Systemic Spread Research Articles

Spontaneous Lymphoma in a SMP30 Knock-Out C57BL/6 Mouse

Abstract 70-weeks-old female C57BL6 senescence marker protein 30 knock out mice exhibited anorexia, lethargy and enlarged abdomen because of an intraperitoneal mass. On necropsy, the mouse revealed a large brown-whitish mass located on the mesentery. The mass also exhibited systemic metastasis and spread over in various organs. On microscopic findings, the neoplastic masses were mainly composed of neoplastic round cells characterized by severe anisokaryosis, narrow cytoplasm, round nuclei, prominent nucleoli, and numerous mitotic figures (13-15 in a 400X field). Consequently, the present case was diagnosed as a metastatic lymphoma arising from a mesenteric lymph node, the tumor spread to other organs such as the intestine, kidney and thoracic cavity. According to previous studies, SMP30 plays an important role in inhibiting cancer in both human and mouse. Taken together, it seems that the present case can be used as a valuable asset for evaluating the potential risks of SMP30 depletion in developing lymphoma.

LEMIERRE'S SYNDROME: A REVIEW

Lemierre's syndrome is a rare and less commonly occurring clinical condition that generally relates to the septic thrombophlebitis of the Internal Jugular vein. Mostly the clinicians have forgotten about this due to less incidence, the most common bacteria causing infection are and Streptococci followed by styaphylococci and Klebsiella [1] . The major proportion of cases that come to light are due to deep neck space infections that ultimately leads to thrombotic involvement of IJV, accounts for for majority of the cases. The other causes include complications of chronic suppurative otitis media and thrombosis occurring in deep veins. Since the Internal Jugular Vein is involved the infection can also undergo hematogenous spread. The infection generally spreads to Spleen, Liver, Kidney, Heart and Brain. [3][4] Lemierre's syndrome can be diagnosed on the basis of clinical symptoms, multitude of blood series and Imaging. Since it is an infectious condition the treatment involves systemic antibiotic therapy and early administration of broad spectrum antibiotics in high dose become necessary for prevention of complications and systemic spread of infection. [3][4] We are presenting a case series of 5 cases over a period of six years from November 2015 to November 2021.

Novel options in diagnosis and treatment of endophthalmitis

AbstractEndophthalmitis remains the most vision‐threatening condition that in most severe cases can result in a loss of an eye and systemic spreading of the infection. It is defined as an acute inflammation of the inner tissues of the eyeball and is usually caused by intraocular contamination and colonization of infectious agents with exudation within intraocular space. The development of endophthalmitis as well as its clinical presentation and functional and anatomical outcomes is predefined by its type, kind of infection and therapy applied. There is a risk of progression of endophthalmitis to panophthalmitis, which could end up with evisceration or enucleation. The involvement of the general physician and other medical specialists into the treatment of the patients with endophthalmitis shall be always considered and should not be underestimated. As one of the most severe emergencies in ophthalmology, this condition requires urgent therapeutical or/and surgical intervention. Numerous studies compare the efficacy of the first line treatment for different types of endophthalmitis. Since decades the management of endophthalmitis is based on prompt recognition of infectious agents, immediate intraocular antimicrobial therapy and removal of the purulent exudate form the eye. Novel diagnostic options for endophthalmitis shall be considered in order to increase the precision of to treat patients with endophthalmitis. Improvement of the surgical techniques with the development of the new less traumatic instruments and he novel antimicrobial drugs can stablish a new standards of endophthalmitis care.

Primary cutaneous peripheral T-cell lymphomas with a T-follicular helper phenotype: an integrative clinical, pathological and molecular case series study.

Primary cutaneous peripheral T-cell lymphomas with a T-follicular helper phenotype (pcTFH-PTCL) are poorly characterized, and often compared to, but not corresponding with, mycosis fungoides (MF), Sézary syndrome, primary cutaneous CD4+ lymphoproliferative disorder, and skin manifestations of angioimmunoblastic T-cell lymphomas (AITL). We describe the clinicopathological features of pcTFH-PTCL in this original series of 23 patients, and also characterize these cases molecularly. Clinical and histopathological data of the selected patients were reviewed. Patient biopsy samples were also analysed by targeted next-generation sequencing. All patients (15 men, eight women; median age 66 years) presented with skin lesions, without systemic disease. Most were stage T3b, with nodular (n = 16), papular (n = 6) or plaque (atypical for MF, n = 1) lesions. Three (13%) developed systemic disease and died of lymphoma. Nine (39%) patients received more than one line of chemotherapy. Histologically, the lymphomas were CD4+ T-cell proliferations, usually dense and located in the deep dermis (n = 14, 61%), with the expression of at least two TFH markers (CD10, CXCL13, PD1, ICOS, BCL6), including three markers in 16 cases (70%). They were associated with a variable proportion of B cells. Eight patients were diagnosed with an associated B-cell lymphoproliferative disorder (LPD) on biopsy, including Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (n = 3), EBV+ LPD (n = 1) and monotypic plasma cell LPD (n = 4). Targeted sequencing showed four patients to have a mutated TET2-RHOAG17V association (as frequently seen in AITL) and another a TET2/DNMT3A/PLCG1/SETD2 mutational profile. The latter patient, one with a TET2-RHOA association, and one with no detected mutations, developed systemic disease and died. Five other patients showed isolated mutations in TET2 (n = 1), PLCG1 (n = 2), SETD2 (n = 1) or STAT5B (n = 1). Patients with pcTFH-PTCL have pathological and genetic features that overlap with those of systemic lymphoma of TFH derivation. Clinically, most remained confined to the skin, with only three patients showing systemic spread and death. Whether pcTFH-PTCL should be integrated as a new subgroup of TFH lymphomas in future classifications is still a matter of debate. What is already known about this topic? There is a group of cutaneous lymphomas that express T-follicular helper (TFH) markers that do not appear to correspond to existing World Health Organization diagnostic entities. These include mycosis fungoides, Sézary syndrome, or primary cutaneous CD4+ small/medium-sized T-cell lymphoproliferative disorder or cutaneous extensions of systemic peripheral T-cell lymphomas (PTCL) with TFH phenotype. What does this study add? This is the first large original series of patients with a diagnosis of primary cutaneous PTCL with a TFH phenotype (pcTFH-PTCL) to be molecularly characterized. pcTFH-PTCL may be a standalone group of cutaneous lymphomas with clinicopathological and molecular characteristics that overlap with those of systemic TFH lymphomas, such as angioimmunoblastic T-cell lymphoma, and does not belong to known diagnostic groups of cutaneous lymphoma. This has an impact on the treatment and follow-up of patients; the clinical behaviour needs to be better clarified in further studies to tailor patient management.

Substantial uneven proliferation of CD4+ T cells during recovery from acute HIV infection is sufficient to explain the observed expanded clones in the HIV reservoir

The HIV reservoir is a population of 1–10 million anatomically dispersed, latently infected memory CD4+ T cells in which HIV DNA is quiescently integrated into human chromosomal DNA. When antiretroviral therapy (ART) is stopped and HIV replication initiates in one of these cells, systemic viral spread resumes, rekindling progression to AIDS. Therefore, HIV latency prevents cure. The detection of many populations of identical HIV sequences at unique integration sites implicates CD4+ T cell proliferation as the critical driver of reservoir sustainment after a prolonged period of effective ART. Initial reservoir formation occurs during the first week of primary infection usually before ART is started. While empirical data indicates that both de novo infection and cellular proliferation generate latently infected cells during early untreated infection, it is not known which of these mechanisms is predominant. We developed a mathematical model that recapitulates the profound depletion and brisk recovery of CD4+ T cells, reservoir creation, and viral load trajectory during primary HIV infection. We extended the model to stochastically simulate individual HIV reservoir clones. This model predicts the first detection of HIV infected clones approximately 5 weeks after infection as has recently been shown in vivo and suggests that substantial, uneven proliferation among clones during the recovery from CD4+ lymphopenia is the most plausible explanation for the observed clonal reservoir distribution during the first year of infection.

Attempts to Reduce the Systemic Spread of Xylella fastidiosa in Olive Trees by Pruning

Xylella fastidiosa subsp. pauca (Xfp) is the plant pathogenic bacterium causing the epidemic of olive quick decline syndrome decimating olive trees in the Apulia region (southern Italy). The lack of any effective therapeutic application for the control of this pathogen and its categorization as a regulated quarantine pathogen in many countries worldwide, impose mandatory eradication and containment measures. Based on current EU legislation, containment measures apply in those areas where the bacterium is widely established, such as in the Apulia region, and thus containment strategies to mitigate and cope with the infections are needed. We set up a field trial to assess if pruning interventions could limit and/or recover Xfp-infected trees by reducing the systemic spread of the bacterium and the severity of the desiccation phenomena typically compromising the crown of the highly susceptible cultivars, e.g., cv. Cellina di Nardò. Trees subjected either to major or light pruning interventions, including the removal of all the symptomatic branches, did not demonstrate a reduced bacterial colonization or development of symptoms. After two years of targeted pruning interventions, no significant amelioration of the sanitary status of the infected olive trees was recorded, suggesting that the sole application of these interventions is not effective to counteract the impact of the bacterium in the susceptible olive trees.

Prothrombotic Transformation of the Endothelium Is Markedly Augmented By Cytokine Priming and Inhibited By Tie2 Activation

The endothelium is an intrinsically anticoagulant surface that upon viral or bacterial infection promotes thrombosis via the upregulation of pro-coagulatory mechanisms and loss of anticoagulant properties. The COVID-19 pandemic has underscored the association between respiratory infection and thrombosis by highlighting the importance of host cytokine responses in mediating systemic vasculopathy. Immune activation within the alveolar-capillary unit precedes systemic pathogen spread and induces marked increases in plasma cytokine levels prior to pathogen circulation. We therefore tested the hypothesis that cytokine exposure primes ECs toward a pro-coagulatory state that is subsequently activated by pathogen-associated molecular patterns (PAMPs). In initial studies, human ECs were exposed to cytokines elevated in the setting of pneumonia including TNFα, IFNα, IFNβ, IFNγ, IL-1β, IL-6, IL-10, and MCP for 24 hours prior to induction with poly(I:C), a viral PAMP mimetic and TLR3 agonist, and subsequently evaluated for thrombin generation in a plasma-based assay. Pre-incubation of ECs with several candidate cytokines enhanced responses to poly(I:C) by 10-20-fold. Focusing on the antiviral type-II interferon cytokine IFNγ, we found that its pre-incubation with ECs enhanced thrombin generation induced by poly(I:C) in a dose-dependent manner. IFNγ followed by poly(I:C) also enhanced factor VIIa-dependent factor Xa (FXa) generation, implicating upregulation of TF activity. SARS-CoV-2 nucleocapsid and spike proteins showed little prothrombotic effects in ECs by themselves. However, following incubation of ECs with IFNγ, both proteins stimulated FXa generation. These observations were not limited to viral PAMPs, as pre-incubation with IFNγ enhanced thrombin and FXa generation in response to lipopolysaccharide (LPS), a bacterial PAMP. Exposure of ECs to IFNγ also resulted in a reduction in total thrombomodulin, even prior to PAMP exposure. To better replicate the alveolar-capillary functional unit, we used an alveolus-on-chip model. The chip includes primary pulmonary microvascular ECs cultured under flow conditions in a vascular channel and small airway epithelial cells in an alveolus channel. The two channels are separated by a collagen matrix and the chip is subject to cyclic stretch to mimic breathing. Exposure of pneumocytes in the pulmonary channel to IFNγ and either poly(I:C) or LPS resulted in decreased production of thrombomodulin in the vascular channel, validating the monoculture results. One strategy for preventing the prothrombotic transformation of ECs is to stimulate cytoprotective endothelial pathways. Tie2 is a cytoprotective receptor found primarily on ECs. Incubation of ECs with the Tie2 ligand angiopoietin-1 (Angpt-1) significantly reversed the marked thrombin generation observed with IFNγ-priming followed by poly(I:C) exposure. Angpt-1 did not directly inhibit thrombin or FXa generation, as measured in standard thrombin time and aPTT assays. However, exposure to Angpt-1 did reverse depletion of protein C generation induced by poly(I:C) or LPS. Angpt-1 also reversed thrombomodulin reduction, providing an explanation for the ability of Angpt-1 to suppress cytokine/PAMP-induced prothrombotic changes on the ECs. To test the effect of Tie2 activation on thrombus formation in vivo, we used an LPS model since LPS was the most thrombotic of the PAMPs that we tested in mice. We used the small molecule [4-[(2S)-2-[[(2S)-2-(methoxycarbonylamino)-3-phenylpropanoyl]amino]-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid to promote Tie2 activation. Infusion of this Tie2 activating compound reduced LPS-induced accumulation of fibrin in both lung and liver. Taken together, these studies show that cytokines prime ECs for prothrombotic changes in response to PAMP exposure. Decreased thrombomodulin expression upon cytokine priming with resultant reduction in activated protein C production is essential to these prothrombotic changes. Tie2 activation inhibits the prothrombotic transformation and represents a potential strategy for reversing thrombosis associated with respiratory infection.

Aggregation of Enveloped Viruses By Platelet Factor 4 (PF4) and Neutrophil Extracellular Traps (NETs): Implications for the Anti-Viral Properties of NETs

As part of the innate immune response, neutrophils release neutrophil extracellular traps (NETs), webs of DNA coated with histones that ensnare and kill bacteria. A growing body of literature suggests that NETs can also capture and inactivate enveloped viruses. The ability of NETs to limit the systemic spread of pathogens occurs at the expense of collateral organ damage induced when high concentrations of NETs are digested by DNases to release toxic NET degradation products (NDPs) including cell free DNA and histones. Our group has shown that the positively charged platelet-specific chemokine (PF4, CXCL4), compacts NETs by forming tetramers that electrostatically cross-bind two polyanionic fragments of DNA, similarly to the way it aggregates heparans. PF4 complexed to NETs induces NET resistance to nuclease digestion, preventing the release of toxic NDPs while enhancing NET-bacterial capture by bridging anionic DNA to the negatively charged microbial surface. PF4 has also been shown limit pulmonary injury and enhance survival in mice infected with PR8, a mouse-adapted H1N1 influenza virus. Our group and others have found that both PF4 and NETs are elevated in the setting of SARS-CoV-2, leading us to hypothesize that they may act synergistically to combat the proliferation of enveloped viruses. To investigate the effect of PF4 on the pathogenicity of enveloped viruses, we studied PR8 and murine hepatitis virus (MHV)-1, a betacoronavirus that induces severe pulmonary disease. Dynamic light scattering (DLS) and scanning electron microscopy (SEM) were used to assess the ability of PF4 and human-derived NETs to aggregate MHV-1 and PR8 virions. ChAdOx1, a replication-deficient adenovirus was used as a non-enveloped viral control. The DLS and SEM studies showed that PF4 (5-20 µg/ml) aggregated MHV-1 and PR8, forming complexes with an average diameter of 500nm, the width of 4-5 virions (Figure 1). In contrast, PF4 did not aggregate non-enveloped adenovirus. DLS studies showed that PF4 does not form complexes with coronavirus spike protein. However, the anti-PF4-polyanion antibody KKO, bound to PF4-viral complexes, leading to an additional 50% increase in viral aggregate size, an effect not seen with an isotype control antibody TRA (Figure A). These results suggest that PF4 binds to polyanions on the viral envelop via electrostatic interaction, much in the same way that it binds to heparans and DNA. We preformed subsequent DLS studies in which MHV-1 virions were incubated with both intact and digested NETs, and viral-NET aggregation was only observed in the presence of PF4. To determine if PF4 aggregates virus in vivo, IHC studies were performed on lungs harvested from MHV-1-infected A/J mice inoculated intranasally with 5 x 103 PFU of virus and sacrificed at 48h. The lungs were prepared for immunohistochemistry (IHC), and labeled with antibodies directed against PF4 and the MHV-1 nucleocapsid protein. We calculated the average Pearson's coefficient in 4 randomly selected 20x confocal images of the lungs of MHV-1 infected animals (n=4 mice, 16 images analyzed) using the FIJI JaCoP colocalization plugin. We observed co-localization of PF4 and MHV-1 within the cytoplasm of a subset of cells (r= 0.70225, p<0.0001), suggesting that PF4-MHV-1 aggregation occurs in vivo (Figure B) Lastly, the plaque forming unit assay was used to measure the effect of PF4 on MHV-1 infectivity of L2 cells. We found that incubating MHV-1 with PF4 (0-100µg/ml), leads to a 50% decrease in infectivity(n=5, p=0.023). Our studies demonstrate that PF4 binds to and aggregates MHV-1 and PR8 in vitro likely through electrostatic interactions with the viral envelop rather than adhesion to the viral spike protein. These results also suggest that PF4-mediated aggregation enhances viral capture by NETs to form NETs:PF4:viral complexes that may limit viral spread. IHC studies of lungs from MHV-1 infected mice demonstrate that PF4 colocalizes with the virus, suggesting that aggregation also occurs in vivo. In ongoing studies, we are investigating whether PF4 and NETs act synergistically to reduce coronavirus and influenza infectivity and enhance immune recognition and subsequent clearance of viral aggregates. These findings will help to define the anti-viral properties of NETs and may generate insights relevant to the treatment of coronavirus, influenza, and other enveloped viruses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract C016: New treatment modality for pancreatic cancer-Vascular Targeted Photodynamic therapy with WST11 (Padeliporfin) combined with endovascular light delivery

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies. Early detection and surgical removal of PDAC, when the cancer is localized with no clinical evidence for systemic spread, may be curative but tumor spread into the vicinity of major blood vessels, e.g. superior mesenteric artery (SMA), can be lethal and therefore avoid surgery. Here we show that Vascular Targeted Photodynamic therapy (VTP) with WST11 in combination with immune modulating chemotherapeutic agents allows PDAC tumors ablation while preserving large normal vessels and tissues in animal models. New endovascular illumination system recently developed by our group (1) provides the light needed for such ablation with no damage to the SMA and complete remodeling of the surrounding normal tissue. Methods: Two orthotopic models of pancreatic cancer (KPC-Luc-mcherry and non-labeled KPC tumors (NL-KPC)) in C57B mice were subjected to VTP, alongside intraperitoneal gemzar (GEM) or cyclophosphamide (CTX) treatment. multiplex immunohistochemistry (mIHC) and single analyses using 10X Genomics platform of tumor were performed for resolving the key factors in the therapeutic process. Results: Comparing the KPC-Luc-mcherry with the NL-KPC tumor, we found that non labeled KPC has the typical morphology of human PDAC, immunologically cold and is highly aggressive compared with KPC-Luc-mcherry. WST11-VTP results in high cure rate (~50%) of animals bearing small KPC-Luc-mcherry tumors, larger tumors required combinations with metronomic administration of GEM. High rate of complete necrosis (95-100%) was achieved also with the non-labled PDAC tumors but prolonged disease- free survival required combination with CTX. The mechanism of action for both tumor models involves co-generation of oxygen and NO radicals through local photoexcitation of WST11, followed by iNOS consumption and vascular break down. Infiltration of immune cells alarmed by HMGB1 and other DAMPs leads to annihilation of residual cancer cells and prolonged anticancer immunity. The administration of CTX amplifies and prolonged the VTP oxidative stress. Conclusion: WST11-VTP combination with immune modulating chemotherapeutic agents administrations, activated by endovascular illumination through the SMA, may provide solution to the unmet need of early stage diagnosed PDAC patients. (1) Franz E. Boas et al, “Downstaging Locally Advanced Pancreatic Cancer To Resectability: Perivascular Ablation Using An Intra-arterial Balloon Laser Catheter In Pigs”, Abstract Archives of the RSNA, RSNA 2021,SDR-IR-13- “Redefining radiology” 11/29-12/4, 2021 Citation Format: Lilach Agemy, Keren Sasson, Tamar Yechezkel, Dina Priese, Yaniv Cohen, Zachary Zacks, Gil Stelzer, David P. Kelsen, Hooman Yarmohammadi, Alice C. Wei, Stephen B. Solomon, Avidgor Scherz. New treatment modality for pancreatic cancer-Vascular Targeted Photodynamic therapy with WST11 (Padeliporfin) combined with endovascular light delivery [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C016.

Hydraulic failure as a primary driver of xylem network evolution in early vascular plants

The earliest vascular plants had stems with a central cylindrical strand of water-conducting xylem, which rapidly diversified into more complex shapes. This diversification is understood to coincide with increases in plant body size and branching; however, no selection pressure favoring xylem strand-shape complexity is known. We show that incremental changes in xylem network organization that diverge from the cylindrical ancestral form lead to progressively greater drought resistance by reducing the risk of hydraulic failure. As xylem strand complexity increases, independent pathways for embolism spread become fewer and increasingly concentrated in more centrally located conduits, thus limiting the systemic spread of embolism during drought. Selection by drought may thus explain observed trajectories of xylem strand evolution in the fossil record and the diversity of extant forms.

IoT-based air pollution monitoring system

Air pollution seriously damages the ecological environment and affects the health of humans, animals and plants. In order to prevent and control air pollution, air quality monitoring has been proposed to accurately monitor the concentration of pollutants and abnormal conditions in a region, which can purify the air. However, conventional fixed monitoring stations are complex, expensive and power hungry, these characteristics lead to monitoring stations being unsuitable for most areas. Here an internet of things (IoT)-based air pollution monitoring system is reported including architecture, principles and monitoring objects, providing detailed information for effective environmental management. It manages the current status and trends of regional air pollution in a simple, portable and cost-effective way. The technologies and applications involved in IoT-based air pollution monitoring systems are also presented, contributing to the development of IoT technologies, cloud computing technologies and smart city. The rapid spread of such monitoring systems would add greenhouse gases, photochemical smog and light detection and ranging (LIDAR) gases to the group of objects to be monitored in the future.

Extranodal Marginal Zone Lymphoma of the Thyroid with Extensive Amyloid Deposition: A Rare Case Presentation

Abstract Introduction/Objective Extranodal marginal zone lymphoma (MZL) is a rare indolent tumor with the potential of recurrence and systemic spread. Thyroid involvement is infrequently reported, and generally seen in the context of Hashimoto thyroiditis. Additionally, amyloid deposition is an exceptional complication of extranodal MZL. We report an unusual case of a 65-year-old woman with a rapidly growing symptomatic nodule of the right thyroid lobe and a previous inconclusive FNA showing benign lymphoid tissue. She was taken to the OR for diagnostic right thyroid lobectomy with neck level 6 dissection. Methods/Case Report The specimen was sent for histologic evaluation, and showed thyroid with marked amyloid deposition, highlighted by Congo Red special stain, distorting normal architecture. Additionally, significant small atypical lymphoid infiltrate was present. Neoplastic lymphocytes were positive for CD20, PAX5 and CD43. Kappa light chain restriction by kappa ISH stain indicated monoclonality. Conversely, CD138, CD10, BCL6 and CyclinD were negative. Ki-67 demonstrated a 15-20% proliferation index. The germinal centers of the secondary follicles demonstrated diminished CD10 and BCL-6 consistent with follicular colonization by neoplastic lymphocytes. One of the regional lymph nodes displayed involvement by lymphoma with amyloid deposition. Medullary carcinoma of the thyroid was ruled out on the basis of incompatible histologic and immunohistochemical profile. Results (if a Case Study enter NA) NA Conclusion While Medullary carcinoma and amyloid goiter are among the top differentials for extensive amyloid deposition in the thyroid gland, we illustrate the need for judicious review of clinical history and careful consideration of immunohistochemistry workup to establish the unusual diagnosis of extranodal MZL of the thyroid with extensive amyloid deposition.

PAD4 and Its Inhibitors in Cancer Progression and Prognosis.

The systemic spread of malignancies and the risk of cancer-associated thrombosis are major clinical challenges in cancer therapy worldwide. As an important post-translational modification enzyme, peptidyl arginine deiminase 4 (PAD4) could mediate the citrullination of protein in different components (including nucleus and cytoplasm, etc.) of a variety of cells (tumor cells, neutrophils, macrophages, etc.), thus participating in gene regulation, neutrophil extracellular trap (NET) and macrophage extracellular trap (MET). Thereby, PAD4 plays an important role in enhancing the growth of primary tumors and facilitating the distant metastasis of cancer cells. In addition, it is related to the formation of cancer-associated thrombosis. Therefore, the development of PAD4-specific inhibitors may be a promising strategy for treating cancer, and it may improve patient prognosis. In this review, we describe PAD4 involvement in gene regulation, protein citrullination, and NET formation. We also discuss its potential role in cancer and cancer-associated thrombosis, and we summarize the development and application of PAD4 inhibitors.

Network structure indexes to forecast epidemic spreading in real-world complex networks

Complex networks are the preferential framework to model spreading dynamics in several real-world complex systems. Complex networks can describe the contacts between infectious individuals, responsible for disease spreading in real-world systems. Understanding how the network structure affects an epidemic outbreak is therefore of great importance to evaluate the vulnerability of a network and optimize disease control. Here we argue that the best network structure indexes (NSIs) to predict the disease spreading extent in real-world networks are based on the notion of network node distance rather than on network connectivity as commonly believed. We numerically simulated, via a type-SIR model, epidemic outbreaks spreading on 50 real-world networks. We then tested which NSIs, among 40, could a priori better predict the disease fate. We found that the “average normalized node closeness” and the “average node distance” are the best predictors of the initial spreading pace, whereas indexes of “topological complexity” of the network, are the best predictors of both the value of the epidemic peak and the final extent of the spreading. Furthermore, most of the commonly used NSIs are not reliable predictors of the disease spreading extent in real-world networks.

Interferon partly dictates a divergent transcriptional response in poxvirus-infected and bystander inflammatory monocytes.

Inflammatory monocytes (iMOs) and B cells are the main targets of the poxvirus ectromelia virus (ECTV) in the lymph nodes of mice and play distinct roles in surviving the infection. Infected and bystander iMOs control ECTV's systemic spread, preventing early death, while B cells make antibodies that eliminate ECTV. Our work demonstrates that within an infected animal that survives ECTV infection, intrinsic and bystander infection of iMOs and B cells differentially control the transcription of genes important for immune cell function and, perhaps, cell identity. Bystander cells upregulate metabolism, antigen presentation, and interferon-stimulated genes. Infected cells downregulate many cell-type-specific genes and upregulate transcripts typical of non-immune cells. Bystander (Bys) and infected (Inf) iMOs non-redundantly contribute to the cytokine milieu and the interferon response. Furthermore, we uncover how type I interferon (IFN-I) or IFN-γ signaling differentially regulates immune pathways in Inf and Bys iMOs and that, at steady state, IFN-I primes iMOs for rapid IFN-I production and antigen presentation.

Correlation between CRISPR Loci Diversity in Three Enterobacterial Taxa.

CRISPR-Cas is an adaptive immunity system of prokaryotes, composed of CRISPR arrays and the associated proteins. The successive addition of spacer sequences in the CRISPR array has made the system a valuable molecular marker, with multiple applications. Due to the high degree of polymorphism of the CRISPR loci, their comparison in bacteria from various sources may provide insights into the evolution and spread of the CRISPR-Cas systems. The aim of this study was to establish a correlation between the enterobacterial CRISPR loci, the sequence of direct repeats (DR), and the number of spacer units, along with the geographical origin and collection source. For this purpose, 3474 genomes containing CRISPR loci from the CRISPRCasdb of Salmonella enterica, Escherichia coli, and Klebsiella pneumoniae were analyzed, and the information regarding the isolates was recorded from the NCBI database. The most prevalent was the I-E CRISPR-Cas system in all three studied taxa. E. coli also presents the I-F type, but in a much lesser percentage. The systems found in K. pneumoniae can be classified into I-E and I-E*. The I-E and I-F systems have two CRISPR loci, while I-E* has only one locus upstream of the Cas cluster. PCR primers have been developed in this study for each CRISPR locus. Distinct clustering was not evident, but statistically significant relationships occurred between the different CRISPR loci and the number of spacer units. For each of the queried taxa, the number of spacers was significantly different (p < 0.01) by origin (Africa, Asia, Australia and Oceania, Europe, North America, and South America) but was not linked to the isolation source type (human, animal, plant, food, or laboratory strains).

Not Policies. People

Not Policies. People

Novel saliva biomarkers for stress and infection in pigs: Changes in oxytocin and procalcitonin in pigs with tail-biting lesions

There is a need for feasible and reliable measures to improve and evaluate production animal health and welfare. Oxytocin is a promising novel stress-related biomarker and procalcitonin may be a measure of sepsis. Both have potential for use in pigs and can be measured from saliva, which allows on-farm sampling with minimal impact on the animals. The current study sought to further validate these measures using a spontaneous situation that causes both stress and an increased risk for infections in pigs, namely a tail-biting outbreak. Grower pigs on a commercial farm belonging to three different phenotype groups were selected: control pigs from control pens (CC, N = 30), control pigs (CTB, N = 10), and pigs with tail lesions from pens with a tail-biting outbreak (LTB, N = 27). A single sample of saliva was collected from each pig and analysed for a range of biomarkers related to stress, infection, inflammation, and immune activation. Oxytocin tended to be higher in CC pigs than in LTB pigs, while cortisol was higher in CTB than CC pigs. Procalcitonin tended to be higher, and haptoglobin was higher in LTB than in CC pigs. Adenosine-deaminase levels were similar between phenotypes. These results provide further evidence for the link between stress and tail biting, and indicate that tail-biting lesions are potential routes for systemic spread of bacteria. Further research into saliva oxytocin as a stress biomarker and saliva procalcitonin as a sepsis biomarker in pigs is warranted.

Intact Type I Interferon Receptor Signaling Prevents Hepatocellular Necrosis but Not Encephalitis in a Dose-Dependent Manner in Rift Valley Fever Virus Infected Mice.

Rift Valley fever (RVF) is a zoonotic and emerging disease, caused by the RVF virus (RVFV). In ruminants, it leads to “abortion storms” and enhanced mortality rates in young animals, whereas in humans it can cause symptoms like severe hemorrhagic fever or encephalitis. The role of the innate and adaptive immune response in disease initiation and progression is still poorly defined. The present study used the attenuated RVFV strain clone 13 to investigate viral spread, tissue tropism, and histopathological lesions after intranasal infection in C57BL/6 wild type (WT) and type I interferon (IFN-I) receptor I knockout (IFNAR−/−) mice. In WT mice, 104 PFU RVFV (high dose) resulted in a fatal encephalitis, but no hepatitis 7–11 days post infection (dpi), whereas 103 PFU RVFV (low dose) did not cause clinical disease or significant histopathological lesions in liver and the central nervous system (CNS). In contrast, IFNAR−/− mice infected with 103 PFU RVFV developed hepatocellular necrosis resulting in death at 2–5 dpi and lacked encephalitis. These results show that IFNAR signaling prevents systemic spread of the attenuated RVFV strain clone 13, but not the dissemination to the CNS and subsequent fatal disease. Consequently, neurotropic viruses may be able to evade antiviral IFN-I signaling pathways by using the transneuronal instead of the hematogenous route.

Oncological outcome after lateral pelvic lymphadenectomy for low rectal carcinoma: not only an N-status matter.

Tumour deposits (TDs), novel pathological entities, should be considered when estimating the regional and systemic spread of rectal carcinoma and formulating treatment strategies. In fact, TDs may have more severe prognostic impact than lymph node positivity or the lymph node ratio. The assessment of the presence of TDs can be performed only through accurate postoperative pathological examination; however, the detection of TDs is not part of any of the procedures currently used to assess preoperative or intraoperative staging. This review aims to analyse and discuss the impact of TDs on the oncological outcome of patients who undergo surgery for advanced low rectal carcinoma. No prospective study has evaluated the impact of lateral pelvic TDs on oncological outcomes following total mesorectal excision with lateral pelvic lymphadenectomy. Although adequate total mesorectal excision allows for the excision of intramesorectal TDs, lateral pelvic lymph node dissection cannot guarantee the removal of lateral pelvic TDs; moreover, it remains to be determined whether surgical excision of lateral pelvic TDs can impact long-term outcomes. However, the identification of lateral pelvic TDs strengthens the 'staging effect' and limits the 'therapeutic effect' of lateral pelvic lymphadenectomy, supporting the rationale for the use of neoadjuvant chemoradiotherapy for rectal cancer. When evaluating the oncological outcomes after total mesorectal excision with lateral pelvic lymphadenectomy, the impact of lateral pelvic TDs should be considered.