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The contact system proteases play disparate roles in streptococcal sepsis

Sepsis causes an activation of the human contact system, an inflammatory response mechanism against foreign surfaces, proteins and pathogens. The serine proteases of the contact system, factor XII and plasma kallikrein, are decreased in plasma of septic patients, which was previously associated with an unfavorable outcome. However, the precise mechanisms and roles of contact system factors in bacterial sepsis are poorly understood. We, therefore, studied the physiological relevance of factor XII and plasma kallikrein in a mouse model of experimental sepsis. We show that decreased plasma kallikrein concentration in septic mice is a result of reduced mRNA expression plasma prekallikrein gene, indicating that plasma kallikrein belong to negative acute phase proteins. Investigations regarding the pathophysiological function of contact system proteases during sepsis revealed different roles for factor XII and plasma kallikrein. In vitro, factor XII decelerated bacteria induced fibrinolysis, whereas plasma kallikrein supported it. Remarkably, depletion of plasma kallikrein (but not factor XII) by treatment with antisense-oligonucleotides, dampens bacterial dissemination and growth in multiple organs in the mouse sepsis model. These findings identify plasma kallikrein as a novel host pathogenicity factor in Streptococcus pyogenes sepsis.




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Structured assessment of frailty in multiple myeloma as a paradigm of individualized treatment algorithms in cancer patients at advanced age




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Characterization of response and corneal events with extended follow-up after belantamab mafodotin (GSK2857916) monotherapy for patients with relapsed multiple myeloma: a case series from the first-time-in-human clinical trial




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First person - Sonu S. Baral [FIRST PERSON]



First Person is a series of interviews with the first authors of a selection of papers published in Biology Open, helping early-career researchers promote themselves alongside their papers. Sonu S. Baral is first author on ‘Nucleolar stress in Drosophila neuroblasts, a model for human ribosomopathies’, published in BiO. Sonu conducted the research described in this article while a PhD student in Patrick J. DiMario's lab at Louisiana State University, Baton Rouge, LA, USA. She is now a R&D scientist at Thermo Fisher Scientific, Santa Clara, CA, USA, investigating various genetic disorders relevant to reproductive health and newborn screening.




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THE DECLARATION OF ASTANA AND WHAT IT MEANS FOR THE GLOBAL ROLE OF NAPCRG AND WONCA [Family Medicine Updates]




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The Role of Fnr Paralogs in Controlling Anaerobic Metabolism in the Diazotroph Paenibacillus polymyxa WLY78 [Environmental Microbiology]

Fnr is a transcriptional regulator that controls the expression of a variety of genes in response to oxygen limitation in bacteria. Genome sequencing revealed four genes (fnr1, fnr3, fnr5, and fnr7) coding for Fnr proteins in Paenibacillus polymyxa WLY78. Fnr1 and Fnr3 showed more similarity to each other than to Fnr5 and Fnr7. Also, Fnr1 and Fnr3 exhibited high similarity with Bacillus cereus Fnr and Bacillus subtilis Fnr in sequence and structures. Both the aerobically purified His-tagged Fnr1 and His-tagged Fnr3 in Escherichia coli could bind to the specific DNA promoter. Deletion analysis showed that the four fnr genes, especially fnr1 and fnr3, have significant impacts on growth and nitrogenase activity. Single deletion of fnr1 or fnr3 led to a 50% reduction in nitrogenase activity, and double deletion of fnr1 and fnr3 resulted to a 90% reduction in activity. Genome-wide transcription analysis showed that Fnr1 and Fnr3 indirectly activated expression of nif (nitrogen fixation) genes and Fe transport genes under anaerobic conditions. Fnr1 and Fnr3 inhibited expression of the genes involved in the aerobic respiratory chain and activated expression of genes responsible for anaerobic electron acceptor genes.

IMPORTANCE The members of the nitrogen-fixing Paenibacillus spp. have great potential to be used as a bacterial fertilizer in agriculture. However, the functions of the fnr gene(s) in nitrogen fixation and other metabolisms in Paenibacillus spp. are not known. Here, we found that in P. polymyxa WLY78, Fnr1 and Fnr3 were responsible for regulation of numerous genes in response to changes in oxygen levels, but Fnr5 and Fnr7 exhibited little effect. Fnr1 and Fnr3 indirectly or directly regulated many types of important metabolism, such as nitrogen fixation, Fe uptake, respiration, and electron transport. This study not only reveals the function of the fnr genes of P. polymyxa WLY78 in nitrogen fixation and other metabolisms but also will provide insight into the evolution and regulatory mechanisms of fnr in Paenibacillus.




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Comparative Whole-Genome Phylogeny of Animal, Environmental, and Human Strains Confirms the Genogroup Organization and Diversity of the Stenotrophomonas maltophilia Complex [Public and Environmental Health Microbiology]

The Stenotrophomonas maltophilia complex (Smc) comprises opportunistic environmental Gram-negative bacilli responsible for a variety of infections in both humans and animals. Beyond its large genetic diversity, its genetic organization in genogroups was recently confirmed through the whole-genome sequencing of human and environmental strains. As they are poorly represented in these analyses, we sequenced the whole genomes of 93 animal strains to determine their genetic background and characteristics. Combining these data with 81 newly sequenced human strains and the genomes available from RefSeq, we performed a genomic analysis that included 375 nonduplicated genomes with various origins (animal, 104; human, 226; environment, 30; unknown, 15). Phylogenetic analysis and clustering based on genome-wide average nucleotide identity confirmed and specified the genetic organization of Smc in at least 20 genogroups. Two new genogroups were identified, and two previously described groups were further divided into two subgroups each. Comparing the strains isolated from different host types and their genogroup affiliation, we observed a clear disequilibrium in certain groups. Surprisingly, some antimicrobial resistance genes, integrons, and/or clusters of attC sites lacking integron-integrase (CALIN) sequences targeting antimicrobial compounds extensively used in animals were mainly identified in animal strains. We also identified genes commonly found in animal strains coding for efflux systems. The result of a large whole-genome analysis performed by us supports the hypothesis of the putative contribution of animals as a reservoir of Stenotrophomonas maltophilia complex strains and/or resistance genes for strains in humans.

IMPORTANCE Given its naturally large antimicrobial resistance profile, the Stenotrophomonas maltophilia complex (Smc) is a set of emerging pathogens of immunosuppressed and cystic fibrosis patients. As it is group of environmental microorganisms, this adaptation to humans is an opportunity to understand the genetic and metabolic selective mechanisms involved in this process. The previously reported genomic organization was incomplete, as data from animal strains were underrepresented. We added the missing piece of the puzzle with whole-genome sequencing of 93 strains of animal origin. Beyond describing the phylogenetic organization, we confirmed the genetic diversity of the Smc, which could not be estimated through routine phenotype- or matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF)-based laboratory tests. Animals strains seem to play a key role in the diversity of Smc and could act as a reservoir for mobile resistance genes. Some genogroups seem to be associated with particular hosts; the genetic support of this association and the role of the determinants/corresponding genes need to be explored.




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Microbial Diversity in Deep-Subsurface Hot Brines of Northwest Poland: from Community Structure to Isolate Characteristics [Geomicrobiology]

Deep-subsurface hot brines in northwest Poland, extracted through boreholes reaching 1.6 and 2.6 km below the ground surface, were microbiologically investigated using culture-independent and culture-dependent methods. The high-throughput sequencing of 16S rRNA gene amplicons showed a very low diversity of bacterial communities, which were dominated by phyla Proteobacteria and Firmicutes. Bacterial genera potentially involved in sulfur oxidation and nitrate reduction (Halothiobacillus and Methylobacterium) prevailed in both waters over the sulfate reducers ("Candidatus Desulforudis" and Desulfotomaculum). Only one archaeal taxon, affiliated with the order Thermoplasmatales, was detected in analyzed samples. Bacterial isolates obtained from these deep hot brines were closely related to Bacillus paralicheniformis based on the 16S rRNA sequence similarity. However, genomic and physiological analyses made for one of the isolates, Bacillus paralicheniformis strain TS6, revealed the existence of more diverse metabolic pathways than those of its moderate-temperature counterpart. These specific traits may be associated with the ecological adaptations to the extreme habitat, which suggest that some lineages of B. paralicheniformis are halothermophilic.

IMPORTANCE Deep-subsurface aquifers, buried thousands of meters down the Earth’s crust, belong to the most underexplored microbial habitats. Although a few studies revealed the existence of microbial life at the depths, the knowledge about the microbial life in the deep hydrosphere is still scarce due to the limited access to such environments. Studying the subsurface microbiome provides unique information on microbial diversity, community structure, and geomicrobiological processes occurring under extreme conditions of the deep subsurface. Our study shows that low-diversity microbial assemblages in subsurface hot brines were dominated by the bacteria involved in biogeochemical cycles of sulfur and nitrogen. Based on genomic and physiological analyses, we found that the Bacillus paralicheniformis isolate obtained from the brine under study differed from the mesophilic species in the presence of specific adaptations to harsh environmental conditions. We indicate that some lineages of B. paralicheniformis are halothermophilic, which was not previously reported.




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Patient and primary care physician characteristics associated with billing incentives for chronic diseases in British Columbia: a retrospective cohort study

Background:

Incentive payments for chronic diseases in British Columbia were intended to support primary care physicians in providing more comprehensive care, but research shows that not all physicians bill incentives and not all eligible patients have them billed on their behalf. We investigated patient and physician characteristics associated with billing incentives for chronic diseases in BC.

Methods:

We conducted a retrospective cohort analysis using linked administrative health data to examine community-based primary care physicians and patients with eligible chronic conditions in BC during 2010–2013. Descriptive analyses of patients and physicians compared 3 groups: no incentives in any of the 4 years, incentives in all 4 years, and incentives in any of the study years. We used hierarchical logistic regression models to identify the patient- and physician-level characteristics associated with billing incentives.

Results:

Of 428 770 eligible patients, 142 475 (33.2%) had an incentive billed on their behalf in all 4 years, and 152 686 (35.6%) never did. Of 3936 physicians, 2625 (66.7%) billed at least 1 incentive in each of the 4 years, and 740 (18.8%) billed no incentives during the study period. The strongest predictors of having an incentive billed were the number of physician contacts a patient had (odds ratio [OR] for > 48 contacts 134.77, 95% confidence interval [CI] 112.27–161.78) and whether a physician had a large number of patients in his or her practice for whom incentives were billed (OR 42.38 [95% CI 34.55–52.00] for quartile 4 v. quartile 1).

Interpretation:

The findings suggest that primary care physicians bill incentives for patients based on whom they see most often rather than using a population health management approach to their practice.




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Characteristics of high-drug-cost beneficiaries of public drug plans in 9 Canadian provinces: a cross-sectional analysis

Background:

Drugs are the fastest growing cost in the Canadian health care system, owing to the increasing number of high-cost drugs. The objective of this study was to examine the characteristics of high–drug-cost beneficiaries of public drug plans across Canada relative to other beneficiaries.

Methods:

We conducted a cross-sectional study among public drug plan beneficiaries residing in all provinces except Quebec. We used the Canadian Institute for Health Information’s National Prescription Drug Utilization Information System to identify all drugs dispensed to beneficiaries of public drug programs in 2016/17. We stratified the cohort into 2 groups: high–drug-cost beneficiaries (top 5% of beneficiaries based on annual costs) and other beneficiaries (remaining 95%). For each group, we reported total drug costs, prevalence of high-cost claims (> $1000), median number of drugs, proportion of beneficiaries aged 65 or more, the 10 most costly reimbursed medications and the 10 medications most commonly reimbursed. We reported estimates overall and by province.

Results:

High–drug-cost beneficiaries accounted for nearly half (46.5%) of annual spending, with an average annual spend of $14 610 per beneficiary, compared to $1570 among other beneficiaries. The median number of drugs dispensed was higher among high–drug-cost beneficiaries than among other beneficiaries (13 [interquartile range (IQR) 7–19] v. 8 [IQR 4–13]), and a much larger proportion of high–drug-cost beneficiaries than other beneficiaries received at least 1 high-cost claim (40.9% v. 0.6%). Long-term medications were the most commonly used medications for both groups, whereas biologics and antivirals were the most costly medications for high–drug-cost beneficiaries.

Interpretation:

High–drug-cost beneficiaries were characterized by the use of expensive medications and polypharmacy relative to other beneficiaries. Interventions and policies to help reduce spending need to consider both of these factors.




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"ERS International Congress 2019: highlights from Best Abstract awardees". Lorna E. Latimer, Marieke Duiverman, Mahmoud I. Abdel-Aziz, Gulser Caliskan, Sara M. Mensink-Bout, Alberto Mendoza-Valderrey, Aurelien Justet, Junichi Omura, Karthi Srika




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Preclinical Activity of JNJ-7957, a Novel BCMAxCD3 Bispecific Antibody for the Treatment of Multiple Myeloma, Is Potentiated by Daratumumab

Purpose:

Multiple myeloma (MM) patients with disease refractory to all available drugs have a poor outcome, indicating the need for new agents with novel mechanisms of action.

Experimental Design:

We evaluated the anti-MM activity of the fully human BCMAxCD3 bispecific antibody JNJ-7957 in cell lines and bone marrow (BM) samples. The impact of several tumor- and host-related factors on sensitivity to JNJ-7957 therapy was also evaluated.

Results:

We show that JNJ-7957 has potent activity against 4 MM cell lines, against tumor cells in 48 of 49 BM samples obtained from MM patients, and in 5 of 6 BM samples obtained from primary plasma cell leukemia patients. JNJ-7957 activity was significantly enhanced in patients with prior daratumumab treatment, which was partially due to enhanced killing capacity of daratumumab-exposed effector cells. BCMA expression did not affect activity of JNJ-7957. High T-cell frequencies and high effector:target ratios were associated with improved JNJ-7957–mediated lysis of MM cells. The PD-1/PD-L1 axis had a modest negative impact on JNJ-7957 activity against tumor cells from daratumumab-naïve MM patients. Soluble BCMA impaired the ability of JNJ-7957 to kill MM cells, although higher concentrations were able to overcome this negative effect.

Conclusions:

JNJ-7957 effectively kills MM cells ex vivo, including those from heavily pretreated MM patients, whereby several components of the immunosuppressive BM microenvironment had only modest effects on its killing capacity. Our findings support the ongoing trial with JNJ-7957 as single agent and provide the preclinical rationale for evaluating JNJ-7957 in combination with daratumumab in MM.




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Genomic Characterization of Neisseria gonorrhoeae Strains from 2016 U.S. Sentinel Surveillance Displaying Reduced Susceptibility to Azithromycin [Epidemiology and Surveillance]

In 2016, the proportion of Neisseria gonorrhoeae isolates with reduced susceptibility to azithromycin rose to 3.6%. A phylogenetic analysis of 334 N. gonorrhoeae isolates collected in 2016 revealed a single, geographically diverse lineage of isolates with MICs of 2 to 16 μg/ml that carried a mosaic-like mtr locus, whereas the majority of isolates with MICs of ≥16 μg/ml appeared sporadically and carried 23S rRNA mutations. Continued molecular surveillance of N. gonorrhoeae isolates will identify new resistance mechanisms.




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In Vitro Activity of KBP-7072, a Novel Third-Generation Tetracycline, against 531 Recent Geographically Diverse and Molecularly Characterized Acinetobacter baumannii Species Complex Isolates [Susceptibility]

KBP-7072 is a novel third-generation tetracycline (aminomethylcycline) antibacterial that overcomes common efflux and ribosomal protection resistance mechanisms that cause resistance in older-generation tetracyclines. KBP-7072 completed phase 1 clinical development studies for safety, tolerability, and pharmacokinetics (ClinicalTrials.gov identifier NCT02454361) and multiple ascending doses in healthy subjects (ClinicalTrials.gov identifier NCT02654626) in December 2015. Both oral and intravenous formulations of KBP-7072 are being developed. In this study, we evaluated the in vitro activities of KBP-7072 and comparator agents by CLSI document M07 (2018) broth microdilution against 531 recent geographically diverse and/or molecularly characterized Acinetobacter baumannii-A. calcoaceticus species complex (A. baumannii) isolates from the United States, Europe, Asia-Pacific (excluding China), and Latin America. A. baumannii isolates included carbapenem-resistant, colistin-resistant, tetracycline-resistant, and extended-spectrum-β-lactamase (ESBL)- and metallo-β-lactamase (MBL)-producing isolates. Overall, KBP-7072 (MIC50/90, 0.25/1 mg/liter) was comparable in activity to colistin (92.8%/92.8% susceptible [S] [CLSI/EUCAST]) against A. baumannii isolates, inhibiting 99.2% of isolates at ≤2 mg/liter and 97.6% of isolates at ≤1 mg/liter. KBP-7072 was equally active against A. baumannii isolates, including carbapenem-resistant, colistin-resistant, and tetracycline-resistant isolates, regardless of geographic location, and maintained activity against ESBL- and MBL-producing isolates. KBP-7072 outperformed comparator agents, including ceftazidime (40.3% S [CLSI]), gentamicin (48.2%/48.2% S [CLSI/EUCAST]), levofloxacin (39.5%/37.9% S [CLSI/EUCAST]), meropenem (42.0%/42.0% S [CLSI/EUCAST]), piperacillin-tazobactam (33.3% S [CLSI]), and all tetracycline-class comparator agents, which include doxycycline (67.3% S [CLSI]), minocycline (73.8% S [CLSI]), tetracycline (37.2% S [CLSI]), and tigecycline (79.5% inhibited by ≤2 mg/liter). The potent in vitro activity of KBP-7072 against recent geographically diverse, molecularly characterized, and drug-resistant A. baumannii isolates supports continued clinical development for the treatment of serious infections, including those caused by A. baumannii.




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Safety and Pharmacokinetic Characterization of Nacubactam, a Novel {beta}-Lactamase Inhibitor, Alone and in Combination with Meropenem, in Healthy Volunteers [Clinical Therapeutics]

Nacubactam is a novel β-lactamase inhibitor with dual mechanisms of action as an inhibitor of serine β-lactamases (classes A and C and some class D) and an inhibitor of penicillin binding protein 2 in Enterobacteriaceae. The safety, tolerability, and pharmacokinetics of intravenous nacubactam were evaluated in single- and multiple-ascending-dose, placebo-controlled studies. Healthy participants received single ascending doses of nacubactam of 50 to 8,000 mg, multiple ascending doses of nacubactam of 1,000 to 4,000 mg every 8 h (q8h) for up to 7 days, or nacubactam of 2,000 mg plus meropenem of 2,000 mg q8h for 6 days after a 3-day lead-in period. Nacubactam was generally well tolerated, with the most frequently reported adverse events (AEs) being mild to moderate complications associated with intravenous access and headache. There was no apparent relationship between drug dose and the pattern, incidence, or severity of AEs. No clinically relevant dose-related trends were observed in laboratory safety test results. No serious AEs, dose-limiting AEs, or deaths were reported. After single or multiple doses, nacubactam pharmacokinetics appeared linear, and exposure increased in an approximately dose-proportional manner across the dose range investigated. Nacubactam was excreted largely unchanged into urine. Coadministration of nacubactam with meropenem did not significantly alter the pharmacokinetics of either drug. These findings support the continued clinical development of nacubactam and demonstrate the suitability of meropenem as a potential β-lactam partner for nacubactam. (The studies described in this paper have been registered at ClinicalTrials.gov under NCT02134834 [single ascending dose study] and NCT02972255 [multiple ascending dose study].)




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Synthesis and Biological Activity of Novel Zinc-Itraconazole Complexes in Protozoan Parasites and Sporothrix spp. [Susceptibility]

The new complexes Zn(ITZ)2Cl2 (1) and Zn(ITZ)2(OH)2 (2) were synthetized by a reaction of itraconazole with their respective zinc salts under reflux. These Zn-ITZ complexes were characterized by elemental analyses, molar conductivity, mass spectrometry, 1H and 13C{1H} nuclear magnetic resonance, and UV-vis and infrared spectroscopies. The antiparasitic and antifungal activity of Zn-ITZ complexes was evaluated against three protozoans of medical importance, namely, Leishmania amazonensis, Trypanosoma cruzi, and Toxoplasma gondii, and two fungi, namely, Sporothrix brasiliensis and Sporothrix schenckii. The Zn-ITZ complexes exhibited a broad spectrum of action, with antiparasitic and antifungal activity in low concentrations. The strategy of combining zinc with ITZ was efficient to enhance ITZ activity since Zn-ITZ-complexes were more active than the azole alone. This study opens perspectives for future applications of these Zn-ITZ complexes in the treatment of parasitic diseases and sporotrichosis.




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Activity of Cefiderocol and Comparators against Isolates from Cancer Patients [Susceptibility]

Cefiderocol inhibited 97.5% of 478 Gram-negative isolates from cancer patients at ≤4 mg/liter. It had potent activity against extended-spectrum β-lactamase-positive Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae (CRE), and nonfermenting Gram-negative bacilli, including Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter species isolates. Amikacin, ceftazidime-avibactam, and meropenem had appreciable activity against non-CRE Enterobacteriaceae. No comparators were active against multidrug-resistant P. aeruginosa isolates. Only trimethoprim-sulfamethoxazole had appreciable activity against S. maltophilia isolates. Overall, cefiderocol was associated with the lowest level of resistance.




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Whole-Genome Characterization of a Shewanella algae Strain Coharboring blaCTX-M-15 and armA Genes on a Novel IncC Plasmid [Letters]




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Antimicrobial Activity of Ceftolozane-Tazobactam and Comparators against Clinical Isolates of Haemophilus influenzae from the United States and Europe [Susceptibility]

Nine hundred Haemophilus influenzae clinical isolates from 83 U.S. and European medical centers were tested for susceptibility by reference broth microdilution methods against ceftolozane-tazobactam and comparators. Results were stratified by β-lactamase production and infection type. Overall, ceftolozane-tazobactam MIC50/90 values were 0.12/0.25 mg/liter, and 99.0% of isolates were inhibited at the susceptible breakpoint of ≤0.5 mg/liter; the highest MIC value was only 2 mg/liter. Our results support using ceftolozane-tazobactam to treat H. influenzae infections.




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Characterization of blaCTX-M-27/F1:A2:B20 Plasmids Harbored by Escherichia coli Sequence Type 131 Sublineage C1/H30R Isolates Spreading among Elderly Japanese in Nonacute-Care Settings [Mechanisms of Resistance]

We characterized 29 blaCTX-M-27-harboring plasmids of Escherichia coli sequence type 131 (ST131) sublineage C1/H30R isolates from healthy individuals and long-term-care facility (LTCF) residents. Most (27/29) plasmids were of the FIA, FIB, and FII multireplicon type with the same plasmid multilocus sequence typing (pMLST). Several plasmids (7/23) from LTCF residents harbored only blaCTX-M-27 as the resistance gene; however, their fundamental structures were very similar to those of previously isolated blaCTX-M-27/F1:A2:B20 plasmids, suggesting their prevalence as a newly arising public health concern.




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Molecular and Clinical Characterization of Multidrug-Resistant and Hypervirulent Klebsiella pneumoniae Strains from Liver Abscess in Taiwan [Epidemiology and Surveillance]

Hypervirulent Klebsiella pneumoniae strains are the major cause of liver abscesses throughout East Asia, and these strains are usually antibiotic susceptible. Recently, multidrug-resistant and hypervirulent (MDR-HV) K. pneumoniae strains have emerged due to hypervirulent strains acquiring antimicrobial resistance determinants or the transfer of a virulence plasmid into a classic MDR strain. In this study, we characterized the clinical and microbiological properties of K. pneumoniae liver abscess (KPLA) caused by MDR-HV strains in Taiwan. Patients with community onset KPLA were retrospectively identified at Taipei Veterans General Hospital during January 2013 to May 2018. Antimicrobial resistance mechanisms, capsular types, and sequence types were determined. MDR-HV strains and their parental antimicrobial-susceptible strains further underwent whole-genome sequencing (WGS) and in vivo mice lethality tests. Thirteen MDR-HV strains were identified from a total of 218 KPLA episodes. MDR-HV strains resulted in similar outcomes to antimicrobial-susceptible strains. All MDR-HV strains were traditional hypervirulent clones carrying virulence capsular types. The major resistance mechanisms were the overexpression of efflux pumps and/or the acquisition of ESBL or AmpC β-lactamase genes. WGS revealed that two hypervirulent strains had evolved to an MDR phenotype due to mutation in the ramR gene and the acquisition of an SHV-12-bearing plasmid, respectively. Both these MDR-HV strains retained high virulence compared to their parental strains. The spread of MDR-HV K. pneumoniae strains in the community raises significant public concerns, and measures should be taken to prevent the further acquisition of carbapenemase and other resistance genes among these strains in order to avoid the occurrence of untreatable KPLA.




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Comparative single-cell RNA sequencing (scRNA-seq) reveals liver metastasis-specific targets in a patient with small intestinal neuroendocrine cancer [RESEARCH REPORT]

Genomic analysis of a patient's tumor is the cornerstone of precision oncology, but it does not address whether metastases should be treated differently. Here we tested whether comparative single-cell RNA sequencing (scRNA-seq) of a primary small intestinal neuroendocrine tumor to a matched liver metastasis could guide the treatment of a patient's metastatic disease. Following surgery, the patient was put on maintenance treatment with a somatostatin analog. However, the scRNA-seq analysis revealed that the neuroendocrine epithelial cells in the liver metastasis were less differentiated and expressed relatively little SSTR2, the predominant somatostatin receptor. There were also differences in the tumor microenvironments. RNA expression of vascular endothelial growth factors was higher in the primary tumor cells, reflected by an increased number of endothelial cells. Interestingly, vascular expression of the major VEGF receptors was considerably higher in the liver metastasis, indicating that the metastatic vasculature may be primed for expansion and susceptible to treatment with angiogenesis inhibitors. The patient eventually progressed on Sandostatin, and although consideration was given to adding an angiogenesis inhibitor to her regimen, her disease progression involved non-liver metastases that had not been characterized. Although in this specific case comparative scRNA-seq did not alter treatment, its potential to help guide therapy of metastatic disease was clearly demonstrated.




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Functional characterization of two rare BCR-FGFR1+ leukemias [RESEARCH REPORT]

8p11 myeloproliferative syndrome (EMS) represents a unique World Health Organization (WHO)-classified hematologic malignancy defined by translocations of the FGFR1 receptor. The syndrome is a myeloproliferative neoplasm characterized by eosinophilia and lymphadenopathy, with risk of progression to either acute myeloid leukemia (AML) or T- or B-lymphoblastic lymphoma/leukemia. Within the EMS subtype, translocations between breakpoint cluster region (BCR) and fibroblast growth factor receptor 1 (FGFR1) have been shown to produce a dominant fusion protein that is notoriously resistant to tyrosine kinase inhibitors (TKIs). Here, we report two cases of BCR–FGFR1+ EMS identified via RNA sequencing (RNA-seq) and confirmed by fluorescence in situ hybridization (FISH). Sanger sequencing revealed that both cases harbored the exact same breakpoint. In the first case, the patient presented with AML-like disease, and in the second, the patient progressed to B-cell acute lymphoblastic leukemia (B-ALL). Additionally, we observed that that primary leukemia cells from Case 1 demonstrated sensitivity to the tyrosine kinase inhibitors ponatinib and dovitinib that can target FGFR1 kinase activity, whereas primary cells from Case 2 were resistant to both drugs. Taken together, these results suggest that some but not all BCR–FGFR1 fusion positive leukemias may respond to TKIs that target FGFR1 kinase activity.




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You Must Remember Meeting Clara: Remembering Clara Derber Bloomfield (1942-2020)




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Involvement of the Olfactory Apparatus by Gliomas [HEAD & NECK]

SUMMARY:

The olfactory bulbs and tracts are central nervous system white matter tracts maintained by central neuroglia. Although rare, gliomas can originate from and progress to involve the olfactory apparatus. Through a Health Insurance Portability and Accountability Act–compliant retrospective review of the institutional teaching files and brain MR imaging reports spanning 10 years, we identified 12 cases of gliomas involving the olfactory bulbs and tracts, including 6 cases of glioblastoma, 2 cases of anaplastic oligodendroglioma, and 1 case each of pilocytic astrocytoma, diffuse (grade II) astrocytoma, anaplastic astrocytoma (grade III), and diffuse midline glioma. All except the pilocytic astrocytoma occurred in patients with known primary glial tumors elsewhere. Imaging findings of olfactory tumor involvement ranged from well-demarcated enhancing masses to ill-defined enhancing infiltrative lesions to nonenhancing masslike FLAIR signal abnormality within the olfactory tracts. Familiarity with the imaging findings of glioma involvement of the olfactory nerves is important for timely diagnosis and treatment of recurrent gliomas and to distinguish them from other disease processes.




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Is Histologic Thrombus Composition in Acute Stroke Linked to Stroke Etiology or to Interventional Parameters? [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Detailed insight into the composition of thrombi retrieved from patients with ischemic stroke by mechanical thrombectomy might improve pathophysiologic understanding and therapy. Thus, this study searched for links between histologic thrombus composition and stroke subtypes and mechanical thrombectomy results.

MATERIALS AND METHODS:

Thrombi from 85 patients who had undergone mechanical thrombectomy for acute ischemic stroke between December 2016 and March 2018 were studied retrospectively. Thrombi were examined histologically. Preinterventional imaging features, stroke subtypes, and interventional parameters were re-analyzed. Statistical analysis was performed with the Kruskal-Wallis test, Mann-Whitney U test, or Spearman correlation as appropriate.

RESULTS:

Cardioembolic thrombi had a higher percentage of macrophages and a tendency toward more platelets than thrombi of large-artery atherosclerotic stenosis (P = .021 and .003) or the embolic stroke of undetermined source (P = .037 and .099) subtype. Thrombi prone to fragmentation required the combined use of contact aspiration and stent retrieval (P = .021) and were associated with an increased number of retrieving maneuvers (P = .001), longer procedural times (P = .001), and a higher lymphocyte content (P = .035).

CONCLUSIONS:

We interpreted the higher macrophage and platelet content in cardioembolic thrombi compared with large-artery atherosclerotic stenosis or embolic stroke of undetermined source thrombi as an indication that the latter type might be derived from an atherosclerotic plaque rather than from an undetermined cardiac source. The extent of thrombus fragmentation was associated with a more challenging mechanical thrombectomy and a higher lymphocyte content of the thrombi. Thus, thrombus fragmentation not only might be caused by the recanalization procedure but also might be a feature of a lymphocyte-rich, difficult-to-retrieve subgroup of thrombi.




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Altara Residences

Altara Residences là tổ hợp căn hộ dịch vụ thương mại cao cấp đầu tiên tại TP. Quy Nhơn, tỉnh Bình Định được cấp giấy chứng nhận sở hữu lâu dài. Dự án gồm các căn hộ 1-2 phòng ngủ được thiết kế thông minh với không gian mở để thâu trọn ánh sáng và gió biển.




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Park Kiara

Park Kiara là dự án căn hộ nằm trong quần thể khu đô thị Park City Hà Nội tại quận Hà Đông do CTCP Phát triển Đô thị Quốc tế Việt Nam làm chủ đầu tư.




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6 guiding parameters to upgrade your workplace environment in the digital economy

Prof. Jason Pomeroy talks about the rise of the digital economy and its impact on the workplace.




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Bán biệt thự 1 trệt 3 lầu, đường nhựa 12m, có bảo vệ 24/24, gara ô tô, khu dân trí, tổng DT: 320m2

Bán căn biệt thự căn cuối diện tích rộng nhất khu, ngay sau UBND Phường Thạnh Lộc, Q. 12. - Dự án tọa lạc tại vị trí đắc địa của phường Thạnh Lộc, thuận lợi về mặt giao thông. * Những ưu điểm nổi bật: - Hồ sơ pháp lý đầy đủ, sổ hồng trao tay. - Môi trường sống lý tưởng, thân thiệ...




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Handwara Encounter: शहीद कर्नल की पत्नी पल्लवी बोलीं- शहादत पर आंसू नहीं बहाऊंगी...ये उनके लिए सम्मान

शहीद कर्नल आशुतोष शर्मा की पत्नी पल्लवी ने भी हिम्मत दिखाते हुए कहा है कि पति की शहादत पर आंसू नहीं बहाऊंगी। उनकी कुर्बानी मेरे लिए और देश के लिए गर्व की बात है। मेरे आंसू उन्हें ठेस पहुंचाएंगे।




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Narad Jayanti 2020 Date: नारद जयंती आज, जानें मुहूर्त, पूजा विधि और जन्म कथा

Narad Jayanti 2020 Date: नारद जयंती 'देवऋषि नारद मुनि' के जन्म दिवस के रूप में वैशाख कृष्ण प्रतिपदा के दिन मनाई जाती है। इस साल यह तिथि 8 मई तो पड़ रही है। इसलिए नारद जयंती 8 मई मनाई जाएगी।




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Narasimha Jayanti 2020: जानिए पूजा विधि और भगवान विष्णु के नरसिंह अवतार के पीछे की कथा

भगवान विष्णु ने नरसिंह का अवतार लेकर हिरण्कश्यपु का वध करके अपने प्रिय भक्त प्रह्रलाद की जान बचाई थी। भगवान विष्णु ने पृथ्वी पर कई अलग-अलग अवतार लेकर अपने भक्तों को मुसीबतों से बचाया है।




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Apara Ekadashi 2020: जानें अपरा एकादशी की तारीख, मुहूर्त और व्रत विधि

Apara Ekadashi 2020: ज्येष्ठ कृष्ण पक्ष की एकादशी तिथि को अपरा एकादशी अथवा अचला एकादशी के नाम से जाना जाता है। अपरा एकादशी पर्व 18 मई को पड़ रही है।




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Narad Jayanti 2020: धरती के पहले पत्रकार हैं देवर्षि नारद, जानिए उनके बारे में महत्वपूर्ण बातें

Narad Jayanti 2020: नारद जयंती 8 मई को है। नारद जयंती प्रति वर्ष ज्येष्ठ कृष्ण पक्ष की द्वितीया तिथि को मनाई जाती है। हिन्दू धार्मिक आस्था के अनुसार, देवर्षि नारद का महत्वपूर्ण स्थान है।




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Vijay Devarakonda Birthday: कभी किराया देने के भी नहीं थे पैसे, आज 'अर्जुन रेड्डी' के पास है करोड़ों का बंगला

विजय देवरकोंडा (Vijay Devarakonda) आज के समय में तेलुगू फिल्मों के सफल एक्टर्स में गिने जाते हैं। आज विजय अपना 31वां जन्मदिन मना रहे हैं। इतनी कम उम्र में ही विजय की फैन फॉलोइंग कोरोड़ों में है। विजय का जन्म 9 मई, 1989 में हैदराबाद में हुआ था।




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Uttarakhand Lockdown : इसी माह हो सकती हैं उत्तराखंड बोर्ड की स्थगित परीक्षाएं

उत्तराखंड बोर्ड की परीक्षाएं इसी महीने हो सकती हैं। वहीं बोर्ड का रिजल्ट भी 10 जून से पहले घोषित किया जा सकता है।




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Coronavirus in Uttarakhand : ठीक हुए छह और संक्रमित, अब रह गए 17 एक्टिव केस

उत्तराखंड में छह और कोरोना पॉजिटिव मरीज ठीक हो चुके हैं। अब राज्य में 45 मरीज ठीक हो चुके हैं। वहीं राज्य में कुल पॉजिटिव मरीजों की संख्या 61 है।




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Uttarakhand Lockdown: कलशों में बंद अस्थियों को अब मिलेगी मुक्ति, गंगा में हो सकेगा विसर्जन

अस्थि विर्सजन से रोक हटने से कई लोगों ने राहत की सास ली है। वे अब श्मशान घाटों में रखीं परिजनों की अस्थियों को गंगा में विर्सजित कर सकेंगे।




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Lockdown Uttarakhand: दूसरे राज्य में काम करने वाले लोग कर सकते हैं ई-पास के लिए आवेदन

प्रदेश के ऐसे लोग जो दूसरे राज्य में नौकरी या अन्य काम करते हैं और निजी वाहन से जाना चाहते हैं, वह http://smartcitydehradun.uk.gov.in/e-pass पर आवेदन कर ई-पास बनवा सकते हैं।




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Coronavirus in Uttarakhand : ऊधमसिंह नगर में आज मिले चार नए संक्रमित, कुल मरीजों की संख्या 67

उत्तराखंड के ऊधमसिंह नगर जिले में शनिवार को चार नए मामले सामने आए हैं। अब राज्य में कुछ मरीजों की संख्या 67 हो गई है।




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Uttarakhand Weather: केदारनाथ व तुंगनाथ में दो घंटे बर्फबारी, निचले इलाकों में बारिश जारी

शनिवार को दोपहर बाद उत्तराखंड के पहाड़ी इलाकों में मौसम बदल गया। वहीं अधिकतर मैदानी इलाकों में बादल छाए रहे।




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Maruti Vitara Brezza से भी महंगा है Vespa का यह स्कूटर, अब 2 लाख रुपये हुआ सस्ता

Piaggio India कंपनी ने Vespa 946 Emporio Armani नाम का एक स्कूटर लॉन्च किया था। इस स्कूटर को दुनिया के जानेमाने डिजाइनर Emporio Armani ने डिजाइन किया था।




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Mortal Kombat 11: Aftermath Expansion Announced, Adds 3 New Characters and New Story

Publisher Warner Bros. Interactive Entertainment and developer NetherRealms Studios have announced a new expansion for Mortal Kombat 11 called Aftermath. It will release on May 26.

The Mortal Kombat 11: Aftermath expansion adds a new cinematic story, three characters and three new skins for $39.99. The three new characters are Fujin, Sheeva, and RoboCop).

A $59.99 Mortal Kombat: Aftermath Kollection has also been announced. It includes the base game, Kombat Pack DLC and the Aftermath expansion. 

View the announcement trailer for the expansion and RoboCop reveal trailer below:

Here is an overview of the expansion:

Mortal Kombat 11: Aftermath is a new expansion for the hit videogame, Mortal Kombat 11, the best-selling title in franchise history that was named Fighting Game of the Year at the 2019 D.I.C.E. Awards. Developed by award-winning NetherRealm Studios, Mortal Kombat 11: Aftermath expands the critically acclaimed story campaign with an all-new, cinematic narrative centered around trust and deceit, while also adding new playable characters in returning Mortal Kombat fighters, Fujin and Sheeva, and guest character, RoboCop, who is making his series debut.

Key Features:

  • Franchise-First Story Expansion – The critically acclaimed story campaign continues with an all-new cinematic narrative that picks up directly where Mortal Kombat 11 left off. Fire God Liu Kang, the new keeper of time and protector of Earthrealm, must now enlist the help of unlikely allies and familiar foes to forge a new history as the fate of two worlds hang in the balance.
  • Exciting New Characters Join the Roster – New playable characters join the fight with the triumphant return of Fujin, the God of Wind who serves as Earthrealm’s protector alongside his brother Raiden, and Sheeva, the fourarmed, half-human and half-dragon queen of the ancient Shokan race. RoboCop, the iconic, highly advanced cybernetic police officer, makes his first appearance in the franchise, continuing the pedigree of popular Mortal Kombat guest fighters. RoboCop in Mortal Kombat 11: Aftermath features the voice and likeness of actor Peter Weller, who portrayed the popular character in both the original RoboCop (1987) film and RoboCop 2 (1990) sequel. Mortal Kombat 11: Aftermath will also include three new character skin packs to be released over time.
  • Fan-Favorite Stages, Stage Fatalities & Friendships Return – In conjunction with the Mortal Kombat 11: Aftermath release, all Mortal Kombat 11 owners will have access to a free content update featuring new Stages, including the return of the Klassic Dead Pool and Soul Chamber arenas; Stage Fatalities, the fan-favorite finishing moves that use the environment to destroy opponents; and the popular Friendships feature, allowing players to take down their adversaries with a hint of kindness.
  • New Players Can Join the Fight with Mortal Kombat 11: Aftermath Kollection – Offers the perfect opportunity for new players to join the fight, featuring all characters, story content, game modes and pre-order bonuses in one ultimate package. This compilation includes Mortal Kombat 11 along with all content from Mortal Kombat 11: Aftermath and the previously released Mortal Kombat 11 Kombat Pack, containing six playable characters—Shang Tsung, Nightwolf, Sindel, Terminator T-800, The Joker and Spawn – plus 25 additional character skins. The Mortal Kombat 11: Aftermath Kollection can be pre-ordered for $59.99 (SRP) with digital pre-orders offering immediate access to Mortal Kombat 11 and the Kombat Pack upon purchase. The physical version will be available this June in the Americas only.
  • Upgrade Options for Current Mortal Kombat 11 Owners – Those who have already purchased Mortal Kombat 11 can pre-order the Mortal Kombat 11 Aftermath expansion for $39.99 (SRP) or the Mortal Kombat 11: Aftermath + Kombat Pack Bundle for $49.99 (SRP).
  • Pre-order for Exclusive Content – All preorders* receive the Eternal Klash Skin Pack at launch, featuring three new character skin variants – “Unbound Rage” Scorpion inspired by Mortal Kombat (2011), “Son of Arctika” Sub-Zero inspired by Mortal Kombat: Deception and “Kori Power” Frost, a Klassic version of the Lin Kuie warrior.
  • Best-In-Class, Brutal Kombat  Mortal Kombat 11 is the latest installment in the critically acclaimed franchise, providing a deeper and more personalized experience than ever before. The best-selling title is packed to the brim with multiple features and modes for all players, including the Story mode, Custom Character Variation System, Towers of Time, Kombat League, The Krypt and the signature roster returning and franchise-first fighters, all equipped with powerful Krushing Blows and unique Fatalities that display devastatingly brutal cinematic visuals.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443404/mortal-kombat-11-aftermath-expansion-announced-adds-3-new-characters-and-new-story/




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Tara Reade Tells Megyn Kelly She’ll ‘Never Forget’ Alleged Biden Assault

via Youtube

Last week, former Vice President Joe Biden told the world that he “unequivocally” denied accusations by Tara Reade, a former staffer in his Senate office, that he sexually assaulted her in the early ’90s.

On Friday evening, Reade responded: Prove it.

“Joe Biden should take the polygraph,” Reade told former television anchor Megyn Kelly, in an interview that aired on Kelly’s YouTube channel. “I will take one if Joe Biden takes one, but I’m not a criminal.”

Read more at The Daily Beast.




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Aramco IPO Enters Final Phase, Shares to Start Trading Wednesday—Energy Journal

Saudi Aramco’s IPO saga has turned into “A Tale of Two Princes.” As Saudi Arabia’s day-to-day ruler Crown Prince Mohammed bin Salman has guided the IPO far from public view, his half-brother Prince Abdulaziz bin Salman stepped onto center stage in Vienna last week, presiding over a crucial gathering of OPEC and its oil-producing allies […]




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Lockdown in Uttarakhand: रेड जोन में अब केवल हरिद्वार, देहरादून- नैनीताल ऑरेंज और 10 जिले ग्रीन जोन घोषित

उत्तराखंड में कोरोना वायरस संक्रमण के मद्देनजर अब सिर्फ हरिद्वार जनपद ही रेड जोन में बचा है। स्वास्थ्य मंत्रालय ने ऊधमसिंह नगर और अल्मोड़ा जनपद को ग्रीन जोन घोषित कर दिया है।




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Uttarakhand: तीन दिन बाद फिर सामने आए दो कोरोना पॉजिटिव मरीज, प्रदेश में संक्रमितों की संख्या हुई 63

उत्तराखंड में तीन दिन राहत के बाद फिर एक एक कारोना संक्रमण का मामला सामने आया है। स्वास्थ्य विभाग की ओर से आई रिपोर्ट में हरिद्वार जिले का एक मरीज कोरोना संक्रमित मिला है।




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We may have spotted a parallel universe going backwards in time

Strange particles observed by an experiment in Antarctica could be evidence of an alternative reality where everything is upside down




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Tara Reade Has Exposed Endless Democratic Hypocrisy