts but becomes di‐sumoylated in complicated cataracts. In contrast, sumoylation of p32 Pax6 is observed in senile cataracts and increases its stability. Treatment of rat lenses with oxidative stress increases Pax6 expression without sumoylation but promotes apoptosis. Thus, our results show that the changing patterns in Ubc9, SENP6, and Pax6 levels can act as molecular markers for senile cataract and the di‐sumoylated p46 Pax6 for complicated cataract. Together, our results reveal the presence of molecular signature for both senile and complicated cataracts. Moreover, our study indicates that sumoylation is implicated in control of aging and cataractogenesis.

Guidance systems: from autonomous directives to legal sensor-bilities

The design of collaborative robotics, such as driver-assisted operations, engineer a potential automation of decision-making predicated on unobtrusive data gathering of human users. This form of ‘somatic surveillance’ (Hayles, Unthought: the power of the cognitive nonconscious. University of Chicago Press, Chicago, 2017, p. 11) increasingly relies on behavioural biometrics and sensory algorithms to verify the physiology of bodies in cabin interiors. Such processes secure cyber-physical space, but also register user capabilities for control that yield data as insured risk. In this technical re-formation of human–machine interactions for control and communication ‘a dissonance of attribution’ (Hancock et al., Proc Natl Acad Sci 116(16):7684, 2019. https://doi.org/10.1073/pnas.1805770115 ) is created between perceptions of phenomena, materials and decision-making. This reconfigures relations not only between humans and machines, objects and subjects, but possibly disrupts attributive functions in the social system of Law. What it requires is shifting a legal accountability for action from a sovereignty of the human to a new materialist account based on a ‘cognitive assemblage’ between physiological data, computation and algorithmic sensing. This paper investigates the function of law as a guidance system to acknowledge this account of sensory and algorithmic computation as autonomous ‘sensing agents’ (Hansen, Feed-forward: on the future of twenty-first-century media. University of Chicago Press, Chicago, 2015) that may be accountable in situations of risk. This assemblage of robotic computation and sensory determination requires a clearer legal differentiation across the current static terminologies of person, property, liability and rights that maintain strict separations of object from subject. To neglect this, we argue, law will solely impute attributions of error to humans despite evidence of operation via mutual control.

Ecological impact of phytoinvasions in Ukraine

Ecological impact of phytoinvasions in Ukraine

Abstract 6242: Development of alphalex™-toxin low pH targeting conjugates for the treatment of solid tumors

Abstract Maytansines and their derived maytansinoid DMx compounds are high potency microtubule targeting compounds that have an extremely narrow therapeutic window. Unacceptable dose limiting systemic toxicity has limited the therapeutic potential of these potent anti-oncogenic compounds. Targeting maytansinoids to the tumor is the only feasible method of unlocking the clinical potential of such toxic molecules. To date Trastuzumab-DM1 (Kadcyla®) remains the only approved antibody-maytansinoid conjugate on the market. Most preclinical maytansinoid conjugates to date face the same issues encountered by Kadcyla® - tumor restriction by target antigen and the potential for off target release of payload. alphalexTM is a tumor targeting technology consisting of a unique variant of pH-Low Insertion Peptide (pHLIP®; references 1-3), cleavable small molecule linker and anti-cancer agent warhead. alphalexTM thereby allows for antigen independent targeting of the tumor and enables intracellular delivery of the warhead by leveraging the low pH microenvironment of the tumor, a universal feature common to all tumors due to the Warburg effect. Here we demonstrate the ability to conjugate the maytansinoids DM1 and DM4 to alphalexTM via both direct and linker-mediated conjugation. We have demonstrated the ability of our alphalexTM-DM4 conjugate candidates (CBX-13) to have single digit nanomolar potency in vitro as well as exquisitely potent and long-lasting anti-tumor activity in a HER2-negative xenograft model that is un-targetable by competing therapies. In particular we have demonstrated that CBX-13 safely delivers amounts of maytansinoid in vivo that otherwise result in systemic toxicity and death when dosed as free warhead. Based on the SAR of this first generation of maytansinoid conjugates we are further optimizing our alphalexTM - maytansinoid conjugation strategy with the goal of moving forward with IND-enabling studies in the near future.

Abstract 2020: Identification of abnormal CSF1 transcripts in tenosynovial giant cell tumors and dose-dependent increase in plasma CSF1 levels in response to pexidartinib treatment

Abstract Background: Tenosynovial giant cell tumors (TGCTs) are characterized by rearrangements of the colony-stimulating factor 1 (CSF1) gene. Dysregulated CSF1 may attract CSF1 receptor (CSF1R)-bearing mononuclear cells that form the bulk of the tumor. CSF1R inhibitors including pexidartinib have been developed and have proven to be effective therapies. Methods: Formalin-fixed paraffin-embedded (FFPE) TGCT specimens from the phase 1 first-in-human study of pexidartinib (NCT01004861) were analyzed using a custom sequencing assay to detect CSF1 genetic alterations. The ArcherDX RNA panel (ArcherDX, Inc., Boulder, CO) consisted of 33 gene-specific primer sets specifically designed to target CSF1, including at least 1 primer set to target each exon/exon boundary as well as primer sets to tile the 3′-untranslated region (3′UTR). Plasma samples from 5 phase 1 trials of pexidartinib across multiple tumor types (NCT02777710, NCT01217229, NCT01525602, NCT01790503, NCT02452424) were assayed for CSF1 protein by solid-phase ELISA (Quantikine® Human MCSF, R&D Systems, Inc., Minneapolis, MN) at baseline and following pexidartinib (200-1200 mg). Results: FFPE TGCT specimens (N=25) were successfully isolated, prepared into libraries, and sequenced; 8 showed evidence of gene rearrangements at the junction of CSF1 exons 5/6, and 15 showed alterations of the CSF1 3′UTR (n=23). All 25 TGCT libraries had higher CSF1 expression, with 24 exceeding 2-fold of the RNA control library. The plasma samples from 132 patients were analyzed for CSF1 protein. Pexidartinib treatment (200-1200 mg) led to a dose-dependent increase in plasma CSF1 by day 8, 15, or 29. Significant (>4-fold) CSF1 elevation was observed at 600 mg or higher doses. Discussion: All 25 analyzed TGCT study patients had tumor tissue with elevated CSF1 ligand transcripts, and 23 had CSF1 genomic alterations identified, thus confirming the TGCT etiology for which pexidartinib therapy was recently approved. The initial discovery of gross chromosomal aberrations involving the CSF1 locus used break-apart FISH probes (West et al. Proc Natl Acad Sci USA. 2006;103:690-695). Details of the CSF1 gene aberrations were obtained here using a sequencing assay suitable for FFPE specimens having partially degraded RNA. Abnormal CSF1 transcripts identified in our study are similar to those published by others (Ho et al. Genes Chromosomes Cancer. 2019[Epub]; Tsuda et al. Int J Cancer. 2019;145:3276-3284) after completion of our work, including both predicted fusion proteins and loss of 3′UTR microRNA negative regulatory sites. Increased plasma CSF1 is a useful pharmacodynamics marker of CSF1R inhibition. One potential mechanism for CSF1 plasma elevations could be the inhibition of liver macrophages, known to express CSF1R and thought to play an essential role in the normal clearance of CSF1 from circulation. Citation Format: Paul Severson, Brian L. West, William D. Tap, Zev A. Wainberg, Sandra Tong-Starksen, Henry H. Hsu, Chao Zhang. Identification of abnormal CSF1 transcripts in tenosynovial giant cell tumors and dose-dependent increase in plasma CSF1 levels in response to pexidartinib treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2020.

Abstract 5133: Optimized RAS top-down proteomic assay reveals expanded proteoform landscape in malignant cells

Abstract Traditional proteomic methods face an inherent challenge with the RAS family of GTPases (HRAS, NRAS, KRAS4A, KRAS4B). Expressed at low endogenous abundance, these four isoforms possess considerable sequence similarity, rendering the confident proteomic linkage of a given isoform with a specific mutation or post-translational modification (PTM) a formidable proposition outside of isoform-specific model cell lines. Conversely, top-down proteomic analysis (TDP), which measures intact protein molecules, can precisely identify modified protein forms, or proteoforms, and confidently localize both mutations and PTMs on each RAS isoform present. Previously, a method combining immunoprecipitation and subsequent TDP (IP-TDP) led to the identification of eleven KRAS4B proteoforms, including four mutations and two novel PTMs, within colorectal cancer cell lines and tumor samples†. These initial results demonstrated the great potential for proteoform-resolved measurements to further illuminate the role of KRAS4B mutations and modifications in human cancer. More recently, the NCI RAS Initiative has developed an enhanced RAS proteoform assay incorporating IP-TDP analysis on an Orbitrap Fusion Lumos mass spectrometer. By employing alternate antibodies, recombinant protein standards, and well-characterized model or malignant cell lines, we have obtained substantial improvements in both RAS proteoform detection and characterization, thus facilitating the identification and localization of low-abundance PTMs. Moreover, we have applied our optimized IP-TDP method to a diverse panel of malignant and RAS mutant cell lines with the goal of expanding our knowledge of the RAS proteoform landscape. In doing so, we have observed a wealth of novel RAS proteoforms, of far greater number and complexity than previously anticipated. We have also observed isoform-specific proteoform variations, most notably between KRAS4A and KRAS4B, and initial indications of proteoform context dependence, namely within a given mutation or tissue background. Our results further underscore the power of proteoform-resolved measurements and indicate that RAS-dependent signaling pathways in normal and cancer contexts may be far more complex than previously thought. † I Ntai et. al. “Precise characterization of KRAS4b proteoforms in human colorectal cells and tumors reveals mutation/modification crosstalk.” Proc Natl Acad Sci U S A. 2018 Apr 17; 115(16):4140-4145. Citation Format: Caroline DeHart, Kanika Sharma, Dominic Esposito, Anna Maciag, Dwight Nissley, Frank McCormick. Optimized RAS top-down proteomic assay reveals expanded proteoform landscape in malignant cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5133.

Training differences predict dogs' (Canis lupus familiaris) preferences for prosocial others.

Humans evaluate other agents' behavior on a variety of different dimensions, including morally, from a very early age. For example, human infants as young as 6-months old prefer prosocial over antisocial others and demonstrate negative evaluations of antisocial others in a variety of paradigms (Hamlin et al. in Nature 450(7169):557, 2007; Dev Sci 13(6):923-929, 2010; Proc Natl Acad Sci 108(50):19931-19936, 2011). While these tendencies are well documented in the human species, less is known about whether similar preference emerge in non-human animals. Here, we explore this question by testing prosocial preferences in one non-human species: the domestic dog (Canis lupus familiaris). Given the ubiquity of dog-human social interactions, it is possible that dogs display human-like social evaluation tendencies. Unfortunately, prior research examining social evaluation in dogs has produced mixed results. To assess whether differences in methodology or training differences account for these contrasting results, we tested two samples of dogs with different training histories on an identical social evaluation task. Trained agility dogs approached a prosocial actor significantly more often than an antisocial actor, while untrained pet dogs showed no preference for either actor. These differences across dogs with different training histories suggest that while dogs may demonstrate preferences for prosocial others in some contexts, their social evaluation abilities are less flexible and less robust compared to those of humans.

The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies.

The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies.

No statistical support for wolf\xa0control and maternal penning as conservation measures for endangered mountain caribou

Mountain caribou, a behaviourally and genetically distinct set of ecotypes of the Woodland caribou (Rangifer tarandus caribou) restricted to the mountains of western Canada, have undergone severe population declines in recent decades. Although a broad consensus exists that the ultimate driver of these declines has been the reduction of habitat upon which mountain caribou depend, research and policy attention has increasingly focused on predation. Recently, Serrouya et al. (Proc Nat Acad Sci USA 116:6181–6186, 2019) analysed population dynamics data from 18 subpopulations in British Columbia and Alberta, Canada, subject to different treatments and ‘controls’, and concluded that lethal wolf control and maternal caribou penning provide the most effective ways to stabilize population declines. Here we show that this inference was based on an unbalanced analytical approach that omitted a null scenario, excluded potentially confounding variables and employed irreproducible habitat alteration metrics. Our reanalysis of available data shows that ecotype identity is a better predictor of population trends than any adaptive management treatments considered by Serrouya et al. Disparate behavioural characteristics and responses to industrial disturbance among ecotypes suggest it may be incorrect to assume that adaptive management strategies that might benefit one ecotype are transferable to another.

N-glycosylated IgG in patients with kidney transplants increases calcium/calmodulin kinase IV in podocytes and causes injury.

Transplant glomerulopathy (TG) is a major cause of late allograft loss. Increased urine podocin/creatinine ratio in TG signifies accelerated podocyte loss. The mechanisms that lead to podocyte injury in TG remain unclear. We report that IgG from kidney transplant recipients with TG, but not from those without TG, cause a reduction in the expression of nephrin, significant podocyte actin cytoskeleton, and motility changes. These changes are preceded by increased expression of calcium/calmodulin kinase IV (CAMK4). Mechanistically, we found that CAMK4 phosphorylates GSK3β (glycogen synthase kinase 3 beta), activates the Wnt pathway and stabilizes the nephrin transcriptional repressor SNAIL. Silencing neonatal Fc Receptor (FcRn) or CAMK4 prevented the podocyte-damaging effects of IgG from patients with TG. Furthermore, we show that removal of N-linked glycosyl residues from these IgG did not interfere with its entry into the podocytes but eliminated its ability to upregulate CAMK4 and cause podocyte injury. The translational value of these findings is signified by the fact that CAMK4 is increased in podocytes of patients with TG but not in those without TG despite other forms of renal dysfunction. Our results offer novel considerations to limit podocyte injury in patients with kidney transplants, which may lead to eventual glomerular destabilization and transplant glomerulopathy.

How race features in pain-treatment disparities.

British Journal of Community NursingVol. 25, No. 7 TreatmentsHow race features in pain-treatment disparitiesAysha MendesAysha MendesE-mail Address: [email protected]Freelance journalist specialising in healthcare and psychologySearch for more papers by this authorAysha MendesPublished Online:2 Jul 2020https://doi.org/10.12968/bjcn.2020.25.7.360AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View article References Bonilla-Silva E. Racism without racists: color-blind racism and the persistence of racial inequality in America. 4th edn. Plymouth: Rowman and Littlefield; 2014 Google ScholarCox D. The trauma trap: what's causing inequalities in emergency care? 2018. https://tinyurl.com/ya5yrkow (accessed 19 June 2020) Google ScholarDrewicki B, Moore C, Ward S, Prkachin K. Reducing racial disparities in pain treatment: the role of empathy and perspective-taking. Pain. 2011; 152(5):1001–1006. https://doi.org/10.1016/j.pain.2010.12.005 Crossref, Medline, Google ScholarGuardian. Prof Donna Kinnair on racism in the NHS: ‘in every community, BAME patients suffer the most’. 2020. https://tinyurl.com/ybr6fy4x (accessed 19 June 2020) Google ScholarHarrison EM, Docherty AB, Barr B et al.. Ethnicity and outcomes from COVID-19: the ISARIC CCP-UK prospective observational cohort study of hospitalised patients. 2020. https://doi.org/10.2139/ssrn.3618215 Google ScholarHoffman KM, Trawalter S, Axt JR, Norman Oliver M. Recommendations, and false beliefs about biological differences between blacks and whites. Proc Natl Acad Sci USA. 2016; 113(16)4296–4301. https://doi.org/10.1073/pnas.1516047113 Crossref, Medline, Google ScholarKennel J. Racial disparities in EMS. 2019. https://tinyurl.com/ybj7h5pc (accessed 19 June 2020) Google ScholarNational Institute for Health Research. First drug to reduce mortality in hospitalised patients with respiratory complications of COVID-19 found. 2020. https://tinyurl.com/y9exbjgr (accessed 19 June 2020) Google ScholarPublic Health England. Disparities in the risk and outcomes of COVID-19. 2020. https://tinyurl.com/y7s6o69g (accessed 19 June 2020) Google Scholar FiguresReferencesRelatedDetails 2 July 2020Volume 25Issue 7ISSN (print): 1462-4753ISSN (online): 2052-2215 Metrics History Published online 2 July 2020 Published in print 2 July 2020 Information© MA Healthcare LimitedPDF download

Some Results of Fractional Integral Involving I-Function and General Class of Polynomial

In the present paper, we have derived two multiplication theorems for I-function by using fractional integral formula $$ \mathop I\nolimits_{0,x}^{\alpha ,\beta ,\eta } f(x) $$ and $$ \mathop J\nolimits_{0,\infty }^{\alpha ,\beta ,\eta } f(x) $$ (Banerji and Choudhary in Proc Natl Acad Sci India Sect A Phys Sci 66:271–278, 1996). Further, we established some applications of the theorem in the form of particular case.

Defect Modes for Dislocated Periodic Media

We study defect modes in a one-dimensional periodic medium perturbed by an adiabatic dislocation of amplitude $$\delta \ll 1$$ . If the periodic background admits a Dirac point—a linear crossing of dispersion curves—then the dislocated operator acquires a gap in its essential spectrum. For this model (and its honeycomb analog) Fefferman et al. (Proc Natl Acad Sci USA 111(24):8759–8763, 2014, Mem Am Math Soc 247(1173):118, 2017, Ann PDE 2(2):80, 2016, 2D Mater 3:1, 2016) constructed (at leading order in $$\delta $$ ) defect modes with energies within the gap. These bifurcate from the eigenmodes of an effective Dirac operator. Here we address the following open problems: We respond positively to both questions. Our approach relies on (a) resolvent estimates for the bulk operators; (b) scattering theory for highly oscillatory potentials [Dr18a, Dr18b, Dr18c]. It has led to an understanding of the topological stability of defect states in continuous dislocated systems—in connection with the bulk-edge correspondence [Dr18d].

Consideration of Pannexin 1 channels in COVID-19 pathology and treatment.

Pannexin1 (PANX1) is a ubiquitously expressed, channel-forming protein found in a number of tissues thoughout the body (e.g. lung, vasculature, liver, central nervous system, immune system) that is important in many key physiological and immune responses. PANX1 channels passively flux ATP (predominantly), multiple metabolites, and likely other small anions. PANX1 channels regulate inflammation and host responses to several pathogens, including viruses. While there is currently no evidence suggesting novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and PANX1 directly interact, there is an urgent need for therapeutic strategies, especially those targeting the hyper-inflammation and cytokine storm that occurs in severe cases of COVID-19. Here we argue that PANX1, and drugs known to target PANX1 (including the FDA-approved drug probenecid), should be the focus of further investigation in the context of SARS-CoV-2 infection and its associated pathology in COVID-19 patients.

Evolution by means of natural selection without reproduction: revamping Lewontin’s account

This paper analyzes recent attempts to reject reproduction with lineage formation as a necessary condition for evolution by means of natural selection (Bouchard in Philos Sci 75(5):560–570, 2008; Stud Hist Philos Sci Part C Stud Hist Philos Biol Biomed Sci 42(1):106–114, 2011; Bourrat in Biol Philos 29(4):517–538, 2014; Br J Philos Sci 66(4):883–903, 2015; Charbonneau in Philos Sci 81(5):727–740, 2014; Doolittle and Inkpen in Proc Natl Acad Sci 115(16):4006–4014, 2018). Building on the strengths of these attempts and avoiding their pitfalls, it is argued that a robust formulation of evolution by natural selection without reproduction can be established. The main contribution of this paper is a reformulation of Lewontin’s three principles (Lewontin in Annu Rev Ecol Syst 1:1–18, 1970) stating that minimal evolution by natural selection occurs when two conditions are met in a population: fitness-related variation and memory (population-level inheritance). Paradigmatic evolution by natural selection, which can generate adaptations, takes place when an additional condition is present, namely regeneration.

Generics and Epistemic Injustice

In this paper, we argue that, although neglected so far, there is a strong link between generics and testimonial injustice. Testimonial injustice is a form of epistemic injustice that “occurs when prejudice causes a hearer to give a deflated level of credibility to a speaker’s word” (Fricker 2007: 1). Generics are sentences that express generalizations about a category or about its members without specifying what proportion of the category members possess the predicated property. We argue that generics are especially suited to cause testimonial injustice for three reasons. First, generics elicit an “inferential asymmetry” (Cimpian et al. Cogn Sci 34(8):1452–1482, 2010). That is, generics are accepted even if only a few individuals possess the predicated property but are, nonetheless, taken to refer to almost all the members of the category. This peculiar combination makes generics particularly apt to cause testimonial injustice. High resistance to counter-evidence is a crucial feature of prejudice, the cause of testimonial injustice, and the more highly predictive a generalization the more it will be employed in concrete situations, leading to instances of testimonial injustice. Second, generics seem to play a key role in leading people to develop essentialist beliefs (Gelman et al. Cogn Psychol 61(3): 273–301, 2010; Rhodes et al. Proc Natl Acad Sci 109(34): 13526–13531, 2012). Subjects holding such beliefs treat categories as warranting strong generaliations over their members. Therefore, they will be more likely to rely on prejudice while dealing with the category members. Finally, generics are outstandingly common in everyday speech. Hence, their noxious effects are amplified by their diffusion and should not be underestimated.

P-selectin blockade in COVID-19-related ARDS

P-selectin blockade in COVID-19-related ARDS

Abstract B062: Genetic driving factors of aggressive Ethiopian breast cancer

Abstract In Ethiopia, a breast cancer diagnosis is associated with a prognosis significantly worse than that of Europe and the US. Further, patients presenting with breast cancer in Ethiopia are far younger, on average, and patients are typically diagnosed at very late stages, relative to breast cancer patients of European descent. The standard of care for Ethiopian breast cancer patients is radiotherapy and broad-spectrum chemotherapy, which is also the case for US patients with triple-negative breast cancer (TNBC). However, the limited publications that do exist on Ethiopian tumors, and our own preliminary data, suggest that a large proportion of these patients have hormone-positive (ER+) breast cancer. This is surprising 1) given the aggressive nature of the disease, 2) given that African Americans with breast cancer frequently have TNBC, and 3) given the non-hormone targeting treatment these patients are receiving. There is a paucity of information on the molecular and genetic driving factors driving Ethiopian breast cancer, and this is critically hindering treatment strategies for these patients. The Black Lion Hospital in Addis Ababa treats patients from all over the country, and so we have partnered with Dr. Daniel Seifu at the Black Lion Hospital to gather more information about this deadly disease. In this project, we have brought together expertise across multiple institutions to collect tumor specimens, subtype the specimens, and perform DNA and RNAseq on these tumors. We used the TruSeq Exome kit (Illumina) to sequence matched normal and tumor tissue from 3 patients from a small pilot collection. We identified mutations in 127 genes across all three patients, unique to the tumor tissue. We found mutations in BARD1, BRCA2, and BRIP1, and each patient had a mutation in a different spot in the BRCA2 gene. Second, we compared our data to a list of mutations found for inherited breast and ovarian cancer (1), and found mutations in BRCA2, BRIP1, and MSH2, but not the other 7 panel genes. Finally, we compared our initial data set to the Personalized Cancer Mutation Panel (covering 737 mutational hotspots on 45 genes, across many different cancers (2), and found mutations in 3 of these genes: ALK, APC, and HNF1A, but not in the other 42 genes in their panel. At the same time, all these mutations we identified were specific to the tumor tissue and were not found in the matched healthy tissue we analyzed. At this conference we will discuss these results and our analysis from the additional collected samples as the project continues.

Liquid Biopsies for Hepatocellular Cancer and Their Potential in Clinical Practice

Clinicians need to be aware of the powerful new technologies that are being directed toward early diagnosis of hepatocellular carcinoma (HCC). A recent article by Qu C, Wang Y, Wang P, et al. Detection of early-stage hepatocellular carcinoma in asymptomatic HBsAg-seropositive individuals by liquid biopsy. Proc Natl Acad Sci U S A. 2019;116:6308-6312 reported that the presence of somatic mutations and HBV integrations in circulating cell free DNA (cfDNA), the concentration of cfDNA and concentration of protein tumor markers in blood were combined with age and gender to develop a "liquid biopsy" to identify early stage HCC.

CircRNA cPWWP2A: an emerging player in diabetes mellitus.

Circular RNAs(CircRNAs), a new class of non-coding RNAs, possess significant capabilities of gene regulation and are disrupted in various diseases, including diabetes mellitus (DM). However, the underlying mechanism of CircRNAs in DM and diabetic complications remains illusive. A recent study published by Liu et al. (Proc Natl Acad Sci USA 116:7455-7464, 2019) shown that a novel diabetic retinopathy (DR)-associated CircRNA cPWWP2A, which could act as a competing endogenous RNA interacting with miR-579 to promote the DR-induced retinal vascular dysfunction through up-regulating the expression of Angiopoietin 1, Occludin, and SIRT1. Their findings may provide new insight into the potential use of CircRNA cPWWP2A for the targeted therapy of DR. However, those promising findings may need to be further evaluated detailedly for the following reason. (1) This study doesn't well clarify why the most significantly up-regulated CircRNA mmu _circ_0000254 the fold change of which is 160.581 is excluded,while the cPWWP2A the fold change of which is only 3.487 is chosen. (2) It is difficult to conclude that cPWWP2A competing with miR-579 only by the analysis of colocalization in pericytes.