bluuebunny/crossref_metadata_2025 huggingface dataset:
PET Imaging of CD8 via SMART for Monitoring the Immunotherapy Response
Authors: Sun Lingyi , Li Zhonghan , Ma Yongyong , Ludwig Johannes , Kim Hyun S. , Zeng Dexing
Published: June 2021

Imaging of CD8 receptors on T‐cells by positron emission tomography (PET) has been considered a promising strategy for monitoring the treatment response to immunotherapy. In this study, a trial of imaging CD8 with our newly developed sequential multiple‐agent receptor targeting (SMART) technology was conducted. Mice bearing a subcutaneous colorectal CT26 tumor received three times different immunotherapy treatments (PD1 or CTLA4 or combined). On either day 7 or day 14 after the first time treatment, the PET imaging study was performed with sequentially administered TCO‐modified anti‐CD8 antibody and 64Cu‐labeled MeTz‐NOTA‐RGD. However, no positive response was detected, probably due to (1) inappropriate selection of biomarkers for the SMART strategy, (2) limited TCO modification on the anti‐CD8 antibody, and (3) inadequate response of the CT26 tumor to the selected immunotherapies. Therefore, the potential of applying SMART in imaging CD8 was not demonstrated in this study, and further optimization will be necessary before it can be applied in imaging CD8.
Effect of Vegetation Roots on the Threshold of Slope Instability Induced by Rainfall and Runoff
Authors: Huang Gang , Zheng Mingxin , Peng Jing
Published: June 2021

Although vegetation is increasingly used to mitigate landslide risks, how vegetation roots affect the landslide threshold of slope has rarely been explored, particularly in the case of lateral runoff. In this study, we established a two-dimensional saturated-unsaturated infiltration equation considering the hydraulic effects of vegetation roots. The analytical solution for the shallow unsaturated two-dimensional coupled infiltration of vegetated slope (VS) was obtained by a Fourier transform technique. The numerical method was used to evaluate the stability of VS caused by four root architectures, the rainfall amount, and the rainfall duration. Subsequently, the transformation law in runoff, vegetation evaporation, and landslide threshold was analyzed. The results indicate that the factor of safety (FOS) increases with increasing drying time and decreases with increasing depth; the minimum FOS is at the junction of the root-rootless zone. Runoff and vegetation evaporation are favorable for the shallow stability of VS. The time of the safe area is 35 h for rainfall amount 500 m in the uniformly root clay slope. Moreover, four landslide threshold curves that reflected the root architecture, rainfall amount, and rainfall duration are developed, which are more realistic than those created using one-dimensional instability modeling.
17β-Estradiol Attenuates LPS-Induced Macrophage Inflammation In Vitro and Sepsis-Induced Vascular Inflammation In Vivo by Upregulating miR-29a-5p Expression
Authors: Zhang Man-li , Chen Hui , Yang Zhan , Zhang Man-na , Wang Xia , Zhao Kun , Li Xuan , Xiu Nan , Tong Fei , Wang Ya-xuan
Published: June 2021

Excessive release of cytokines such as IL-1β and other inflammatory mediators synthesized and secreted by macrophages is the fundamental link of uncontrolled inflammatory response in sepsis. 17β-Estradiol (E2) plays anti-inflammatory and vascular protective effects by regulating leukocyte infiltration and the expression of chemokines or cytokines induced by injury. However, the role of E2 in the inflammatory response of macrophages in sepsis and its mechanism are still not fully understood. In the present study, we show that E2 alleviates vascular inflammation in sepsis mice induced by cecal ligation puncture (CLP). E2 significantly decreases RAW 264.7 cell inflammation response by downregulating the expression of NLRP3. Furthermore, we found that miR-29a-5p was significantly downregulated in LPS-treated macrophages. Treating RAW 264.7 cells with E2 markedly upregulated the miR-29a-5p expression level. More importantly, we demonstrated that miR-29a-5p repressed NLRP3 expression by directly targeting its 3

′

-UTR. Loss- and gain-of-function experiments revealed that transfection of the miR-29a-5p mimic abrogates LPS-induced macrophage inflammation. Moreover, depletion of miR-29a-5p by its inhibitor largely promotes LPS-induced macrophage inflammation. In summary, miR-29a-5p upregulation induced by E2 alleviated RAW 264.7 cell inflammation response by aggravating miR-29a-5p repression of NLRP3 expression. E2 exerts significant anti-inflammatory efficacy in macrophages by regulating the miR-29a-5p/NLRP3 axis. Targeting miR-29a-5p may be a novel therapeutic strategy to suppress sepsis-induced vascular inflammation.
Cognitive Covert Traffic Synthesis Method Based on Generative Adversarial Network
Authors: Tang Zhangguo , Wang Junfeng , Li Huanzhou , Zhang Jian , Wang Junhao
Published: June 2021

In the intelligent era of human‐computer symbiosis, the use of machine learning method for covert communication confrontation has become a hot topic of network security. The existing covert communication technology focuses on the statistical abnormality of traffic behavior and does not consider the sensory abnormality of security censors, so it faces the core problem of lack of cognitive ability. In order to further improve the concealment of communication, a game method of “cognitive deception” is proposed, which is aimed at eliminating the anomaly of traffic in both behavioral and cognitive dimensions. Accordingly, a Wasserstein Generative Adversarial Network of Covert Channel (WCCGAN) model is established. The model uses the constraint sampling of cognitive priors to construct the constraint mechanism of “functional equivalence” and “cognitive equivalence” and is trained by a dynamic strategy updating learning algorithm. Among them, the generative module adopts joint expression learning which integrates network protocol knowledge to improve the expressiveness and discriminability of traffic cognitive features. The equivalent module guides the discriminant module to learn the pragmatic relevance features through the activity loss function of traffic and the application loss function of protocol for end‐to‐end training. The experimental results show that WCCGAN can directly synthesize traffic with comprehensive concealment ability, and its behavior concealment and cognitive deception are as high as 86.2% and 96.7%, respectively. Moreover, the model has good convergence and generalization ability and does not depend on specific assumptions and specific covert algorithms, which realizes a new paradigm of cognitive game in covert communication.
Abstract B05: ASN007, an oral ERK1/2 inhibitor, shows strong antitumor activity across a panel of KRAS subtype mutant cancer models
Authors: Reddy Sanjeeva P. , Thompson Scott K. , Usansky Helen , Smith Roger A. , Denis Louis , Gupta Sandeeep
Published: June 2021

The RAS/MAPK pathway is one of the most commonly dysregulated signaling pathways found in human cancers. KRAS, HRAS and NRAS genes, which play a critical role in transducing the signal from receptor tyrosine kinases to the downstream target proteins such as BRAF and MEK1/2, are frequently mutated in most solid tumors. The extracellular signal-regulated kinases, ERK1 and ERK2 (ERK1/2), which are downstream of MEK and RAF kinases, serve as a key node in this crucial signaling pathway in tumor cells. Targeting ERK1/2 offers a promising therapeutic strategy for a broad range of cancers, particularly the ones driven by RAS mutations, and in overcoming resistance to MEK/BRAF inhibitors. In this report, we present discovery and characterization of a novel orally bioavailable compound, ASN007, that showed potent inhibition of ERK1/2 kinases in a biochemical assay with IC50 = 2 nM for both targets. Interestingly, ASN007 displayed a much slower dissociation rate (longer target residence time) as compared to other ERK inhibitors. ASN007 showed potent antiproliferative activity that was selective for RAS/MAPK pathway dependent cancer cell lines, and did not affect the growth of cell lines harboring PI3K pathway or receptor tyrosine kinase mutations. Of note, ASN007 showed much more potent and broader activity against a panel of RAS mutant cell lines as compared to other ERK1/2 inhibitors. In a panel of 96 KRAS mutant cell lines, ASN007 showed strong activity across all KRAS subtype mutations, including G12C, G12D, G12V and G13D. In tumor xenograft models harboring KRAS and NRAS mutations, a daily oral dosing regimen of ASN007 provided strong tumor growth inhibition and was well tolerated. ASN007 also showed strong single-agent antitumor activity in colorectal PDX models with various KRAS subtype mutations including G12C, G12D, and G12S. A clinical phase 1 trial of ASN007 in patients with BRAF and KRAS, HRAS and NRAS mutant melanoma, colorectal, non-small lung and pancreatic cancers is currently ongoing (NCT03415126).

Citation Format: Sanjeeva P. Reddy, Scott K. Thompson, Helen Usansky, Roger A. Smith, Louis Denis, Sandeeep Gupta. ASN007, an oral ERK1/2 inhibitor, shows strong antitumor activity across a panel of KRAS subtype mutant cancer models [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B05.
Abstract B45: Surveillance of RAS-RAF dynamics in vivo: Tracking activity conformations and drug-induced interactions
Authors: Röck Ruth , Mayrhofer Johanna , Torres-Quesada Omar , Enzler Florian , Troppmair Jakob , Stefan Eduard
Published: June 2021

Live-cell recordings of protein conformations and interactions yield novel mechanistic insights into physiologic and pathologic protein functions. We have developed an adaptable and genetically encoded bioluminescence-based biosensor platform to precisely measure signaling dynamics of full-length RAS GTPases and RAF kinases upon physiologic pathway activation, post-translational modifications, mutagenesis, and drug binding. We have recorded the impact of both patient mutations and bioactive small-molecule binding on kinase conformations and binary interactions of GTP-loaded H, N, KRAS with kinases such as RAF. Systematic profiling of αC-helix-OUT BRAF inhibitors (BRAFi) vemurafenib, dabrafenib, encorafenib, and PLX8394 using the BRAF reporter reporter platform (displaying 10 different patient mutations) revealed differences in drug specificities and efficacies. Unexpectedly, the αC-helix-OUT BRAFi engagement with the catalytic pocket of mutated BRAF stabilized an inactive and intermediate full-length kinase conformation, which provoked the enhancement of binary RAS:RAF interactions. We showed that the interference with RAS interactions and nanoclustering has the potential to antagonize the sequential formation of drug-induced tetrameric RAS:RAF complexes. Recently, we have bioengineered a reporter toolbox for direct in vivo recordings of RAS activity conformations. First, we demonstrated that the wild-type RAS reporter—expressed at levels far below endogenous RAS proteins—responds to physiologic pathway activation. Second, we showed that hot-spot RAS mutations display a similar effect on the intramolecular dynamics. The systematic implementation, combination, and advancement of the GTPase and kinase reporter platform have the potential to be used to identify novel means for regulating or perturbing RAS-RAF-ERK signaling in vivo.

Citation Format: Ruth Röck, Johanna Mayrhofer, Omar Torres-Quesada, Florian Enzler, Jakob Troppmair, Eduard Stefan. Surveillance of RAS-RAF dynamics in vivo: Tracking activity conformations and drug-induced interactions [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B45.
Abstract DP-011: PRE-DIAGNOSIS USE OF MENOPAUSAL HORMONE THERAPY ASSOCIATED WITH BETTER OVARIAN CANCER SURVIVAL
Authors: Lee Alice W. , Peterson Siri , Wiensch Ashley , Pike Malcolm C. , Pearce Celeste L.
Published: June 2021

BACKGROUND: Several lifestyle factors have consistently been associated with survival of ovarian cancer, including body mass index, analgesic medications, physical activity, and smoking. Menopausal hormone therapy (HT), which can comprise of estrogen only (ET) or a combination of estrogen and progestin (EPT), has also been studied for its impact on ovarian survival. Randomized trials as well as a recent meta-analysis have shown better survival for women who took HT after their diagnosis in comparison to women who did not (HR=0.67, 95% CI 0.47-0.97). However, the relationship between use of HT prior to ovarian cancer diagnosis and survival is less clear.

METHODS: Approximately 4,700 ovarian cancer patients across nine population-based studies participating in the Ovarian Cancer Association Consortium (OCAC) were included in our analysis. Information on HT use prior to diagnosis and potential confounders was obtained via phone or in-person interviews. To estimate the effect of pre-diagnostic HT use on ovarian cancer survival, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models with left and right truncation to account for different observation times. Effects by type and duration of HT use as well as disease histotype were also evaluated.

RESULTS: Women who used HT before diagnosis had an 11% decreased risk of death in comparison to those who did not use HT (95% CI 0.82-0.97). Similar effects were observed for both types of HT (HR=0.86, 95% CI 0.75-0.98 for ET and HR=0.89, 95% CI 0.80-0.99 for EPT). In addition, there appeared to be a duration effect with longer HT use conferring better survival (p-trend=0.07 for ET, p-trend=0.003 for EPT). When histotype was considered, the overall decreased risk was driven by serous and mucinous ovarian cancers (HR=0.85, 95% CI 0.77-0.93 and HR=0.54, 95% CI 0.28-1.07, respectively).

CONCLUSIONS: Use of HT after diagnosis also affords a survival advantage based on published observational and clinical trials data. We now report that pre-diagnosis HT use may confer a survival advantage among women with ovarian cancer. Interestingly, use of ET prior to diagnosis is associated with increased risk of ovarian cancer, but better survival among women diagnosed with the disease. These observations taken together demonstrate the complex nature of ovarian cancer.

Citation Format: Alice W. Lee, Siri Peterson, Ashley Wiensch, Malcolm C. Pike, Celeste L. Pearce on behalf of the Ovarian Cancer Association Consortium. PRE-DIAGNOSIS USE OF MENOPAUSAL HORMONE THERAPY ASSOCIATED WITH BETTER OVARIAN CANCER SURVIVAL [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr DP-011.
Abstract NT-099: NOVEL ANTIBODY DRUG CONJUGATE (ADC) AND COMPANION DIAGNOSTICS AGAINST CD248+ CANCER
Authors: Guo Yi , Wang Yujue , Peng Xiaohui , Coukos George , Li Chunsheng
Published: June 2021

Antibodies recognizing specific tumor targets can be used to deliver therapeutic payloads with high degree of specificity. The simultaneous use of antibody against same target for imaging and for therapy, an approach named “theranostics”, offers unique opportunities for precision medicine and rapidly assessing therapeutic response at molecular level. The first example of such antibody-based theranotics is Herceptin in HER2-positive breast cancer: Herceptin is used as companion diagnostic imaging tool as well as the targeted therapy.

To develop effective anti-tumor therapeutics, one needs a robust biomarker, AND a good antibody that can specifically bind to the target. We and others have found one for EOC: CD248/TEM1. It is present at high level in tumor and its microenvironment in EOC and almost absent in normal organs. Importantly, CD248 is expressed by >90% EOC patients on the tumor or tumor vasculature, and its high expression correlates with poor survival. This means that if we can target it, we may destroy tumor but leave normal tissues intact. We also have developed robust antibody against CD248 (78Fc panel, US Patent 61/639,325). We showed that our patented antibodies can find the biomarker and upon binding deliver a payload, for PET imaging, near-infrared optical imaging or therapeutic, to CD248-expressing cells. Different toxin payload, such as auristatin and MD117, were conjugated to the antibody, and such ADCs were tested in vitro and in vivo in mice models. Surprisingly, we found such immunotherapies only directly kill, but also induce significant lymphocyte infiltration into tumors. In addition, tumor rejection was observed upon re-challenging in preclinical models. Such immune activation we observed could in turn sensitizing previously “cold tumor” EOC, to checkpoint inhibitors such as PD-1/CDLA4.

The long term goal is to develop companion diagnostics and antibody-immunotherapy: screening methods (such as antibody-based immunoPET and serum ELISA) to identify patients with EOC that can be treated with anti-CD248 drugs; and develop drugs that are linked to the antibody (such as antibody-drug conjugate) so it can be delivered to the tumor directly to kill. In addition, combined with PD-1 blockade, ADC therapies may exert antitumor immune response to sensitize “cold” tumors that previously resistant to PD-1 therapy.

Citation Format: Yi Guo, Yujue Wang, Xiaohui Peng, George Coukos, Chunsheng Li. NOVEL ANTIBODY DRUG CONJUGATE (ADC) AND COMPANION DIAGNOSTICS AGAINST CD248+ CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-099.
Abstract B24: The macrophage-drug conjugate (MDC) as a “Trojan horse” approach in cancer therapy
Authors: Taciak Bartłomiej , Białasek Maciej , Kucharzewska-Siembieda Paulina , Kiraga Łukasz , Szulc Aleksandra , Górka Emilia , Kubiak Małgorzata , Pilch Zofia , Tonecka Katarzyna , Sas Zuzanna , Braniewska Agata , Cheda Łukasz , Rogulski Zbigniew , Godlewski Michał , Boffi Alberto , Rygiel Tomasz , Król Magdalena
Published: June 2021

Unsatisfactory response of tumors to chemotherapy is mainly related to impaired diffusion of the anticancer drug because of decreased drug uptake due to poor vasculature. Moreover, the drug is not able to penetrate the most hypoxic sites. Cells from these “untreated” sites are responsible for relapse and metastasis. However, these avascular regions attract macrophages that migrate even to areas far away from blood vessels. Therefore, they might constitute a unique delivery system of drug-containing particles to these parts of the tumor mass. A promising example of such particles that could be used is ferritins, whose caged architecture allows for efficient drug encapsulation and whose uptake from macrophage cells has been well demonstrated. Macrophages are also able to specifically and actively transfer these taken-up ferritins (loaded with the anticancer drugs) to cancer cells. This is the new mechanism discovered by our team and named TRAIN (TRAnsfer of Iron-binding proteiN). Thus, there is a possibility to use macrophages to deliver ferritin-encapsulated compounds directly to the tumor cells (MDC technology—Macrophage-Drug Conjugate). This is a completely new and modern approach to anticancer therapy and drug delivery. As such, we expect to be able to precisely administer drugs to the tumor site (even to the hypoxic regions), decreasing side effects of anticancer therapy.

Acknowledgments: This research is founded by the European Research Council, Starting Grant McHAP: 715048. The dissemination of the project is founded by the KNOW (Leading National Research Centre), Scientific Consortium “Healthy Animal-Safe Food,” decision of Ministry of Science and Higher Education No. 05-1/KNOW2/2015.

Citation Format: Bartłomiej Taciak, Maciej Białasek, Paulina Kucharzewska-Siembieda, Łukasz Kiraga, Aleksandra Szulc, Emilia Górka, Małgorzata Kubiak, Zofia Pilch, Katarzyna Tonecka, Zuzanna Sas, Agata Braniewska, Łukasz Cheda, Zbigniew Rogulski, Michał Godlewski, Alberto Boffi, Tomasz Rygiel, Magdalena Król. The macrophage-drug conjugate (MDC) as a “Trojan horse” approach in cancer therapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B24.
Abstract B66: High-throughput synthesis and screening for tumor-targeting liposomal nanoparticles
Authors: Audeh Mark , Dwarakanath Manali , Hopkins Michael , Knudson Alisha , Kwok Sally , Morton Stephen , Peck Nikki , Ruckh Tim , Sanowar Sarah , Scott Zach , Thana Peter , Tong Gary , Topol Aaron , Vitari Alberto C , Vaisberg Eugeni , Wang Jane , Wong Stanley
Published: June 2021

The identification of therapeutic nanoparticles formulation with preferential distribution to the tumor microenvironment remains an unsolved challenge. We have developed a high-throughput synthesis and screening platform to discover novel tumor-targeting liposomal nanoparticles. Over 1,000 unique liposomal formulations were synthesized using a combinatorial approach. The characterization of physicochemical properties (e.g., size, charge and stability) allowed the prioritization of ~500 formulations further profiled with in vitro cell-based assays (e.g., cell binding, cytotoxicity and cell barrier crossing). A subset of formulations with diverse properties was selected to create a library of 47 DNA-barcoded nanoparticles. The pharmacokinetics and biodistribution of the formulations library were measured in tumor xenografts mouse models in a highly multiplexed fashion by sequencing the DNA barcodes. The established synthesis and screening platform provides an effective approach to identify novel liposomal formulations with improved tumor and tissue distribution profile.

Note: This abstract was not presented at the conference.

Citation Format: Mark Audeh, Manali Dwarakanath, Michael Hopkins, Alisha Knudson, Sally Kwok, Stephen Morton, Nikki Peck, Tim Ruckh, Sarah Sanowar, Zach Scott, Peter Thana, Gary Tong, Aaron Topol, Alberto C Vitari, Eugeni Vaisberg, Jane Wang, Stanley Wong. High-throughput synthesis and screening for tumor-targeting liposomal nanoparticles [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B66.
The Neuroinflammasome in Alzheimer’s Disease and Cerebral Stroke
Authors: Lee Jong-hoon , Lee Chul Joong , Park Jungwuk , Lee So Jeong , Choi Su-hee
Published: June 2021

Aim/Background: This review investigated a patient with Alzheimer’s disease (AD) treated with 4,4’-diaminodiphenyl sulfone (DDS) as a neuroinflammasome competitor. Methods: We monitored AD’s progression through numeric clinical staging (NCS) with a new biomarker. NCS was determined by the presence of AD symptoms and neuropsychiatric (NP) symptoms caused by anti-AD (AAD) drugs (D) as a biomarker. We also monitored the function of DDS for stroke in a no-intake emergency state. Results: By introducing (D), AD’s progression was monitored through NCS staging. AAD side effects and neuropsychiatric symptoms were identified. DDS was stopped in patients with stroke with NCS 6 caused by AAD, and it rapidly proceeded to cerebral infarct. Conclusions: AAD can occasionally exacerbate AD and stroke. DDS can alleviate mild cognitive impairment (MCI), early AD and stroke. We clinically confirmed the role of DDS as a neuroinflammasome competitor after stroke. DDS preserved neuronal survival within 24–55 h in the Seoul Study cohort.
Microvascular Disease and Incident Heart Failure Among Individuals With Type 2 Diabetes Mellitus
Authors: Kaze Arnaud D. , Santhanam Prasanna , Erqou Sebhat , Ahima Rexford S. , Bertoni Alain , Echouffo‐Tcheugui Justin B.
Published: June 2021

Background

Microvascular disease (MVD) is a potential contributor to the pathogenesis of diabetes mellitus–related cardiac dysfunction. However, there is a paucity of data on the link between MVD and incident heart failure (HF) in type 2 diabetes mellitus. We examined the association of MVD with incident HF in adults with type 2 diabetes mellitus.

Methods and Results

A total of 4095 participants with type 2 diabetes mellitus and free of HF were assessed for diabetes mellitus–related MVD including nephropathy, retinopathy, or neuropathy at baseline in the Look AHEAD (Action for Health in Diabetes) study. Incident HF events were prospectively assessed and adjudicated using hospital and death records. Cox models were used to generate hazard ratios and 95% CIs for HF. Of 4095 participants, 34.8% (n=1424) had MVD, defined as the presence of ≥1 of nephropathy, retinopathy, or neuropathy at baseline. Over a median of 9.7 years, there were 117 HF events. After adjusting for relevant confounders, participants with MVD had a 2.5‐fold higher risk of incident HF than those without MVD (hazard ratio, 2.54; 95% CI, 1.73–3.75). This association remained significant after additional adjustment for interval development of coronary artery disease (hazard ratio, 2.42; 95% CI, 1.64–3.57). The hazard ratios for HF by type of MVD were 2.22 (95% CI, 1.51–3.27), 1.30 (95% CI, 0.72–2.36), and 1.33 (95% CI, 0.86–2.07) for nephropathy, retinopathy, and neuropathy, respectively.

CONCLUSIONS

MVD is associated with an excess HF risk in individuals with type 2 diabetes mellitus after adjusting for other known risk factors. Our findings underscore the contribution of MVD to the development of diabetes mellitus–related HF.

REGISTRATION: URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00017953.
Linking Shrimp Farmers and Food Processors
Authors: Schwabe Julian , Nguyen Chung Van , Hassler Markus
Published: June 2021

This study explores the barriers faced by white shrimp farmers in Vietnam in linking directly with food processing companies. The shrimp sector in Vietnam is still characterised by highly informal structures, weak implementation of food safety regulations and a lack of expertise among farmers to comply with international standards. The Vietnamese government anticipates modernising shrimp production and enabling farmers to achieve the quality standards of international retailers. While international food processing companies have established locations in Vietnam to serve international markets, farmers often lack the resources and expertise to comply with their requirements. The main challenges are related to infrastructure for transport and payment transfers, risk management and overcoming established production routines which are mostly based on tacit knowledge and experience. Hence, efforts are needed to improve infrastructures, establish risk management tools for farmers and promote successful cases which can act as guiding examples for adapting white shrimp production.
The Concepts and Ideas of ‘Spirituality’ Within Worldviews of Alternative Religiosities in the Post-Communist Region: Vissarionites and Anastasians
Authors: Pranskevičiūtė-Amoson Rasa
Published: June 2021

The article presents research on contemporary religiosities related to individuality and subcultural features, influenced by the processes of social change and religious diversification in the post-communist region. Its aim is to discuss individual and communal thinking (orientated to esotericism, magic, and ecology) typical for representatives of two nature-based spirituality movements—Vissarionites and Anastasians, which is expressed through concepts of New Age spirituality of Oriental origin. The concepts of energy, non-violence, vegetarianism, karma, and reincarnation are used in both movements and appear as an example of how such concepts arrived through Western cultural influences, transformed, and took root in the post-communist cultural context of New Age spirituality. The findings are based on data obtained from fieldwork in 2004–2015, including participant observation and interviews with respondents in the Baltic states and Russia.
A new cavernicolous harvestman, Texella martensi n. sp., from the Mojave Desert, California (Opiliones: Laniatores: Phalangodidae)
Authors: UBICK DARRELL
Published: June 2021

A new species of Texella, T. martensi n. sp., is described on the basis of a single male specimen from Titus Canyon Cave, Inyo County, California. The species belongs to the kokoweef group in having a spur on trochanter IV and lacking a postopercular process on the abdomen. Texella martensi n. sp. is the most troglomorphic of the four species of Texella now recorded from the Mojave Desert and it is the northernmost member of the group.
Seasonal Variation of the Surface Kuroshio Intrusion into the South China Sea Evidenced by Satellite Geostrophic Streamlines
Authors: Zhong Yisen , Zhou Meng , Waniek Joanna J. , Zhou Lei , Zhang Zhaoru
Published: June 2021

The long-term satellite altimeter and reanalysis data show that large seasonal variations are associated with geostrophic Kuroshio intrusion, but not with the current intensity, width and axis position east of Philippine. To address this issue, we examine the seasonal variability of surface intrusion patterns by a new streamline-based method. The along-streamline analysis reveals that the seasonality of geostrophic intrusion is only attributed to the cyclonic shear part of the flow, while the anticyclonic shear part always leaps across the Luzon Strait. A possible physical mechanism is proposed to accommodate these seasonal characteristics based on globally the vorticity (torque work) balance between the basin-wide negative wind stress curl and the positive vorticity fluxes induced by the lateral wall, as well as locally loss of balance between the torques of frictional stresses and normal stresses owing to the boundary gap. Through modifying the nearshore sea surface level, the northeasterly/southeasterly monsoon increases/decreases the positive vorticity fluxes in response to global vorticity balance, and simultaneously amplifies/alleviates the local imbalance by enhancing/reducing the positive frictional stress torque within the cyclonic shear layer. Therefore, in winter when the positive torque is large enough, the Kuroshio splits and the intrusion occurs, while in summer the stress torque is so weak that the entire current keeps flowing north.
Wind- and Wave-driven Ocean Surface Boundary Layer in a Frontal Zone: Roles of Submesoscale Eddies and Ekman-Stokes Transport
Authors: Yuan Jianguo , Liang Jun-Hong
Published: June 2021

Large-eddy simulations are used to investigate the influence of a horizontal frontal zone, represented by a stationary uniform background horizontal temperature gradient, on the wind- and wave-driven ocean surface boundary layers. In a frontal zone, the temperature structure, the ageostrophic mean horizontal current, and the turbulence in the ocean surface boundary layer all change with the relative angle among the wind and the front. The net heating and cooling of the boundary layer could be explained by the depth-integrated horizontal advective buoyancy flux, called the Ekman Buoyancy Flux (or the Ekman-Stokes Buoyancy Flux if wave effects are included). However, the detailed temperature profiles are also modulated by the depth-dependent advective buoyancy flux and submesoscale eddies. The surface current is deflected less (more) to the right of the wind and wave when the depth-integrated advective buoyancy flux cools (warms) the ocean surface boundary layer. Horizontal mixing is greatly enhanced by submesoscale eddies. The eddy-induced horizontal mixing is anisotropic and is stronger to the right of the wind direction. Vertical turbulent mixing depends on the superposition of the geostrophic and ageostrophic current, the depth-dependent advective buoyancy flux, and submesoscale eddies.
Development of a track-pattern-based medium-range tropical cyclone forecasting system for the western North Pacific
Authors: Cheung Hung Ming , Ho Chang-Hoi , Chang Minhee , Kim Dasol , Kim Jinwon , Choi Woosuk
Published: June 2021

Despite tremendous advancements in dynamical models for weather forecasting, statistical models continue to offer various possibilities for tropical cyclone (TC) track forecasting. Herein, a track-pattern-based approach was developed to predict a TC track for a lead time of 6–8 days over the western North Pacific (WNP), utilizing historical tracks in conjunction with dynamical forecasts. It is composed of four main steps: (1) clustering historical tracks similar to that of an operational five-day forecast in their early phase into track patterns, and calculating the daily mean environmental fields (500-hPa geopotential height and steering flow) associated with each track; (2) deriving the two environmental variables forecasted by dynamical models; (3) evaluating pattern correlation coefficients between the two environmental fields from step (1) and those from dynamical model for a lead times of 6–8 days; and (4) producing the final track forecast based on relative frequency maps obtained from the historical tracks in step (1) and the pattern correlation coefficients obtained from step (3). TCs that formed in the WNP and lasted for at least seven days, during the 9-year period 2011–2019 were selected to verify the resulting track-pattern-based forecasts. In addition to the performance comparable to dynamical models under certain conditions, the track-pattern-based model is inexpensive, and can consistently produce forecasts over large latitudinal or longitudinal ranges. Machine learning techniques can be implemented to incorporate non-linearity in the present model for improving medium-range track forecasts.
miR-130b and miR-128a are essential lineage-specific codrivers of t(4;11) MLL-AF4 acute leukemia
Authors: Malouf Camille , Antunes Eric T. B. , O’Dwyer Michael , Jakobczyk Hélène , Sahm Franziska , Landua Sophie-Luise , Anderson Richard A. , Soufi Abdenour , Halsey Christina , Ottersbach Katrin
Published: June 2021

t(4;11) MLL-AF4 acute leukemia is one of the most aggressive malignancies in the infant and pediatric population, yet we have little information on the molecular mechanisms responsible for disease progression. This impairs the development of therapeutic regimens that can address the aggressive phenotype and lineage plasticity of MLL-AF4–driven leukemogenesis. This study highlights novel mechanisms of disease development by focusing on 2 microRNAs (miRNAs) upregulated in leukemic blasts from primary patient samples: miR-130b and miR-128a. We show that miR-130b and miR-128a are downstream targets of MLL-AF4 and can individually drive the transition from a pre-leukemic stage to an acute leukemia in an entirely murine Mll-AF4 in vivo model. They are also required to maintain the disease phenotype. Interestingly, miR-130b overexpression led to a mixed/B-cell precursor (BCP)/myeloid leukemia, propagated by the lymphoid-primed multipotent progenitor (LMPP) population, whereas miR-128a overexpression resulted in a pro-B acute lymphoblastic leukemia (ALL), maintained by a highly expanded Il7r+c-Kit+ blast population. Molecular and phenotypic changes induced by these two miRNAs fully recapitulate the human disease, including central nervous system infiltration and activation of an MLL-AF4 expression signature. Furthermore, we identified 2 downstream targets of these miRNAs, NR2F6 and SGMS1, which in extensive validation studies are confirmed as novel tumor suppressors of MLL-AF4+ leukemia. Our integrative approach thus provides a platform for the identification of essential co-drivers of MLL-rearranged leukemias, in which the preleukemia to leukemia transition and lineage plasticity can be dissected and new therapeutic approaches can be tested.
Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia
Authors: Chang Yunchao , Min Jaeki , Jarusiewicz Jamie A. , Actis Marisa , Yu-Chen Bradford Shanshan , Mayasundari Anand , Yang Lei , Chepyala Divyabharathi , Alcock Lisa J. , Roberts Kathryn G. , Nithianantham Stanley , Maxwell Dylan , Rowland Lauren , Larsen Randolph , Seth Aman , Goto Hiroaki , Imamura Toshihiko , Akahane Koshi , Hansen Baranda S. , Pruett-Miller Shondra M. , Paietta Elisabeth M. , Litzow Mark R. , Qu Chunxu , Yang Jun J. , Fischer Marcus , Rankovic Zoran , Mullighan Charles G.
Published: June 2021

CRLF2-rearranged (CRLF2r) acute lymphoblastic leukemia (ALL) accounts for more than half of Philadelphia chromosome-like (Ph-like) ALL and is associated with a poor outcome in children and adults. Overexpression of CRLF2 results in activation of Janus kinase (JAK)-STAT and parallel signaling pathways in experimental models, but existing small molecule inhibitors of JAKs show variable and limited efficacy. Here, we evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) directed against JAKs. Solving the structure of type I JAK inhibitors ruxolitinib and baricitinib bound to the JAK2 tyrosine kinase domain enabled the rational design and optimization of a series of cereblon (CRBN)-directed JAK PROTACs utilizing derivatives of JAK inhibitors, linkers, and CRBN-specific molecular glues. The resulting JAK PROTACs were evaluated for target degradation, and activity was tested in a panel of leukemia/lymphoma cell lines and xenograft models of kinase-driven ALL. Multiple PROTACs were developed that degraded JAKs and potently killed CRLF2r cell lines, the most active of which also degraded the known CRBN neosubstrate GSPT1 and suppressed proliferation of CRLF2r ALL in vivo, e.g. compound 7 (SJ988497). Although dual JAK/GSPT1-degrading PROTACs were the most potent, the development and evaluation of multiple PROTACs in an extended panel of xenografts identified a potent JAK2-degrading, GSPT1-sparing PROTAC that demonstrated efficacy in the majority of kinase-driven xenografts that were otherwise unresponsive to type I JAK inhibitors, e.g. compound 8 (SJ1008030). Together, these data show the potential of JAK-directed protein degradation as a therapeutic approach in JAK-STAT–driven ALL and highlight the interplay of JAK and GSPT1 degradation activity in this context.
Depalmitoylation rewires FLT3-ITD signaling and exacerbates leukemia progression
Authors: Lv Kaosheng , Ren Jian-Gang , Han Xu , Gui Jun , Gong Chujie , Tong Wei
Published: June 2021

Internal tandem duplication within FLT3 (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and correlates with a poor prognosis. Whereas the FLT3 receptor tyrosine kinase is activated at the plasma membrane to transduce PI3K/AKT and RAS/MAPK signaling, FLT3-ITD resides in the endoplasmic reticulum and triggers constitutive STAT5 phosphorylation. Mechanisms underlying this aberrant FLT3-ITD subcellular localization or its impact on leukemogenesis remain poorly established. In this study, we discovered that FLT3-ITD is S-palmitoylated by the palmitoyl acyltransferase ZDHHC6. Disruption of palmitoylation redirected FLT3-ITD to the plasma membrane and rewired its downstream signaling by activating AKT and extracellular signal-regulated kinase pathways in addition to STAT5. Consequently, abrogation of palmitoylation increased FLT3-ITD–mediated progression of leukemia in xenotransplant-recipient mouse models. We further demonstrate that FLT3 proteins were palmitoylated in primary human AML cells. ZDHHC6-mediated palmitoylation restrained FLT3-ITD surface expression, signaling, and colonogenic growth of primary FLT3-ITD+ AML. More important, pharmacological inhibition of FLT3-ITD depalmitoylation synergized with the US Food and Drug Administration–approved FLT3 kinase inhibitor gilteritinib in abrogating the growth of primary FLT3-ITD+ AML cells. These findings provide novel insights into lipid-dependent compartmentalization of FLT3-ITD signaling in AML and suggest targeting depalmitoylation as a new therapeutic strategy to treat FLT3-ITD+ leukemias.
Migraine and neuroinflammation: the inflammasome perspective
Authors: Kursun Oguzhan , Yemisci Muge , van den Maagdenberg Arn M. J. M. , Karatas Hulya
Published: June 2021

Background

Neuroinflammation has an important role in the pathophysiology of migraine, which is a complex neuro-glio-vascular disorder. The main aim of this review is to highlight findings of cortical spreading depolarization (CSD)-induced neuroinflammatory signaling in brain parenchyma from the inflammasome perspective. In addition, we discuss the limited data of the contribution of inflammasomes to other aspects of migraine pathophysiology, foremost the activation of the trigeminovascular system and thereby the generation of migraine pain.

Main body

Inflammasomes are signaling multiprotein complexes and key components of the innate immune system. Their activation causes the production of inflammatory cytokines that can stimulate trigeminal neurons and are thus relevant to the generation of migraine pain. The contribution of inflammasome activation to pain signaling has attracted considerable attention in recent years. Nucleotide-binding domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) is the best characterized inflammasome and there is emerging evidence of its role in a variety of inflammatory pain conditions, including migraine. In this review, we discuss, from an inflammasome point of view, cortical spreading depolarization (CSD)-induced neuroinflammatory signaling in brain parenchyma, the connection with genetic factors that make the brain vulnerable to CSD, and the relation of the inflammasome with diseases that are co-morbid with migraine, including stroke, epilepsy, and the possible links with COVID-19 infection.

Conclusion

Neuroinflammatory pathways, specifically those involving inflammasome proteins, seem promising candidates as treatment targets, and perhaps even biomarkers, in migraine.
Female paraurethral leiomyoma: a case report
Authors: Mazhari Farhat , Singh Roopam , Kerketta Kirti Anima , Pathak Nilay , Singh Neha
Published: June 2021

Background

Leiomyoma is a benign fibromuscular neoplasm originating from smooth muscle cells. Paraurethral leiomyoma is an extremely rare, benign, hormone-dependent growth from the mesenchymal cells in paraurethral space of female urethra. They usually appear in the reproductive age group women, mean age of presentation being approximately 41 years.

Case presentation

A 48-year-old woman presented with palpable mass at vagina and weak urinary stream. She underwent clinical examination and CT scan and MRI imaging followed by transvaginal excision of the mass. Histopathological examination confirmed paraurethral leiomyoma.

Conclusions

Paraurethral leiomyoma owing to its rare incidence poses a diagnostic dilemma for the gynecologists. Radiological imaging techniques help in diagnosis. Surgical excision via vaginal route is the treatment of choice. Diagnosis is confirmed by histopathology.
Multiple paths to cold tolerance: the role of environmental cues, morphological traits and the circadian clock gene vrille
Authors: Poikela Noora , Tyukmaeva Venera , Hoikkala Anneli , Kankare Maaria
Published: June 2021

Background

Tracing the association between insect cold tolerance and latitudinally and locally varying environmental conditions, as well as key morphological traits and molecular mechanisms, is essential for understanding the processes involved in adaptation. We explored these issues in two closely-related species, Drosophila montana and Drosophila flavomontana, originating from diverse climatic locations across several latitudes on the coastal and mountainous regions of North America. We also investigated the association between sequence variation in one of the key circadian clock genes, vrille, and cold tolerance in both species. Finally, we studied the impact of vrille on fly cold tolerance and cold acclimation ability by silencing it with RNA interference in D. montana.

Results

We performed a principal component analysis (PCA) on variables representing bioclimatic conditions on the study sites and used latitude as a proxy of photoperiod. PC1 separated the mountainous continental sites from the coastal ones based on temperature variability and precipitation, while PC2 arranged the sites based on summer and annual mean temperatures. Cold tolerance tests showed D. montana to be more cold-tolerant than D. flavomontana and chill coma resistance (CTmin) of this species showed an association with PC2. Chill coma recovery time (CCRT) of both species improved towards northern latitudes, and in D. flavomontana this trait was also associated with PC1. D. flavomontana flies were darkest in the coast and in the northern mountainous populations, but coloration showed no linkage with cold tolerance. Body size decreased towards cold environments in both species, but only within D. montana populations largest flies showed fastest recovery from cold. Finally, both the sequence analysis and RNAi study on vrille suggested this gene to play an essential role in D. montana cold resistance and acclimation, but not in recovery time.

Conclusions

Our study demonstrates the complexity of insect cold tolerance and emphasizes the need to trace its association with multiple environmental variables and morphological traits to identify potential agents of natural selection. It also shows that a circadian clock gene vrille is essential both for short- and long-term cold acclimation, potentially elucidating the connection between circadian clock system and cold tolerance.
Transcriptomic analysis of shell repair and biomineralization in the blue mussel, Mytilus edulis
Authors: Yarra Tejaswi , Ramesh Kirti , Blaxter Mark , Hüning Anne , Melzner Frank , Clark Melody S.
Published: June 2021

Background

Biomineralization by molluscs involves regulated deposition of calcium carbonate crystals within a protein framework to produce complex biocomposite structures. Effective biomineralization is a key trait for aquaculture, and animal resilience under future climate change. While many enzymes and structural proteins have been identified from the shell and in mantle tissue, understanding biomieralization is impeded by a lack of fundamental knowledge of the genes and pathways involved. In adult bivalves, shells are secreted by the mantle tissue during growth, maintenance and repair, with the repair process, in particular, amenable to experimental dissection at the transcriptomic level in individual animals.

Results

Gene expression dynamics were explored in the adult blue mussel, Mytilus edulis, during experimentally induced shell repair, using the two valves of each animal as a matched treatment-control pair. Gene expression was assessed using high-resolution RNA-Seq against a de novo assembled database of functionally annotated transcripts. A large number of differentially expressed transcripts were identified in the repair process. Analysis focused on genes encoding proteins and domains identified in shell biology, using a new database of proteins and domains previously implicated in biomineralization in mussels and other molluscs. The genes implicated in repair included many otherwise novel transcripts that encoded proteins with domains found in other shell matrix proteins, as well as genes previously associated with primary shell formation in larvae. Genes with roles in intracellular signalling and maintenance of membrane resting potential were among the loci implicated in the repair process. While haemocytes have been proposed to be actively involved in repair, no evidence was found for this in the M. edulis data.

Conclusions

The shell repair experimental model and a newly developed shell protein domain database efficiently identified transcripts involved in M. edulis shell production. In particular, the matched pair analysis allowed factoring out of much of the inherent high level of variability between individual mussels. This snapshot of the damage repair process identified a large number of genes putatively involved in biomineralization from initial signalling, through calcium mobilization to shell construction, providing many novel transcripts for future in-depth functional analyses.