bluuebunny/crossref_metadata_2025 huggingface dataset:
The Damage Sensory Molecule TRPA1 Positively Regulates Endogenous Thymic Regeneration after Damage
Authors: Argyropoulos Kimon , Velardi Enrico , Tsai Jennifer , Lazrak Amina , Jahn Lorenz , Dudakov Jarrod A , van den Brink Marcel R.M.
Published: April 2021

The thymus is extremely sensitive to exogenous insults but has a remarkable capacity to regenerate which is lost with age. Reactive oxygen species (ROS) accumulate early after tissue damage and despite their toxic potential, ROS and their byproducts (such as lipid peroxidation products-LPPs) can act as regeneration signals by activating membrane or intracellular sensors and subsequent stress-response signalling pathways. Using Sublethal Total Body Irradiation (SL-TBI) as a model of acute thymic injury, we found a rapid accumulation of thymic ROS as well as lipid peroxidation products on cell membranes after SLTBI (Figure 1A&B).

The damage-sensing ion channel Transient Receptor Potential cation channel family A member 1 (TRPA1) represents one of the major damage sensing receptors that can mediate cellular responses to oxidative stress mediators, such as LPPs. Using immunofluorescence (IF) microscopy we found that TRPA1 is enriched in the thymic medulla. Interestingly, although TRPA1 has been classically identified in nociceptive fibers, the major TRPA1 expressing structures in the thymus were not nerve fiber terminals, but primarily thymic endothelial cells (Figure1C), fibroblasts and subsets of epithelial cells. We have recently demonstrated that thymic endothelial cells can regulate regeneration through secretion of BMP-4, which can enhance Foxn1 expression and proliferation of thymic epithelial cells. In order to assess the functional role of TRPA1 in thymic regeneration after injury, we utilized TRPA1 knockout (TRPA1-/-) mice and quantified thymic reconstitution after SL-TBI. TRPA1-/- mice had significantly lower thymic cellularity compared to their age- and sex-matched WT controls, suggesting an association between TRPA1 deficiency and delayed endogenous thymic recovery (Figure 1D). The major deficit in thymocyte counts primarily affected double negative-4 (DN4), double positive (DP) and CD4+ single positive (SP-CD4+) thymocyte numbers. The thymic stroma of TRPA1-/- mice had lower endothelial cell and fibroblast counts (Figure 1D). In accordance with these findings drinking water administration of the TRPA1 agonist Allyl-Isothiocyanate (AITC), resulted in enhanced thymic regeneration after radiation exposure. Besides its positive effects on thymocyte counts, AITC significantly augmented endothelial cell counts after irradiation (Figure 1E).

In conclusion these results suggest that TRPA1 plays a non-redundant role in thymic regeneration and that exogenous TRPA1 stimulation can enhance immune recovery after damage.

Disclosures

van den Brink: Seres: Research Funding; Jazz Pharmaceuticals: Consultancy; PureTech Health: Consultancy; Therakos Institute: Other: Speaking engagement.
Fine Temporal Mapping of Plasmodium Falciparum growth Inhibition in Hypoxic Sickle Cell Trait Erythrocytes
Authors: Archer Natasha , Petersen Nicole , Clark Martha , Duraisingh Manoj
Published: April 2021

Background: Despite the global acceptance of Haldane's hypothesis that individuals with sickle cell trait (AS) are protected against malaria, an exact mechanism of resistance remains unknown. Several theories to explain the resistance such as increased splenic destruction, impaired hemoglobin digestion, reduced cytoadherence and specific translocation of host specific microRNAs have been proposed. Here we carefully examine the influence of hypoxia and its relation to parasite cytoadherence and growth in AS and normal (AA) human red blood cells (RBCs).

Materials and Methods: To assess the influence of oxygen tension on parasite proliferation in AS RBCs, we followed the proliferation of tightly synchronized P. falciparum within AS and AA RBCs at 1, 5, 10, and 17% oxygen by flow cytometry and microscopy. Carbon monoxide (CO) studies were performed by introducing 100% CO gas into our enclosed chamber system every 21 hours to prevent sickling at low oxygen.

Results: Flow cytometry assessment of DNA content confirms the absence of DNA replication within parasites in AS erythrocytes at low oxygen, however normal DNA replication is observed in the presence of high oxygen tension and when CO is introduced at low oxygen. Moving parasites from high to low oxygen tension greatly influences the extent of parasite maturity; parasites moved at 16 and 20 hours post invasion (hpi) do not mature beyond that of the late ring/early trophozoite stage while parasites moved at 24, 28, and 32 hpi develop increasingly more merozoites.

Conclusion: Here, we show that in hypoxic conditions parasites in AS erythrocytes stall at the late ring/early trophozoite stage and do not replicate their DNA. We also show that treatment of AS erythrocytes with high oxygen tension or carbon monoxide, a potent inhibitor of sickle hemoglobin polymerization, reverses this phenotype. We propose that the mechanism of AS protection is largely due to P.falciparum's inability to digest polymerized sickle hemoglobin once the parasite sequesters in the hypoxic microvasculature. This is likely a key driver of the reduced parasite densities observed in actual infections in AS individuals.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Pegylated Carboxyhemoglobin Bovine (SANGUINATE®) Restores RBCs Roundness and Reduces Pain during a Sickle Cell Vaso-Occlusive Crisis
Authors: Buontempo Peter , Jubin Ronald G. , Buontempo Cathy , Real Rosa , Kazo Friedericke , O'Brien Siobhan , Adeel Faiza , Abuchowski Abraham
Published: April 2021

Background: Pain during Vaso-Occlusive Crisis (VOC) is a hallmark of sickle cell disease (SCD) as deoxygenated (sickled) red blood cells (RBC) aggregate in the microvasculature due to Hemoglobin S (HbS) polymerization. PEGylated carboxyhemoglobin bovine (PEG-COHb; SANGUINATE®) was designed as a gas transfer agent to depolymerize HbS resulting from hypoxia. Prior in vitro studies have shown PEG-COHb capability to transfer carbon monoxide (CO) and oxygen (O2) to SCD hypoxic RBCs, reversing sickling. A prospective, randomized, single-dose Phase II clinical study is in progress (NCT02411708) evaluating the safety and efficacy of PEG-COHb in the treatment of severe VOC including pain reduction in the ambulatory setting. This study is also evaluating the levels of RBC sickling following treatment and association with pain scoring.

Methods: Participants were randomized to a PEG-COHb (320 mg/kg) or saline (placebo) arm, in addition to standard treatment and IV opioid per institutional practice. Pain was assessed using a 10-point pain scale at screening, pre-infusion, hourly until discharge, 24-hours, 72-hours, and Day 7 post-infusion. Blood was collected at pre-infusion, time for readiness to discharge and 72 hours post-infusion to assess RBC shape morphology changes using image-based flow cytometry.

Results: Interim results showed PEG-COHb treated subjects experienced significant reduction at discharge in pain score of 4.3 (±0.3) compared to 2.4 (±0.6) reduction in the placebo arm (p<0.01) (Fig 1). All PEG-COHb participants exhibited RBC morphology changes consistent with unsickling shortly after administration (Fig 2). There were no drug-related severe adverse events.

Conclusions: PEG-COHb appeared to be safe, well tolerated, and associated with significantly reduced pain scores. The flow cytometry analysis of blood samples revealed PEG-COHb treatment reverted RBC to a more normal round morphology when compared to the placebo group. Individual patient data showed a trend between RBC unsickling (roundness) and pain score reductions. These results are consistent with depolymerization of HbS resulting from transfer of CO and/or O2 to sickled RBCs and O2 delivery to hypoxic tissue. This study supports advanced clinical trials of PEG-COHb as a potential therapy to reduce the pain associated with VOC.

Disclosures

Buontempo: Prolong Pharmaceuticals: Employment. Jubin: Prolong Pharmaceuticals: Employment. Buontempo: Prolong Pharmaceuticals: Employment. Real: Prolong Pharmaceuticals: Employment. Kazo: Prolong Pharmaceuticals: Employment. O'Brien: Prolong Pharmaceuticals: Employment. Adeel: Prolong Pharmaceuticals: Employment. Abuchowski: Prolong Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees.
Apolipoprotein L1 Genetic Variants Are Associated with Evidence of Early Kidney Injury in Sickle Cell Disease
Authors: Moodalbail Divya G , Falkner Bonita
Published: April 2021

Background and Objectives: Apolipoprotein L1 (APOL1) renal risk variants prevalent in African-ancestry populations are associated with chronic kidney disease (CKD). CKD is a major cause of morbidity and mortality in sickle cell disease (SCD) in adults; yet the prevalence and significance of APOL1 renal-risk variants in this population remains unknown. Our objective was to determine expression of biomarkers of early kidney disease in African American youth with SCD, based on their APOL1 genotype.

Methods:We enrolled65 African American subjects between 5 to 21 years of age with SCD (Hb SS or Hb S β0 thalassemia). Blood and concurrent urine samples were collected. Allenrolled subjects underwent APOL1 genotyping by PCR analysis of DNA extracted from whole blood. Presence of two renal-risk variants qualified for APOL1 High Risk (HR) genotype, while presence of zero or one copy of renal-risk variants qualified for APOL1 Low Risk (LR) genotype.

Results: APOL1 HR genotype was expressed by 22% of our subjects; this is comparable to 23% prevalence of APOL1 HR genotype in African American adults with CKD (AASK study). Both groups were similar with respect to distribution of age, BMI z-scores, renal function and urine osmolality. Hyperfiltration was noted in both groups based on low serum creatinine for age, and elevated eGFR based on creatinine clearance. However, median urine albumin excretion rate was significantly higher in HR group vs. LR group.

Conclusions: Preliminary data in this cohort of 65 children and adolescents with SCD detected greater urine albumin excretion rate in the presence of APOL1 HR genotype. Screening SCD youth for heightened CKD risk may be an avenue to initiate targeted preventive interventions to preserve renal function and reduce progression of kidney disease.

Acknowledgment: Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under Award Number P20GM109021; National Kidney Foundation Young Investigator Grant and DE-CTR-ACCEL grant number U54-GM104941 (PI: Binder-Macleod).

Disclosures

No relevant conflicts of interest to declare.
Poly-P as Modulator of Hemostasis, Thrombosis, and Inflammation
Authors: Morrissey James H.
Published: April 2021

Polyphosphate (polyP), consisting of linear polymers of inorganic phosphates, is ubiquitous in biology. PolyP metabolism has been most extensively explored in microbes, but until very recently, roles for polyP in mammalian cells have been poorly understood. In 2004, polyP was shown to be a major component of dense granules in human platelets, and to be secreted upon platelet activation.1 In 2006, we demonstrated that polyP is a potent modulator of the blood clotting system.2 Subsequent work from our lab and others has shown that polyP accelerates blood clotting and slows fibrinolysis, in a manner that is highly dependent on polymer length.3 Long-chain polyP (present in infectious microorganisms) potently triggers the contact pathway and may participate in innate immunity/host responses to pathogens. PolyP of the size secreted by platelets (60 to 100 phosphates long) accelerates factor V activation, abrogates the anticoagulant activity of tissue factor pathway inhibitor, enhances fibrin clot structure, and greatly accelerates factor XI activation by thrombin. PolyP also enhances the proinflammatory activity of histones and inhibits complement. PolyP is a potential antithrombotic drug target, with a novel mechanism of action and possibly fewer bleeding side-effects compared to conventional anticoagulant drugs.4

1. Ruiz FA, Lea CR, Oldfield E, Docampo R. Human platelet dense granules contain polyphosphate and are similar to acidocalcisomes of bacteria and unicellular eukaryotes. J Biol Chem . 2004;279(43):44250-44257.

2. Smith SA, Mutch NJ, Baskar D, Rohloff P, Docampo R, Morrissey JH. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci U S A . 2006;103(4):903-908.

3. Morrissey JH, Smith SA. Polyphosphate as modulator of hemostasis, thrombosis, and inflammation. J Thromb Haemost . 2015;13 Suppl 1:S92-97.

4. Travers RJ, Shenoi RA, Kalathottukaren MT, Kizhakkedathu JN, Morrissey JH. Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis. Blood . 2014;124(22):3183-3190.

Disclosures

Morrissey: Novo Nordisk: Consultancy, Honoraria, Research Funding; rEVO Biologics: Consultancy, Honoraria; Paul, Weiss, Rifkind, Wharton & Garrison LLP: Consultancy; Cayuga Pharmaceuticals: Consultancy; PrevThro Pharmaceuticals: Equity Ownership; Kerafast, Inc.: Research Funding.
Reciprocal Interactions Between Platelets and Metastatic Tumors
Authors: Byzova Tatiana V.
Published: April 2021

The presentation will address the possible mechanisms underlying the crosstalk between circulating platelets and the growing tumor. The emphasis will be on the reciprocal nature of this crosstalk. It is well accepted that the presence of platelets and their activation generally promotes tumor growth and its metastasis; the effect of tumor on platelet activation and subsequent thrombosis have been also known for many years. The highly metastatic tumors are able to affect the gene expression and functional characteristics of other cells in their micro and macro environment. The easiest targets for tumor interference are blood cells. Due to their ability to capture and accumulate proteins, small particles and even cell fragments, platelets represent a unique "delivery" system. Many proteins stored in alpha-granules of platelets circulating in blood of tumor-bearing host carry proteins of the tumor rather than the host origin. Tumor hijacks the platelet system for the delivery of its growth factors and cytokines and it also induces platelet activation. The possible mechanisms of tumor-induced platelet activation will be discussed. Results demonstrating the mode of tumor-platelet interactions in animal models will be combined with clinical evidence. Understanding of these mechanisms will facilitate the development of therapeutic strategies aimed to prevent cancer-induced thrombosis without disturbing the hemostatic balance.

Disclosures

No relevant conflicts of interest to declare.
NGS-Based Diagnostics in Hematopathology: Strategies for Implementation in a Clinical Environment
Authors: Elenitoba-Johnson Kojo S.J.
Published: April 2021

The advent of next generation sequencing (NGS) has dramatically impacted the practice of hematopathology and the role of the clinical laboratory in information management and reporting. While the ability to simultaneously interrogate multiple gene loci for copy number, single nucleotide and large structural variations from one platform affords detailed examination of the genomes of hematologic malignancies, the integration of pre-analytical and technical workflows in genomic diagnostics and bioinformatics to ensure a seamless transmission of clinically relevant information offers opportunities for enhancement. In this session, a review of the parameters to be considered encompassing target selection, assay design, validation and performance specification test implementation will be covered. Considerations for options for reporting of clinical laboratory results to clinicians and oncologists to facilitate delivery of precision medicine will be examined.

Disclosures

Elenitoba-Johnson: Genomenon: Equity Ownership.
Clonal Evolution and Relapse in Adult De Novo Acute Myeloid Leukemia
Authors: Ley Timothy J.
Published: April 2021

Patients with intermediate risk AML have unpredictable outcomes. Some do extremely well with conventional induction and consolidation chemotherapy, while others do poorly. The discovery of nearly all mutations associated with AML pathogenesis created an important database that has allowed investigators from around the world to use panel tests to assess the mutational landscapes of thousands of patients with known outcomes. Although these studies have been extremely informative, they have not dramatically altered the ability to accurately predict whether an individual intermediate-risk AML patient will relapse. The reasons are multifold. First, there is enormous combinatorial complexity of the mutations associated with AML. At least three mutations are required for the development of most AML cases, but since there are more than 250 recurrently mutated genes, the combinatorial possibilities are enormous. Secondly, because virtually all patients with AML present with clonal heterogeneity, and since individual subclones have different susceptibilities to chemotherapy, it has been difficult to predict outcomes based solely on the mutational composition of a patient at presentation. Further, since most subclones are 'invisible' to flow cytometric methods, and do not contain well-established mutations in genes that are recurrently mutated in AML, we cannot yet predict whether a subclone may be refractory to chemotherapy, or have extraordinary relapse potential . To overcome these issues, we asked whether information based on the clearance of the subclones from each patient could "integrate" this critical information in a practical way, and ultimately improve risk assessment. This study (Klco et al, JAMA 2015) suggested that a practical evaluation of mutation clearance after induction therapy could represent an improvement in our ability to predict whether intermediate risk patients who fail to clear their mutations after induction would benefit from allogeneic transplantation as their primary consolidation. A prospective clinical trial designed to answer this question is underway. Efforts to identify the properties of subclones that have high relapse potential, using single cell RNA-seq, and the sequencing of the relapse genomes of additional AML cases, will also be discussed.

Disclosures

No relevant conflicts of interest to declare.
Congenital Sideroblastic Anemias: Iron and Heme Lost in Mitochondrial Translation
Authors: Fleming Mark D.
Published: April 2021

The congenital sideroblastic anemias (CSAs) are an uncommon, diverse class of inherited hematopoietic disorders characterized by pathological deposition of iron in the mitochondria of erythroid precursors. In recent years, the genetic causes of several clinically distinctive forms of CSA have been elucidated, which has revealed common themes in their pathogenesis. In particular, most, if not all, can be attributed to disordered mitochondrial heme synthesis, iron-sulfur cluster biogenesis or pathways related to mitochondrial protein synthesis. This presentation will summarize the clinical features, molecular genetics, and pathophysiology of the CSAs in the context of these pathways with particular emphasis on new disease entities and how characterization these phenotypes can contribute to CSA diagnostics and therapeutics.

Disclosures

No relevant conflicts of interest to declare.
RNA Methylation and Its Role in the Hematopoietic System
Authors: Lyko Frank
Published: April 2021

RNA methylation represents a novel expansion of traditional epigenetic concepts. RNAs can be methylated at adenine and at cytosine residues, and both modifications have distinct regulatory potential. Our work focuses on the DNMT2 enzyme, which is a member of the animal (cytosine-5) DNA methyltransferase family and has long been considered to function as a DNA methyltransferase. However, a DNA methyltransferase activity could not be confirmed conclusively and more recent work clearly demonstrates that DNMT2 is a tRNA methyltransferase. This unexpected substrate is interpreted to reflect an evolutionary ancient substrate switch from DNA to tRNA that expanded the epigenetic regulatory capacity of the DNMT family to also include RNA. To analyze the function of DNMT2, we performed a detailed analysis of knockout mice. These mice are viable and fertile, but also show a reduction of hematopoietic stem and progenitor cell populations and a cell-autonomous defect in their differentiation.1 RNA bisulfite sequencing revealed that Dnmt2 methylates C38 of tRNA Asp(GTC), Gly(GCC), and Val(AAC). Proteomic analyses from primary bone marrow cells uncovered systematic differences in protein expression that are due to specific codon mistranslation by tRNAs lacking DNMT2-dependent methylation. Together, these results illustrate the regulatory capacity of DNMT2-mediated tRNA methylation in genome recoding.2 Our current work addresses additional mechanistic aspects that link tRNA methylation to translational fidelity and investigates the relevance of DNMT2-mediated tRNA methylation for leukemogenesis.

1. Tuorto F, Herbst F, Alerasool N, et al. The tRNA methyltransferase Dnmt2 is required for accurate polypeptide synthesis during haematopoiesis. EMBO J. 2015;34(18):2350-2362.

2. Tuorto F, Lyko F. Genome recoding by tRNA modifications. Open Biol. 2016;6(12):160287.

Disclosures

No relevant conflicts of interest to declare.
Whole Exome Sequencing in Patients With Hematologic Malignancies: Ready for Real-Time Precision Medicine?
Authors: Haferlach Torsten
Published: April 2021

In the last decade the landscape in hematological diseases has been newly defined. New platforms and assays in research have been used, new pathways, variations in genes and targets for precision medicine have been detected. Next generation sequencing (NGS) contributed a lot to these important achievements. In parallel, NGS has emerged from a research tool to a diagnostic tool and is increasingly applied in routine diagnostic laboratories. Today, NGS techniques are capable of facilitating diagnostics to detect mutations, many variants of uncertain significance, translocations but also gains and losses of chromosomal material. We now have to define, which scenario will be useful for daily routine, which application should still be considered research and how we can improve in the next few years. For sure, NGS is able to reproduce findings from Sanger sequencing to detect variants in single genes as well as to apply gene panels. The latter approach is increasingly used. It will substitute Sanger sequencing in many cases. Also the investigation of gene fusions and translocations will soon be available by NGS based assays in a routine setting. So far, whole exome sequencing (WES) studies have been published from several groups on AML, MDS, CML, ALL, lymphoma entities, CLL or myeloma, in a total ~ 1,500 cases. However, the investigation by WES or even whole genome sequencing so far is not a method of choice in routine diagnostics in hematology. The drawbacks are not only the technical applicability or costs but much more important: data handling and interpretation, and data storage. This is especially true as curated data is still limited and easy-to-use software applications are needed for routine application. If big data sets shall contribute in a routine diagnostic approach, significant bioinformatic processing is mandatory. Further, in many circumstances today WES is hampered as germline material is often missing and data have to be calculated from the "tumor only" sample. Therefore, the routine use of WES to define targets for precision medicine in hematology in a timely manner has only been established in very few places worldwide. The technique itself, instruments, assays and bioinformatic tools will however have the chance to be included in routine workflows at a reasonable turn-around-time within the next 5 years. This will shift or abolish several of today´s standard techniques.

Disclosures

Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
Reversible cerebral vasoconstriction syndrome (RCVS): an interesting case report
Authors: Togha Mansoureh , Babaei Mahsa , Ghelichi Parvin Ganji
Published: April 2021

Background

Reversible Cerebral Vasoconstriction Syndrome is a condition of transient cerebral vascular spasms, which usually presents with recurrent thunderclap headaches and recovers within 3 months. Several probable triggers and underlying factors, such as sex hormones, vasoactive drugs, head trauma or surgery, and tumors, have been implicated.

Case presentation

In this paper, we presenta53-year-old woman with thunderclap headaches and normal lab tests who was radio-clinically diagnosed with reversible cerebral vasoconstriction syndrome and treated accordingly. Then, she experienced the recurrence of RCVS after about 2 years and headaches after 1 year in association with high blood pressure, high blood sugar, hypothyroidism, hyperlipidemia, and a urine metanephrine level of 5 times higher than the normal limit, suggesting a diagnosis of pheochromocytoma. After confirmation of the diagnosis with further imaging studies, surgical removal of the tumor resolved all the signs and symptoms.

Conclusion

Often underdiagnosed, pheochromocytoma could be an important condition associated with RCVS. It is important for clinicians to bear this diagnosis in mind while dealing with similar cases of recurrent thunderclap headaches.
Behavioral sensitization induced by methamphetamine causes differential alterations in gene expression and histone acetylation of the prefrontal cortex in rats
Authors: Li Hui , Chen Jing-An , Ding Qian-Zhi , Lu Guan-Yi , Wu Ning , Su Rui-Bin , Li Fei , Li Jin
Published: April 2021

Background

Methamphetamine (METH) is one of the most widely abused illicit substances worldwide; unfortunately, its addiction mechanism remains unclear. Based on accumulating evidence, changes in gene expression and chromatin modifications might be related to the persistent effects of METH on the brain. In the present study, we took advantage of METH-induced behavioral sensitization as an animal model that reflects some aspects of drug addiction and examined the changes in gene expression and histone acetylation in the prefrontal cortex (PFC) of adult rats.

Methods

We conducted mRNA microarray and chromatin immunoprecipitation (ChIP) coupled to DNA microarray (ChIP-chip) analyses to screen and identify changes in transcript levels and histone acetylation patterns. Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, were performed to analyze the differentially expressed genes. We then further identified alterations in ANP32A (acidic leucine-rich nuclear phosphoprotein-32A) and POU3F2 (POU domain, class 3, transcription factor 2) using qPCR and ChIP-PCR assays.

Results

In the rat model of METH-induced behavioral sensitization, METH challenge caused 275 differentially expressed genes and a number of hyperacetylated genes (821 genes with H3 acetylation and 10 genes with H4 acetylation). Based on mRNA microarray and GO and KEGG enrichment analyses, 24 genes may be involved in METH-induced behavioral sensitization, and 7 genes were confirmed using qPCR. We further examined the alterations in the levels of the ANP32A and POU3F2 transcripts and histone acetylation at different periods of METH-induced behavioral sensitization. H4 hyperacetylation contributed to the increased levels of ANP32A mRNA and H3/H4 hyperacetylation contributed to the increased levels of POU3F2 mRNA induced by METH challenge-induced behavioral sensitization, but not by acute METH exposure.

Conclusions

The present results revealed alterations in transcription and histone acetylation in the rat PFC by METH exposure and provided evidence that modifications of histone acetylation contributed to the alterations in gene expression caused by METH-induced behavioral sensitization.
Crystalline deposits in the cornea and various areas of the kidney as symptoms of an underlying monoclonal gammopathy: a case report
Authors: Lindemann C. , Enders P. , Brinkkoetter P. T. , Völker L. A.
Published: April 2021

Background

Plasma cell dyscrasias (PCD) are characterized by an abnormal production of intact monoclonal immunoglobulins or parts such as heavy or light chains. In most cases, the monoclonal protein (also termed paraprotein) is produced by a clonal plasma cell population. The production of monoclonal proteins can result in deposits of various types and localization depending on the type, amount, and electrochemical properties of the paraprotein. One histopathologic presentation, albeit rare, are crystalline deposits. They can form in various organs and hence cause a wide spectrum of symptoms.

Case presentation

A 49-year-old man presented to the emergency department with eyestrain and foreign body sensation after overhead drilling. Examination of the eyes revealed crystalline deposits in the cornea of both eyes. After additional diagnostic testing, deposits were attributed to free light chains. Monoclonal gammopathy of undetermined significance (MGUS) was diagnosed according to serum electrophoresis and immunofixation. Four years later, new onset of proteinuria was detected. A percutaneous biopsy of the kidney showed severe light chain podocytopathy with secondary focal segmental glomerulosclerosis (FSGS) and light chain proximal tubulopathy (LCPT). In these lesions, crystalline deposits identical to the corneal deposits were found in ultrastructural and immunofluorescent analysis. The patient was diagnosed with monoclonal gammopathy of renal significance (MGRS), and a plasma cell directed therapy was initiated.

Conclusions

PCD can present with a wide array of symptoms and are notoriously difficult to diagnose. Extrarenal manifestations such as crystalline deposits in the cornea are one possible manifestation. The case presented herein emphasizes the notion that extrarenal paraprotein deposits warrant a thorough search for the underlying clonal disease.
TIM3 expression on TILs is associated with poor response to neoadjuvant chemotherapy in patients with locally advanced triple-negative breast cancer
Authors: Cabioglu Neslihan , Onder Semen , Oner Gizem , Karatay Hüseyin , Tukenmez Mustafa , Muslumanoglu Mahmut , İgci Abdullah , Eralp Yeşim , Aydiner Adnan , Saip Pınar , Yavuz Ekrem , Ozmen Vahit
Published: April 2021

Background

The expression of immune checkpoint receptors (ICRs) on tumor-infiltrating lymphocytes (TILs) is associated with better response to immunotherapies via immune checkpoint inhibitors. Therefore, we investigated various ICR expressions on TILs in patients with locally advanced triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC).

Methods

Expressions of ICRs were examined immunohistochemically in surgical specimens (n = 61) using monoclonal antibodies for PDL-1, PD-1, TIM-3, LAG-3, and CTLA-4. Positivity was defined as staining > 1% on TILs.

Results

The median age was 49 (24–76) years. The majority of patients were clinically T3–4 (n = 31, 50.8%) and clinically N1–3 (n = 58, 95.1%) before NAC. Of those, 82% were found to have CTLA-4 positivity, whereas PD1, PDL-1, LAG3, and TIM-3 expressions on TILs were 62.3, 50.9, 26.2, and 68.9%. A high expression of CTLA-4 was found to be associated with a better chemotherapy response (OR = 7.94, 95% CI: 0.9–70.12, p = 0.06), whereas TIM-3 positivity was contrarily associated with a worse chemotherapy response (OR = 0.253, 95% CI: 0.066–0.974, p = 0.047) as measured by the MDACC Residual Cancer Burden Index. At a 47-month follow-up, ypN0 (DFS; HR = 0.31, 95% CI: 0.12–0.83, p = 0.02 and DSS; HR = 0.21, 95% CI: 0.07–0.62, p = 0.005) and CTLA-4 high expression on TILs (DFS; HR = 0.38, 95% CI: 0.17–0.85, p = 0.019 and DSS; HR = 0.34, 95% CI: 0.15–0.78, p = 0.01) were found to be associated with improved survival.

Conclusions

These findings demonstrate that CTLA-4, PD-1, PDL-1, and TIM-3 were highly expressed in TNBC. Based on these high expression patterns, further studies directed towards combined therapies are warranted in advanced TNBC in future.
Factors for the optimal selection of granulocyte colony-stimulating factor preparations and predictors for R-CHOP dose reductions/delays among patients with non-Hodgkin B-cell lymphoma (STOP FN in NHL 2 subanalysis)
Authors: Yokoyama Masahiro , Kusano Yoshiharu , Inoue Norihito , Nishimura Noriko , Mishima Yuko , Nukada Tomoyuki , Hatake Kiyohiko , Terui Yasuhito
Published: April 2021

Background

A classification tree was used to analyze background factors for granulocyte colony-stimulating factor (G-CSF) preparation selection for febrile neutropenia (FN) prophylaxis in Japanese patients with non-Hodgkin B-cell lymphoma receiving the first R-CHOP cycle.

Methods

This was a subanalysis of the retrospective observational study STOP FN in NHL 2 (UMIN000029534). Patient characteristics, changes in neutrophil count, incidence and severity of neutropenia, and risk factors for dose reduction/delay of R-CHOP were assessed by G-CSF formulation.

Results

Among 234 patients in cycle 1, 25.6% received no G-CSF preparation, 52.1% received daily G-CSF, and 22.2% received pegfilgrastim. Pegfilgrastim use was most frequent among patients aged ≥ 80 years, while that of daily G-CSF was most frequent in patients with lymphocyte count (LC) < 1000 cells/μL. Changes in neutrophil count were more marked with pegfilgrastim compared with daily G-CSF and no G-CSF. Relevant factors for G-CSF preparation selection in the first R-CHOP cycle were age ≥ 80 years and LC < 1000 cells/μL; for chemotherapy dose reduction were FN onset in cycle 1 and female sex; and for dose delay was hemoglobin (< 12 g/dL). After cycle 2 and onward, pegfilgrastim use increased markedly (72.6%) compared with cycle 1 (22.2%), with significantly greater proportions continuing pegfilgrastim use and switching from daily G-CSF.

Conclusion

Relevant factors for G-CSF preparation selection were age ≥ 80 years and LC < 1000 cells/μL. The use of pegfilgrastim increased markedly after cycle 2. These results may be useful for selecting appropriate G-CSF preparations in the first R-CHOP cycle.

Trial registration

UMIN000029534; registered on 13 October 2017, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000033733.
Sleep problems are related to commuting accidents rather than to workplace accidents
Authors: Vargas-Garrido Héctor , Moyano-Díaz Emilio , Andrades Katherinne
Published: April 2021

Background

This study aimed to verify the relationships between sleep problems and both commuting and workplace accidents in workers of both sexes.

Methods

The study was carried out with a sample of workers (n = 2993; 50.2% female) from the Chilean Quality of Life Survey (ENCAVI) 2015–2016, while the rates of both workplace and commuting accidents were extracted from the statistics of the Superintendence of Social Security (SUSESO 2015; 180,036 and 52,629 lost-time accidents, respectively).

Results

Chilean workers sleep less than the rest of the people in the country (MW = 7.14 vs. MO = 7.33; t (6789) = − 5.19; p < .001), while the Chilean people as a whole sleep less compared to those of other countries (7.24 h per day). Likewise, it was found that sleep problems are more strongly related to commuting than to workplace accidents. In this vein, sleep quantity can explain 24% of the variance in commuting accidents’ rates (Stepwise Method; R2 = .30, F (1.14) = 5.49, p < .05; β = −.55, p < .05), by using aggregated data with all types of commuting roles (driver of a vehicle, a passenger of public or private transport, or as a pedestrian).

Conclusions

Our findings show that sleep quantity has a more robust relationship with commuting than workplace accidents, a neglected issue so far. Future prevention programs should emphasize sleep hygiene and focus on commuting to and from work.
Application of 3D modeling and fusion technology of medical image data in image teaching
Authors: Yuan Quan , Chen Xiaomei , Zhai Jian , Chen Yadi , Liu Qingxiang , Tan Zhongxiao , Chen Gao , Zhuang Kangle , Zhang Jianying , Xu Xi , Qiang Di , Shao Xuefei
Published: April 2021

Background

We combined anatomy with imaging, transformed the 2D information of various imaging techniques into 3D information, and form the assessment system of real medical imaging cases in order to make up for the deficiencies in the current teaching of the medical imaging technology students.

Methods

A total of 460 medical imaging students were selected and randomly divided into two groups. The research group received the teaching of the fusion of the original CT and MR data 3D model and the original image combined with 3D anatomical image. CT and MRI data are imported through load DICOM of 3D slicer. Different tissues and organs are segmented by threshold and watershed algorithm of segment editor module. Models are exported through export / import models and label maps in segmentation. Save the NHDR file of the original data and Obj file of the corresponding model through save the NHDR and corresponding Obj files are loaded into probe 1.0 software. The software can give different colors to the three-dimensional models of different organs or tissues to display the stereo models and related data, and display the hook edges of organ models on coronal, sagittal and axial images. At the same time, annotation can be established in the corresponding anatomical position. Finally, it can be saved as a single file of Hwl, and the teaching can be opened at any time through the program of probe 1.0. Statistical analysis Academic self-efficacy scale and Self-directed learning ability scale was adopted by self-directed learning evaluation scale between two groups.

Results

Compare the theoretical scores and case analysis scores of the two groups. The scores of the study and control groups were significantly higher than those of the control group. Before the experiment, no significant difference was detected in the self-efficacy of learning ability and learning behavior between the two groups, while after the experiment, these differences between the two groups were statistically significan. Moreover, the learning ability self-efficacy and learning behavior of the two groups of students after the experiment was significantly higher than that before the experiment. The self-efficacy of the learning behavior of the control group was higher after the experiment than that before the experiment, albeit the difference was not statistically significant.

Conclusions

The modern, information-based and humanized experimental teaching mode will be constantly improved under the support of PACS system in order to optimize the medical imaging teaching activities for the development of modern medical education.
Aggressive squamous cell carcinoma of the cranium of a dog
Authors: Łojszczyk Anna , Łopuszyński Wojciech , Szadkowski Mateusz , Orzelski Maciej , Twardowski Piotr
Published: April 2021

Background

The authors report a case of keratinized squamous cell carcinoma (SCC) in a 14-year-old dog with extensive cranial bone invasion. To our knowledge, this is the first description of such a case of cranial keratinized SCC with aggressive generalized osteolysis described in a dog.

Case presentation

The 14-year-old dog was referred for radiological examination with suspicion of head trauma with clinical signs of head deformation, exophthalmos and nasal discharge. The skull radiographs showed a large osteolytic defect of the frontal bone and parietal bone in the region of the external sagittal crest. Findings from the skull CT scan included generalized osteolysis in the region of parietal bone, frontal bones, maxilla on the right side and the nasal bone including the dorsal nasal concha. In the area of bone loss, new soft tissue formation with multifocal foci of mineralization was visible. The ultrasound examination revealed hypoechogenic changes with hyperechoic foci consistent with mineralization and poor vascularization. The brain and ocular structures were without visible changes. Fine needle aspiration cytology (FNAC) was performed, and squamous cell carcinoma was suspected. After 3 months, the re-presented to the clinic. The dog became progressively listless, his appetite was decreased, and he became acutely blind. Follow-up skull CT scan revealed significant osteolysis, which affected a significant aspect of the cranium. All bone defects had been replaced by new 3.5 cm-thick soft tissue formations with multifocal small 1–2 mm areas of mineralization. There was no evidence of metastasis. Histological examination confirmed the suspicion of squamous cell carcinoma.

Conclusions

This paper is the first report of cranial SCC in a dog causing extensive bone osteolysis. The lesions in this dog originated from the frontal and parietal bones including frontal sinuses.

There are variants of tumors that arise from squamous epithelium or resemble SCC in the skull. These examples include adenosquamous carcinoma and proliferating trichilemmal tumours. In addition, there is possible malignant transformation caused by papilloma viruses. In the veterinary literature, there is only one similar description of adenosquamous carcinoma in a cat with similar clinical manifestations. It is justified to suspect a process of neoplastic epithelial origin in all cases of aggressive and extensive skull bone lysis. This issue should be subject to further investigation.
Ugandan stakeholder hopes and concerns about gene drive mosquitoes for malaria control: new directions for gene drive risk governance
Authors: Hartley Sarah , Smith Robert D. J. , Kokotovich Adam , Opesen Chris , Habtewold Tibebu , Ledingham Katie , Raymond Ben , Rwabukwali Charles B.
Published: April 2021

Background

The African Union’s High-Level Panel on Emerging Technologies identified gene drive mosquitoes as a priority technology for malaria elimination. The first field trials are expected in 5–10 years in Uganda, Mali or Burkina Faso. In preparation, regional and international actors are developing risk governance guidelines which will delineate the framework for identifying and evaluating risks. Scientists and bioethicists have called for African stakeholder involvement in these developments, arguing the knowledge and perspectives of those people living in malaria-afflicted countries is currently missing. However, few African stakeholders have been involved to date, leaving a knowledge gap about the local social-cultural as well as ecological context in which gene drive mosquitoes will be tested and deployed. This study investigates and analyses Ugandan stakeholders’ hopes and concerns about gene drive mosquitoes for malaria control and explores the new directions needed for risk governance.

Methods

This qualitative study draws on 19 in-depth semi-structured interviews with Ugandan stakeholders in 2019. It explores their hopes for the technology and the risks they believed pertinent. Coding began at a workshop and continued through thematic analysis.

Results

Participants’ hopes and concerns for gene drive mosquitoes to address malaria fell into three themes: (1) ability of gene drive mosquitoes to prevent malaria infection; (2) impacts of gene drive testing and deployment; and, (3) governance. Stakeholder hopes fell almost exclusively into the first theme while concerns were spread across all three. The study demonstrates that local stakeholders are able and willing to contribute relevant and important knowledge to the development of risk frameworks.

Conclusions

International processes can provide high-level guidelines, but risk decision-making must be grounded in the local context if it is to be robust, meaningful and legitimate. Decisions about whether or not to release gene drive mosquitoes as part of a malaria control programme will need to consider the assessment of both the risks and the benefits of gene drive mosquitoes within a particular social, political, ecological, and technological context. Just as with risks, benefits—and importantly, the conditions that are necessary to realize them—must be identified and debated in Uganda and its neighbouring countries.
Predicting plaque vulnerability change using intravascular ultrasound + optical coherence tomography image-based fluid–structure interaction models and machine learning methods with patient follow-up data: a feasibility study
Authors: Guo Xiaoya , Maehara Akiko , Matsumura Mitsuaki , Wang Liang , Zheng Jie , Samady Habib , Mintz Gary S. , Giddens Don P. , Tang Dalin
Published: April 2021

Background

Coronary plaque vulnerability prediction is difficult because plaque vulnerability is non-trivial to quantify, clinically available medical image modality is not enough to quantify thin cap thickness, prediction methods with high accuracies still need to be developed, and gold-standard data to validate vulnerability prediction are often not available. Patient follow-up intravascular ultrasound (IVUS), optical coherence tomography (OCT) and angiography data were acquired to construct 3D fluid–structure interaction (FSI) coronary models and four machine-learning methods were compared to identify optimal method to predict future plaque vulnerability.

Methods

Baseline and 10-month follow-up in vivo IVUS and OCT coronary plaque data were acquired from two arteries of one patient using IRB approved protocols with informed consent obtained. IVUS and OCT-based FSI models were constructed to obtain plaque wall stress/strain and wall shear stress. Forty-five slices were selected as machine learning sample database for vulnerability prediction study. Thirteen key morphological factors from IVUS and OCT images and biomechanical factors from FSI model were extracted from 45 slices at baseline for analysis. Lipid percentage index (LPI), cap thickness index (CTI) and morphological plaque vulnerability index (MPVI) were quantified to measure plaque vulnerability. Four machine learning methods (least square support vector machine, discriminant analysis, random forest and ensemble learning) were employed to predict the changes of three indices using all combinations of 13 factors. A standard fivefold cross-validation procedure was used to evaluate prediction results.

Results

For LPI change prediction using support vector machine, wall thickness was the optimal single-factor predictor with area under curve (AUC) 0.883 and the AUC of optimal combinational-factor predictor achieved 0.963. For CTI change prediction using discriminant analysis, minimum cap thickness was the optimal single-factor predictor with AUC 0.818 while optimal combinational-factor predictor achieved an AUC 0.836. Using random forest for predicting MPVI change, minimum cap thickness was the optimal single-factor predictor with AUC 0.785 and the AUC of optimal combinational-factor predictor achieved 0.847.

Conclusion

This feasibility study demonstrated that machine learning methods could be used to accurately predict plaque vulnerability change based on morphological and biomechanical factors from multi-modality image-based FSI models. Large-scale studies are needed to verify our findings.