scholarly journals Aberrant CXCR4 Signaling at Crossroad of WHIM Syndrome and Waldenstrom’s Macroglobulinemia

2020 ◽  
Vol 21 (16) ◽  
pp. 5696 ◽  
Author(s):  
Samantha Milanesi ◽  
Massimo Locati ◽  
Elena Monica Borroni
Keyword(s):  
Current Knowledge ◽  
Biochemical Properties ◽  
Response To Therapy ◽  
Cxcr4 Signaling ◽  
Whim Syndrome ◽  
Open Questions ◽  
Congenital Immunodeficiency ◽  
Pleiotropic Functions ◽  
The Impact ◽  
Significant Attention

Given its pleiotropic functions, including its prominent role in inflammation, immune responses and cancer, the C-X-C chemokine receptor type 4 (CXCR4) has gained significant attention in recent years and has become a relevant target in drug development. Although the signaling properties of CXCR4 have been extensively studied, several aspects deserve deeper investigations. Mutations in the C-term tail of the CXCR4 gene cause WHIM syndrome, a rare congenital immunodeficiency associated by chronic leukopenia. Similar mutations have also been recently identified in 30% of patients affected by Waldenstrom’s macroglobulinaemia, a B-cell neoplasia with bone marrow accumulation of malignant cells. An ample body of work has been generated to define the impact of WHIM mutations on CXCR4 signaling properties and evaluate their role on pathogenesis, diagnosis, and response to therapy, although the identity of disease-causing signaling pathways and their relevance for disease development in different genetic variants are still open questions. This review discusses the current knowledge on biochemical properties of CXCR4 mutations to identify their prototypic signaling profile potentially useful to highlighting novel opportunities for therapeutic intervention.

scholarly journals The Emerging Role of Microbiota and Microbiome in Pancreatic Ductal Adenocarcinoma

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 565
Author(s):  
Sona Ciernikova ◽  
Maria Novisedlakova ◽  
Danka Cholujova ◽  
Viola Stevurkova ◽  
Michal Mego
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Malignant Tumors ◽  
Current Knowledge ◽  
Early Stage ◽  
Poor Response ◽  
Response To Therapy ◽  
Oral Microbiome ◽  
Ductal Adenocarcinoma ◽  
The Impact

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant tumors due to the absence of biomarkers for early-stage detection and poor response to therapy. Since mounting evidence supports the role of microbiota composition in tumorigenesis and cancer treatment, the link between microbiome and PDAC has been described. In this review, we summarize the current knowledge regarding the impact of the gut and oral microbiome on the risk of PDAC development. Microenvironment-driven therapy and immune system interactions are also discussed. More importantly, we provide an overview of the clinical trials evaluating the microbiota role in the risk, prognosis, and treatment of patients suffering from PDAC and solid tumors. According to the research findings, immune tolerance might result from the microbiota-derived remodeling of pancreatic tumor microenvironment. Thus, microbiome profiling and targeting represent the potential trend to enhance antitumor immunity and improve the efficacy of PDAC treatment.

scholarly journals New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 164 ◽  
Author(s):  
Stefania Scala ◽  
Crescenzo D’Alterio ◽  
Samantha Milanesi ◽  
Alessandra Castagna ◽  
Roberta Carriero ◽  
...  
Keyword(s):  
Chemokine Receptors ◽  
Cancer Biology ◽  
Current Knowledge ◽  
Chemotherapy Resistance ◽  
Response To Therapy ◽  
Aberrant Expression ◽  
Molecular Alterations ◽  
Whim Syndrome ◽  
C Terminus ◽  
Genomic Landscape

Deciphering the molecular alterations leading to disease initiation and progression is currently crucial to identify the most relevant targets for precision therapy in cancer patients. Cancers express a complex chemokine network influencing leucocyte infiltration and angiogenesis. Moreover, malignant cells also express a selective repertoire of chemokine receptors that sustain their growth and spread. At present, different cancer types have been shown to overexpress C-X-C chemokine receptor type 4 (CXCR4) and to respond to its ligand C-X-C motif chemokine 12 (CXCL12). The CXCL12/CXCR4 axis influences cancer biology, promoting survival, proliferation, and angiogenesis, and plays a pivotal role in directing migration of cancer cells to sites of metastases, making it a prognostic marker and a therapeutic target. More recently, mutations in the C-terminus of CXCR4 have been identified in the genomic landscape of patients affected by Waldenstrom’s macroglobulinemia, a rare B cell neoplasm. These mutations closely resemble those occurring in Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis (WHIM) syndrome, an immunodeficiency associated with CXCR4 aberrant expression and activity and with chemotherapy resistance in clinical trials. In this review, we summarize the current knowledge on the relevance of CXCR4 mutations in cancer biology, focusing on its importance as predictors of clinical presentation and response to therapy.

scholarly journals π-Excess-aromatic and non-aromatic 1,3-azaphospholes – impact of annulation and multiple reactivity

2019 ◽  
Vol 91 (5) ◽  
pp. 761-771
Author(s):  
Joachim W. Heinicke
Keyword(s):  
Current Knowledge ◽  
Substituent Effects ◽  
Open Questions ◽  
The Impact ◽  
Aromatic Stabilization

Abstract Syntheses, properties, structure aspects and reactivity of non- and aromatically carbo- and heterocyclic annulated 1H- and 3H-1,3-azaphospholes are compared to illuminate the impact of annulation, substituent effects, aromatic stabilization and π-excess at phosphorus of the 1H-isomers, to demonstrate the current knowledge and open questions in this field of research.

scholarly journals Cytoplasmic RNA Granules in Somatic Maintenance

Gerontology ◽  
2018 ◽  
Vol 64 (5) ◽  
pp. 485-494 ◽  
Author(s):  
Ossama Moujaber ◽  
Ursula Stochaj
Keyword(s):  
Somatic Cell ◽  
Current Knowledge ◽  
Physiological State ◽  
Physiological Role ◽  
Cellular Functions ◽  
Rna Granules ◽  
Cytoplasmic Rna ◽  
Open Questions ◽  
And Function ◽  
The Impact

Cytoplasmic RNA granules represent subcellular compartments that are enriched in protein-bound RNA species. RNA granules are produced by evolutionary divergent eukaryotes, including yeast, mammals, and plants. The functions of cytoplasmic RNA granules differ widely. They are dictated by the cell type and physiological state, which in turn is determined by intrinsic cell properties and environmental factors. RNA granules provide diverse cellular functions. However, all of the granules contribute to aspects of RNA metabolism. This is exemplified by transcription, RNA storage, silencing, and degradation, as well as mRNP remodeling and regulated translation. Several forms of cytoplasmic mRNA granules are linked to normal physiological processes. For instance, they may coordinate protein synthesis and thereby serve as posttranscriptional “operons”. RNA granules also participate in cytoplasmic mRNA trafficking, a process particularly well understood for neurons. Many forms of RNA granules support the preservation of somatic cell performance under normal and stress conditions. On the other hand, severe insults or disease can cause the formation and persistence of RNA granules that contribute to cellular dysfunction, especially in the nervous system. Neurodegeneration and many other diseases linked to RNA granules are associated with aging. Nevertheless, information related to the impact of aging on the various types of RNA granules is presently very limited. This review concentrates on cytoplasmic RNA granules and their role in somatic cell maintenance. We summarize the current knowledge on different types of RNA granules in the cytoplasm, their assembly and function under normal, stress, or disease conditions. Specifically, we discuss processing bodies, neuronal granules, stress granules, and other less characterized cytoplasmic RNA granules. Our focus is primarily on mammalian and yeast models, because they have been critical to unravel the physiological role of various RNA granules. RNA granules in plants and pathogens are briefly described. We conclude our viewpoint by summarizing the emerging concepts for RNA granule biology and the open questions that need to be addressed in future studies.

scholarly journals Genomic Heterogeneity of Pancreatic Ductal Adenocarcinoma and Its Clinical Impact

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4451
Author(s):  
María Laura Gutiérrez ◽  
Luis Muñoz-Bellvís ◽  
Alberto Orfao
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Patient Outcomes ◽  
Current Knowledge ◽  
Genomic Data ◽  
Response To Therapy ◽  
Ductal Adenocarcinoma ◽  
Tumor Resistance ◽  
Driver Genes ◽  
Genetic Traits ◽  
The Impact

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death due to limited advances in recent years in early diagnosis and personalized therapy capable of overcoming tumor resistance to chemotherapy. In the last decades, significant advances have been achieved in the identification of recurrent genetic and molecular alterations of PDAC including those involving the KRAS, CDKN2A, SMAD4, and TP53 driver genes. Despite these common genetic traits, PDAC are highly heterogeneous tumors at both the inter- and intra-tumoral genomic level, which might contribute to distinct tumor behavior and response to therapy, with variable patient outcomes. Despite this, genetic and genomic data on PDAC has had a limited impact on the clinical management of patients. Integration of genomic data for classification of PDAC into clinically defined entities—i.e., classical vs. squamous subtypes of PDAC—leading to different treatment approaches has the potential for significantly improving patient outcomes. In this review, we summarize current knowledge about the most relevant genomic subtypes of PDAC including the impact of distinct patterns of intra-tumoral genomic heterogeneity on the classification and clinical and therapeutic management of PDAC.

scholarly journals The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome

Blood ◽  
2011 ◽  
Vol 118 (18) ◽  
pp. 4957-4962 ◽  
Author(s):  
David H. McDermott ◽  
Qian Liu ◽  
Jean Ulrick ◽  
Nana Kwatemaa ◽  
Sandra Anaya-O'Brien ◽  
...  
Keyword(s):  
Rank Order ◽  
Phase 1 ◽  
Cell Types ◽  
Dependent Manner ◽  
Cxcr4 Antagonist ◽  
Dose Escalation Study ◽  
Cxcr4 Signaling ◽  
Whim Syndrome ◽  
Immunodeficiency Disorder ◽  
Congenital Immunodeficiency

Abstract WHIM syndrome is a rare congenital immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (neutropenia because of impaired egress from the BM); most patients also have severe panleukopenia. Because WHIM syndrome is caused by mutations in the chemokine receptor CXCR4 that result in increased agonist-dependent signaling, we hypothesized that the CXCR4 antagonist plerixafor (Mozobil [Genyzme Corporation], AMD3100), might be an effective treatment. To test this, we enrolled 3 unrelated adult patients with the most common WHIM mutation, CXCR4R334X, in a phase 1 dose-escalation study. Plerixafor increased absolute lymphocyte, monocyte, and neutrophil counts in blood to normal without significant side effects in all 3 patients. Peak responses occurred at 3-12 hours after injection and waned by 24 hours after injection which tracked the drug's pharmacokinetics. All 3 cell types increased in a dose-dependent manner with the rank order of responsiveness absolute lymphocyte > monocyte > neutrophil. These data provide the first pharmacologic evidence that panleukopenia in WHIM syndrome is caused by CXCL12-CXCR4 signaling-dependent leukocyte sequestration, and support continued study of plerixafor as mechanism-based therapy in this disease. This study is registered at http://www.clinicaltrials.gov as NCT00967785.

DAMPAK PROGRAM DIKLAT ONLINE TIK GURU PUSTEKKOM TERHADAP AKSESBILITAS KONTEN PEMBELAJARAN PADA FITUR RUMAH BELAJAR

2018 ◽  
Vol 19 (2) ◽  
pp. 84
Author(s):  
Eni Susilawati
Keyword(s):  
Teacher Training ◽  
Quantitative Research ◽  
Online Training ◽  
Research Approach ◽  
Intensity Level ◽  
Web Based ◽  
Learning Content ◽  
Open Questions ◽  
Ict Training ◽  
The Impact

The research objective is to analyze the impact of the participation of online  ICT teacher training to increase the number of accessibility the learning content of features in Rumah Belajar. This research used the quantitative research approach with descriptive quantitative analysis methods to be able to describe how the increase in accessibility features of Rumah Belajar and utilization in learning in school. Samples were selected in this study are all online training participants at 15 locations online training that has been conducted by Pustekkom in 2015 and 2016 in 2015. The data was collected using a questionnaire and a list of open questions in accordance with the purpose of research. The results showed that 1) online ICT teacher training participants, after completing the Pustekkom  training online  using become more motivated to access other feature in Rumah Belajar; 2) The order of the percentage of the intensity level of accessibility to the other features of Rumah Belajar are: Sumber Belajar 23%, BSE 23%, Bank Soal 21%, Kelas Maya 13%, Lab Maya 6%, Karya Guru 4%, Wahana Jelajah Angkasa 4%, Peta Budaya 4% and Karya Komunitas 2%, and ICT training online using the application PKB Rumah Belajar can be used as a reference for efforts to develop a web-based learning applications, in particular for the development of Rumah belajar portal belongs Pustekkom Kemendikbud. Tujuan penelitian yaitu untuk menganalisis dampak keikutsertaan diklat online  TIK guru Belajar terhadap peningkatan jumlah aksebilitas konten pembelajaran pada fitur-fitur rumah belajar. Penelitian ini menggunakan pendekatan penelitian kuantitatif dengan metode analisis kuantitatif secara deskriptif untuk bisa menggambarkan bagaimana peningkatan aksesbilitas fitur-fitur rumah belajar dan pemanfaatannya dalam pembelajaran di sekolah. Sampel yang dipilih dalam penelitian ini adalah semua peserta diklat online  pada 15 lokasi diklat online yang telah dilaksanakan oleh Pustekkom pada tahun 2015 dan 2016. Pengumpulan data menggunakan kuesioner dan daftar pertanyaan terbuka sesuai dengan tujuan penelitian. Hasil penelitian menunjukkan bahwa 1) peserta diklat online TIK Guru, setelah mengikuti diklat online Pustekkom, menjadi lebih termotivasi untuk mengakses fitur-fitur lainnya dalam Rumah Belajar; 2) Urutan prosentase tingkat intensitas aksesbilitas terhadap fitur-fitur Rumbel selain Pengembangan Keprofesian berkelanjutan (PKB) adalah: Sumber Belajar 23%, Buku Sekolah Elektronik (BSE) 23%, Bank Soal 21%, Kelas Maya 13%, Lab Maya 6%, Karya Guru 4%, Wahana Jelajah Angkasa 4%, Peta Budaya 4% dan Karya Komunitas 2%; dan 3) diklat online TIK menggunakan aplikasi PKB. Rumah belajar bisa dijadikan referensi bagi upaya pengembangan aplikasi pembelajaran berbasis web, khususnya bagi pengembangan portal Rumah Belajar milik Pustekkom Kemendikbud.

scholarly journals Predictors and Early Markers of Response to Biological Therapies in Inflammatory Bowel Diseases

2021 ◽  
Vol 10 (4) ◽  
pp. 853
Author(s):  
Giuseppe Privitera ◽  
Daniela Pugliese ◽  
Gian Ludovico Rapaccini ◽  
Antonio Gasbarrini ◽  
Alessandro Armuzzi ◽  
...  
Keyword(s):  
Inflammatory Bowel Diseases ◽  
Current Knowledge ◽  
Real Life ◽  
Response To Therapy ◽  
Significant Heterogeneity ◽  
Intestinal Damage ◽  
Biological Therapies ◽  
Early Markers ◽  
Bowel Diseases ◽  
Inflammatory Bowel

Inflammatory bowel diseases (IBD) are chronic conditions that primarily affect the gastrointestinal tract, with a complex pathogenesis; they are characterized by a significant heterogeneity of clinical presentations and of inflammatory pathways that sustain intestinal damage. After the introduction of the first biological therapies, the pipeline of therapies for IBD has been constantly expanding, and a significant number of new molecules is expected in the next few years. Evidence from clinical trials and real-life experiences has taught us that up to 40% of patients do not respond to a specific drug. Unfortunately, to date, clinicians lack a valid tool that can predict each patient’s response to therapies and that could help them in choosing what drug to administer. Several candidate biomarkers have been investigated so far, with conflicting results: clinical, genetic, immunological, pharmacokinetic and microbial markers have been tested, but no ideal marker has been identified so far. Based on recent evidence, multiparametric models seemingly hold the greatest potential for predicting response to therapy. In this narrative review, we aim to summarize the current knowledge on predictors and early markers of response to biological therapies in IBD.

scholarly journals Urban Fire Severity and Vegetation Dynamics in Southern California

2020 ◽  
Vol 13 (1) ◽  
pp. 19
Author(s):  
Lauren E. H. Mathews ◽  
Alicia M. Kinoshita
Keyword(s):  
Vegetation Cover ◽  
Vegetation Index ◽  
Normalized Difference Vegetation Index ◽  
Current Knowledge ◽  
Fire Severity ◽  
Satellite Image ◽  
Burn Severity ◽  
Native Vegetation ◽  
Riparian Areas ◽  
The Impact

A combination of satellite image indices and in-field observations was used to investigate the impact of fuel conditions, fire behavior, and vegetation regrowth patterns, altered by invasive riparian vegetation. Satellite image metrics, differenced normalized burn severity (dNBR) and differenced normalized difference vegetation index (dNDVI), were approximated for non-native, riparian, or upland vegetation for traditional timeframes (0-, 1-, and 3-years) after eleven urban fires across a spectrum of invasive vegetation cover. Larger burn severity and loss of green canopy (NDVI) was detected for riparian areas compared to the uplands. The presence of invasive vegetation affected the distribution of burn severity and canopy loss detected within each fire. Fires with native vegetation cover had a higher severity and resulted in larger immediate loss of canopy than fires with substantial amounts of non-native vegetation. The lower burn severity observed 1–3 years after the fires with non-native vegetation suggests a rapid regrowth of non-native grasses, resulting in a smaller measured canopy loss relative to native vegetation immediately after fire. This observed fire pattern favors the life cycle and perpetuation of many opportunistic grasses within urban riparian areas. This research builds upon our current knowledge of wildfire recovery processes and highlights the unique challenges of remotely assessing vegetation biophysical status within urban Mediterranean riverine systems.

scholarly journals Effects of the Marine Biotoxins Okadaic Acid and Dinophysistoxins on Fish

2021 ◽  
Vol 9 (3) ◽  
pp. 293
Author(s):  
Mauro Corriere ◽  
Lucía Soliño ◽  
Pedro Reis Costa
Keyword(s):  
Okadaic Acid ◽  
Harmful Algal Blooms ◽  
Algal Blooms ◽  
Current Knowledge ◽  
Global Climate ◽  
Scientific Evidence ◽  
Shellfish Poisoning ◽  
Morphological Alterations ◽  
The Impact ◽  
Dsp Toxins

Natural high proliferations of toxin-producing microorganisms in marine and freshwater environments result in dreadful consequences at the socioeconomically and environmental level due to water and seafood contamination. Monitoring programs and scientific evidence point to harmful algal blooms (HABs) increasing in frequency and intensity as a result of global climate alterations. Among marine toxins, the okadaic acid (OA) and the related dinophysistoxins (DTX) are the most frequently reported in EU waters, mainly in shellfish species. These toxins are responsible for human syndrome diarrhetic shellfish poisoning (DSP). Fish, like other marine species, are also exposed to HABs and their toxins. However, reduced attention has been given to exposure, accumulation, and effects on fish of DSP toxins, such as OA. The present review intends to summarize the current knowledge of the impact of DSP toxins and to identify the main issues needing further research. From data reviewed in this work, it is clear that exposure of fish to DSP toxins causes a range of negative effects, from behavioral and morphological alterations to death. However, there is still much to be investigated about the ecological and food safety risks related to contamination of fish with DSP toxins.

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