Site Of Invasion Research Articles

Artemisinin inhibits neutrophil and macrophage chemotaxis, cytokine production and NET release

Immune cell chemotaxis to the sites of pathogen invasion is critical for fighting infection, but in life-threatening conditions such as sepsis and Covid-19, excess activation of the innate immune system is thought to cause a damaging invasion of immune cells into tissues and a consequent excessive release of cytokines, chemokines and neutrophil extracellular traps (NETs). In these circumstances, tempering excessive activation of the innate immune system may, paradoxically, promote recovery. Here we identify the antimalarial compound artemisinin as a potent and selective inhibitor of neutrophil and macrophage chemotaxis induced by a range of chemotactic agents. Artemisinin released calcium from intracellular stores in a similar way to thapsigargin, a known inhibitor of the Sarco/Endoplasmic Reticulum Calcium ATPase pump (SERCA), but unlike thapsigargin, artemisinin blocks only the SERCA3 isoform. Inhibition of SERCA3 by artemisinin was irreversible and was inhibited by iron chelation, suggesting iron-catalysed alkylation of a specific cysteine residue in SERCA3 as the mechanism by which artemisinin inhibits neutrophil motility. In murine infection models, artemisinin potently suppressed neutrophil invasion into both peritoneum and lung in vivo and inhibited the release of cytokines/chemokines and NETs. This work suggests that artemisinin may have value as a therapy in conditions such as sepsis and Covid-19 in which over-activation of the innate immune system causes tissue injury that can lead to death.

Roles of Arbuscular mycorrhizal Fungi as a Biocontrol Agent in the Control of Plant Diseases.

Arbuscularmycorrhizal fungi (AMF) are a class of beneficial microorganisms that are widely distributed in soil ecosystems and can form symbionts with 80% of terrestrial higher plants, and improve the nutritional status of plants. The use of AMF as a biocontrol method to antagonize soil-borne pathogens has received increasing interest from phytopathologists and ecologists. In this paper, the mechanisms of resistance to diseases induced by AMF and the application of AMF to plant fungal, bacterial, and nematode diseases have been summarized. This study aimed to enhance the potential use of AMF as a biological control method to prevent plant diseases in the future. Root morphological alteration characteristics were explained, including the influence of AMF on root structure, function, and the regulation of AMF via secondary metabolites. AMF can improve the rhizosphere environment by influencing the physical and chemical proprieties of soil, enhancing the growth of other beneficial microorganisms, and by competing with pathogenic microorganisms. Two microorganism types may compete for the same invasive sites in root systems and regulate nutrition distribution. AMF can induce the host plant to form defense systems, including improving phytohormone concentrations, inducing signal substrate production, gene expression regulation, and enhancing protein production.

Abstract 5793: Comprehensive characterization of FGF/FGFR alterations in invasive breast cancers

Abstract BACKGROUND FGFR signaling is central for cancer cell proliferation, migration, angiogenesis, and survival. The frequency and type of FGF/FGFR aberrations are not well-characterized across invasive breast cancer subtypes and metastatic sites of disease. In hormone receptor positive breast cancers, FGFR1 amplification correlates with early progression on endocrine therapy and promotes resistance to CDK4/6 inhibition. Our study evaluated the incidence and characterization of FGF alterations in invasive breast cancers and examined differences based on histologic subtype, molecular subtype and site. METHODS Breast cancer samples underwent molecular profiling by Caris Life Sciences. Analyses included NGS of DNA (592 Gene Panel, NextSeq, and WES, NovaSEQ), and IHC (Caris Life Sciences, Phoenix, AZ). Biomarker results were compiled from cases within the breast cohort including data from any sequencing panel, gene expression/RNA seq panel, and IHC. All results listed below were statistically significant (p < 0.05) as determined by chi-square test and Benjamini Hochberg correction. RESULTS 12058 breast cancer tumors were analyzed: 4189 from primary breast specimens (35%) and 7869 from metastatic sites (65%). 4305 (36%) were ductal and 671 (6%) were lobular histology with remaining other/unknown. 6413 (53%) were HR+HER2-, 3504 (29%) were triple negative, 403 (3%) were HR+HER2+ and 363 (3%) were HR-HER2+ with 1375 (13%) of unknown subtype. In the entire cohort, the most commonly amplified genes were FGF19 (11.49%), FGF3 (10.75%), FGF4 (9.98%), CCND1 (12.36%), and FGFR1 (9.08%). FGFR1-4 amplification was present in 11.01% of all cases. FGF19 amplification was more prevalent in lobular breast cancer compared to ductal (12.1% vs 9.1%). FGF19, FGF23, FGF3, FGF4, FGF6 amplification varied across molecular subtypes being most prevalent in HR+/HER2- (15.7%), HR+/HER2+ (12.1%), and least prevalent in HR-/HER+ tumors (3.4%). FGFR1 amplification was most common among FGFR1-4 amplifications and most prevalent in HR+HER2- (12%). Across metastatic sites, FGF ligands displayed different patterns of amplification with FGF19, FGF3 and FGF4 amplification most prevalent in liver and bone metastases. FGFR1 amplification was statistically different across metastatic sites and most prevalent in liver metastases (16%) followed by bone (10%). Patients receiving CDK4/6 inhibitors with FGFR1 amplification had shorter time on treatment than FGFR1 wild type (HR = 0.892, p = 0.03). CONCLUSION FGF alterations in invasive breast cancers vary by molecular subtype and site of disease. FGFR1, FGF19, FGF23, FGF3, FGF4, and FGF6 amplifications were statistically different across subtypes (most prevalent in HR+/HER2- and HR+/HER2+) and metastatic sites (most prevalent in liver and bone metastases). The prevalence in HR+ subtypes lend support to the role of FGF in endocrine resistance. Citation Format: Kush C. Gaur, Justin Tiu-Lim, Julie McGrath, Phil Walker, Michael Korn, Joanne Xiu, Arielle Heeke, Virginia Kaklamani, Antoinette Tan, Janice Lu, Darcy Spicer, Evanthia Roussos-Torres, Priya Jayachandran, Audrey Saghian, Amir Goldkorn, Irene Kang. Comprehensive characterization of FGF/FGFR alterations in invasive breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5793.

Human Disseminated Protothecosis: The Skin is the "Window"?

Human disseminated protothecosis is a rare infection caused by members of the genus Prototheca, an achlorophyllic algae always associated with debilitated hosts. The presence of non-budding cells and large, spherical cells (sporangia) with endosporulation (morula) in histology is proof of Prototheca infection. Regrettably, due to the lack of specificity of clinical features and low awareness among clinicians, protothecosis is always underestimated and misdiagnosed. The available data on a species-specific analysis of this infection are limited. In this review, we summarize the etiological, epidemiological, and clinical aspects of disseminated protothecosis. The potential pathogenicity and clinical differences between P. zopfii and P. wickerhamii were observed. Additionally, the skin not only became the main invasion site but also the most involved organ by the pathogen. With the increasing numbers of immunocompromised individuals throughout the world, the incidence of disseminated infection caused by Prototheca is bound to increase, and disseminated protothecosis that accompanies skin symptoms should be taken into account by clinicians.

Innate Immune Responses and P. falciparum CS Repeat-Specific Neutralizing Antibodies Following Vaccination by Skin Scarification.

The skin is the site of host invasion by the mosquito-borne Plasmodium parasite, which caused an estimated 229 million infections and 409,000 deaths in 2019 according to WHO World Malaria report 2020. In our previous studies, we have shown that skin scarification (SS) with a P. falciparum circumsporozoite (CS) peptide in the oil-in-water adjuvant AddaVax containing a combination of TLR 7/8 and TLR 9 agonists can elicit sporozoite neutralizing antibodies. SS with AddaVax + TLR agonists, but not AddaVax alone, elicited CD4+ Th1 cells and IgG2a/c anti-repeat antibody. To explore the innate immune responses that may contribute to development of adaptive immunity following SS, we examined the skin at 4h and 24h post priming with CS peptide in AddaVax with or without TLR agonists. H&E stained and IHC-labeled dorsal skin sections obtained 24h post SS demonstrated a marked difference in the pattern of infiltration with F4/80+, CD11b+ and Ly6G+ cells at the immunization site, with the lowest intensity noted following SS with AddaVax + TLR agonists. Serum collected at 4h post SS, had reproducible increases in IL-6, MIP-3α, IL-22 and IP-10 (CXCL10) following SS with AddaVax + TLR agonists, but not with AddaVax alone. To begin to decipher the complex roles of these pro-inflammatory cytokines/chemokines, we utilized IP-10 deficient (IP-10 -/-) mice to examine the role of this chemokine in the development of anti-repeat antibody response following SS. In the absence of IP-10, the levels of Th1-type IgG2a/c antibody and kinetics of the primary anti-repeat antibody response were reduced following prime and boost. The IP-10 chemokine, present as early as 4h post prime, may provide an early serological marker for rapid screening of adjuvant formulations and delivery platforms to optimize SS-induced humoral immunity to CS repeats as well as other pathogens.

Progesterone Signaling in Endometrial Epithelial Organoids.

For pregnancy to be established, uterine cells respond to the ovarian hormones, estrogen, and progesterone, via their nuclear receptors, the estrogen receptor (ESR1) and progesterone receptor (PGR). ESR1 and PGR regulate genes by binding chromatin at genes and at distal enhancer regions, which interact via dynamic 3-dimensional chromatin structures. Endometrial epithelial cells are the initial site of embryo attachment and invasion, and thus understanding the processes that yield their receptive state is important. Here, we cultured and treated organoids derived from human epithelial cells, isolated from endometrial biopsies, with estrogen and progesterone and evaluated their transcriptional profiles, their PGR cistrome, and their chromatin conformation. Progesterone attenuated estrogen-dependent gene responses but otherwise minimally impacted the organoid transcriptome. PGR ChIPseq peaks were co-localized with previously described organoid ESR1 peaks, and most PGR and ESR1 peaks were in B (inactive) compartment regions of chromatin. Significantly more ESR1 peaks were assigned to estrogen-regulated genes by considering chromatin loops identified using HiC than were identified using ESR1 peak location relative to closest genes. Overall, the organoids model allowed a definition of the chromatin regulatory components governing hormone responsiveness.

Coconut Rhinoceros Beetle in Samoa: Review of a Century-Old Invasion and Prospects for Control in a Changing Future.

Simple SummaryCoconut rhinoceros beetle (CRB) is one of the major pests of coconut and oil palms in the Asia-Pacific region. Since its accidental introduction in Samoa in 1909, the invasive CRB has spread to several countries and territories within the Pacific and Indian Oceans, severely damaging coconut palms and affecting peoples’ livelihoods. In the 100 years since CRB established on Samoa, it remains the primary pest on the island with periods of heavy damage when integrated pest management (IPM) breaks down. The Samoan case is an excellent example of implementing biocontrol and IPM in a dynamic Pacific environment. As society and the economics of production in Samoa have changed, the level of control has varied, with recent concern about surges of the pest. The review synthesizes historical lessons and provide recommendations on how to protect coconut palms in the changing environment of Samoa which are also applicable for protection of palms in the wider Asia/Pacific region.It is now more than 100 years since the coconut rhinoceros beetle (CRB: Oryctes rhinoceros L.) was first detected in the Pacific Island state of Samoa. The exotic pest from Asia became the principal pest of coconut palms in Samoa and, from this first point of invasion, spread to several surrounding countries in the South-West Pacific Ocean. An intensive control operation was initiated, but the beetle could not be eliminated. Various pest management strategies were attempted but had limited success until the introduction of a biological control agent (BCA), Oryctes rhinoceros nudivirus (OrNV), during the late 1960s and early 1970s. The biocontrol release was very successful and became the prime example of “classical biological control” of an insect pest by a virus. Changing economic and social conditions in Samoa and other islands of the Pacific require a re-evaluation of the threat of CRB to coconut production to suggest how the IPM system may be modified to meet future needs. Therefore, it is timely to review the history of CRB in Samoa and summarize experiences in development of an integrated pest management (IPM) system limiting the impact of the pest. We also present results from a recent study conducted in 2020 on the island of Upolu to define the current status of the CRB population and its BCA, OrNV. The lessons from Samoa, with its long history of containment and management of CRB, are applicable to more recent invasion sites. Recommendations are provided to modify the IPM programme to enhance the sustainable control of CRB and support the ongoing coconut replantation program promoted by the Samoan government.

Epidemiological, pathological and statistical analysis of penis cancer in Espírito Santo - analysis of 79 cases / Análise epidemiológica, patológica e estatística do cancro do pénis no Espírito Santo - análise de 79 casos

Purpose: To determine the epidemiological and pathological characteristics of penile cancer (PeCa) and to verify the independence between two statistical variables of patients with PeCa treated at the Urology Service of the Cassiano Antônio de Moraes University Hospital (HUCAM), Vitória, ES, Brazil .Patients and Methods: Between 2010 and 2020, 79 patients with histologically confirmed PeCa were evaluated in our institution considering age, birthplace, ethnicity, marital status, practice of circumcision, histological type, growth pattern, site of tumor, tumor size, grade tumor, Chaux index, vascular invasion, lymphatic invasion, perineural invasion and pathologic stage (TNM staging). For the statistical treatment of square-data with p-value by Monte Carlo statistical calculations, in order to verify the independence between two variables, being the following: Degree of Pathological - TNM, Chaux Index, Lymphatic Invasion, Vascular Invasion and Perineural Invasion, with the patient's race and age group.Results: The ages ranged from 25 to 87 years, with an average of 62 years. Of the 79 patients, 36 (45,56%) were from the metropolitan region, 07 (8,86%) were from the north, 14 (17,72%) were from the northwest and 22 (27,86%) from the south of the Espírito Santo state. Most patients were brown 45 (56,96%), married 51 (64,55%) and had not completed primary school 59 (74,68%). Of the 79 patients, only 4 (6,32%) circumcised. Grade I tumors were present in 35 (44,30%) of the patients, grade II in 32 (40,50%) and grade III in 10 (12,65%). Vascular invasion was observed in 13 (16,45%) and lymphatic in 7 (8,86%) patients. Regarding Chaux Index, 16 patients (20,25%) had Index 2, 19 (24,05%) had Index 3, 13 (16,45%) had Index 4, 19 (24,05%) had Index 5, 9 (11,39%) had Index 6, 1 (1,26%) had Index 7 and 2 (2,53%) were not evaluated. Of the total, 20 (25,31%) had corpora cavernosa and 24 (30,37%) corpus spongiosum infiltration. According to the statistical analysis, there is evidence to reject the null hypothesis, that is, vascular invasion is related to the patient's age group, as p-value = 0.00449 p-value =0.05.Conclusion: Considering that the majority of penile cancer cases in the state of Espírito Santos are treated at the Department of urology of HUCAM, it can be concluded hat all patients in the study were residents of the state of Espírito Santo and had a low socioeconomic status. Most were brown hemones, married with low schooling and an average age of 62 years. The majority of cases have already been diagnosed with advanced disease. And after performing the chi-square tests and calculating the p value, we were able to conclude with statistical significance (p0.05) the relationship between age group and vascular invasion, which may justify a worse prognosis the more the age group.

Characteristics of the white matter involvement sites on MRI in patients with multiple gliomas

The retrospective study included 122 cases of multiple glioma and 183 cases of single glioma. Of these, there were 74 males and 48 female with multiple gliomas, aged 18 to 83 (53±13) years, and 104 males and 79 females with single gliomas, aged 10 to 84 (51±14) years. A standard spatial-based lesion analysis method was used for constructing a spatially distributed frequency heatmap of multiple gliomas, to observe the characteristics of their white matter invasion sites. The spatial distribution was more frequent in the subventricular zone, corpus callosum and cingulate gyrus in the multiple glioma group compared to the single glioma group (P<0.001).The white matter areas of multiple gliomas were more extensively involved, with more frequent involvement of the conjoined fibers (corpus callosum, P<0.05) and contact fibers (cingulate, dome, 0.05<P<0.10) areas.The spatial distribution of the brain and the white matter invasion of multiple gliomas have certain site specificity.

Transsphenoidal Surgery of Giant Pituitary Adenoma: Results and Experience of 239 Cases in A Single Center.

BackgroundTranssphenoidal surgery (TSS) is first-line treatment for giant pituitary adenomas (PAs). Although PA is a benign neuroendocrine tumor that originates from adenohypophysial cells, the surgical outcomes and prognosis of giant PAs differ significantly due to multiple factors such as tumor morphology, invasion site, pathological characteristics and so on. The aim of this study was to evaluate surgical outcomes of giant PAs in a single-center cohort.MethodsThe clinical features and outcomes of 239 patients with giant PA who underwent sphenoidal surgery at the Second Affiliated Hospital of Zhejiang University School of Medicine from January 2015 to October 2021 were collected from medical records. The basic clinical information (age, gender, function etc.), surgical procedure, imaging features (maximum diameter, invasion characteristics, tumor shape etc.) and histopathological characteristics (pathological results, Ki-67, P53 etc.) were retrospectively reviewed. SPSS 25.0 and Stata 12.0 software were used for statistical analysis.ResultsA total of 239 patients with giant PAs underwent TSS, of which 168 surgeries (70.29%) were endoscopic endonasal transsphenoidal (EETS) and 71 (29.71%) were microscopic transsphenoidal (MTS). The mean preoperative maximum diameter in the cohort was 45.64 mm. Gross-total resection was achieved in 46 patients (19.25%), near-total in 56 (23.43%), subtotal in 68 (28.45%), and partial in 69 (28.87%) patients. The maximum tumor diameter and Knosp grade were the significant factors that limited the extent of the resection of giant PAs. A total of 193 patients (80.75%) experienced surgical complications, and the most common complications were postoperative diabetes insipidus (DI) (91, 38.08%), intracranial infection (36, 15.06%) and cerebrospinal fluid (CSF) leaks (37, 15.48%). In addition, there was a significant difference in the incidence of CSF leaks between the neuroendoscopy group and the microscopic group (P < 0.05).ConclusionThe management of giant PAs remains a therapeutic challenge due to their large size and postoperative complications. The maximum diameter and Knosp grade of giant PAs significantly limited the extent of resection, which warrants a reasonable surgical plan.

Necrotizing Fasciitis- A Lethal Soft Tissue Infection: Review Article

Background: Necrotizing Fasciitis is a rapidly progressive soft tissue infection that is almost fatal without prompt treatment. This review highlights about the basic approach to the diagnosis and treatment of NF. Description: Various nomenclatures have been used to describe necrotizing soft tissue infections. These infections are classified on the basis of the microbes involved, depth of invasion and anatomical sites involved. Diabetes is the most common risk factor for NF. The masquerading cutaneous manifestations make the diagnosis of NF a challenge. Laboratory parameters, imaging techniques and scoring systems have been designed to aid in early diagnosis. Conclusion: High index of clinical suspicion is needed to make prompt diagnosis of NF. Urgent aggressive surgical debridement with antimicrobial therapy limits the morbidity and mortality associated with NF.

Tetraspanin CD9 Expression Predicts Sentinel Node Status in Patients with Cutaneous Melanoma.

The tetraspanin CD9 is considered a metastasis suppressor in many cancers, however its role is highly debated. Currently, little is known about CD9 prognostic value in cutaneous melanoma. Our aim was to analyse CD9 expression in melanocytic nevi and primary cutaneous melanomas through immunohistochemistry and immunofluorescence approaches to determine its correlation with invasiveness and metastatic potential. CD9 displayed homogeneous staining in all melanocytic nevi. In contrast, it showed a complete loss of reactivity in all thin melanomas. Interestingly, CD9 was re-expressed in 46% of intermediate and thick melanomas in small tumor clusters predominantly located at sites of invasion near or inside the blood or lymphatic vessels. The most notable finding is that all CD9 stained melanomas presented sentinel node positivity. Additionally, a direct association between CD9 expression and presence of distant metastasis was reported. Finally, we confirm that CD9 expression is consistent with an early protective role against tumorigenesis, however, our data endorse in melanoma a specific function of CD9 in vascular dissemination during late tumor progression. The presence of CD9 hotspots could be essential for melanoma cell invasion in lymphatic and endothelial vessels. CD9 could be a valid prognostic factor for lymph node metastasis risk.

Epidemiological, pathological and statistical analysis of penis cancer in Espírito Santo - analysis of 79 cases / Análise epidemiológica, patológica e estatística do cancro do pénis no Espírito Santo - análise de 79 casos

To determine the epidemiological and pathological characteristics of penile cancer (PeCa) and to verify the independence between two statistical variables of patients with PeCa treated at the Urology Service of the Cassiano Antônio de Moraes University Hospital (HUCAM), Vitória, ES, Brazil.Patients and Methods: Between 2010 and 2020, 79 patients with histologically confirmed PeCa were evaluated in our institution considering age, birthplace, ethnicity, marital status, practice of circumcision, histological type, growth pattern, site of tumor, tumor size, grade tumor, Chaux index, vascular invasion, lymphatic invasion, perineural invasion and pathologic stage (TNM staging). For the statistical treatment of square-data with p-value by Monte Carlo statistical calculations, in order to verify the independence between two variables, being the following: Degree of Pathological - TNM, Chaux Index, Lymphatic Invasion, Vascular Invasion and Perineural Invasion, with the patient's race and age group.Results: The ages ranged from 25 to 87 years, with an average of 62 years. Of the 79 patients, 36 (45,56%) were from the metropolitan region, 07 (8,86%) were from the north, 14 (17,72%) were from the northwest and 22 (27,86%) from the south of the Espírito Santo state. Most patients were brown 45 (56,96%), married 51 (64,55%) and had not completed primary school 59 (74,68%). Of the 79 patients, only 4 (6,32%) circumcised. Grade I tumors were present in 35 (44,30%) of the patients, grade II in 32 (40,50%) and grade III in 10 (12,65%). Vascular invasion was observed in 13 (16,45%) and lymphatic in 7 (8,86%) patients. Regarding Chaux Index, 16 patients (20,25%) had Index 2, 19 (24,05%) had Index 3, 13 (16,45%) had Index 4, 19 (24,05%) had Index 5, 9 (11,39%) had Index 6, 1 (1,26%) had Index 7 and 2 (2,53%) were not evaluated. Of the total, 20 (25,31%) had corpora cavernosa and 24 (30,37%) corpus spongiosum infiltration. According to the statistical analysis, there is evidence to reject the null hypothesis, that is, vascular invasion is related to the patient's age group, as p-value = 0.00449 &lt; p-value =0.05.Conclusion: Considering that the majority of penile cancer cases in the state of Espírito Santos are treated at the Department of urology of HUCAM, it can be concluded hat all patients in the study were residents of the state of Espírito Santo and had a low socioeconomic status. Most were brown hemones, married with low schooling and an average age of 62 years. The majority of cases have already been diagnosed with advanced disease. And after performing the chi-square tests and calculating the p value, we were able to conclude with statistical significance (p&lt;0.05) the relationship between age group and vascular invasion, which may justify a worse prognosis the more the age group.

You shall not pass! Protective role of autophagic machinery in response to plasma membrane damage triggered by Candida albicans invasion

ABSTRACT Candida albicans (C. albicans) is an opportunistic pathogen causing infections ranging from superficial to life-threatening dissemination, in which C. albicans is able to translocate through the gut barrier into deeper organs. In its filamentous form (hyphae), C. albicans can invade epithelial cells by two mechanisms: epithelial cell-driven endocytosis and C. albicans-driven active penetration of host cell plasma membrane (PM). Autophagic machinery is known to be involved in the epithelial barrier maintenance, especially the intestinal barrier that is continuously challenged by exposure to the gut microbiota or to xenobiotics. The protective role of autophagy during C. albicans infection has been investigated in myeloid cells, however, far less was known regarding its role during infection of epithelial cells. Here, we demonstrated that key proteins of the autophagic machinery and vesicles presenting features of autophagosomes are recruited at C. albicans invasion sites. These events are associated with host PM damage caused by the active penetration of C. albicans. We showed that ATG5 and ATG16L1 proteins contribute to PM repair mediated by lysosomal membrane exocytosis and participate in protection of epithelial cells’ integrity against C. albicans-induced cell death. Our findings extend the knowledge on emerging roles of the autophagic machinery in stress-related membrane dynamics.

Periprostatic Adipose Tissue Microenvironment: Metabolic and Hormonal Pathways During Prostate Cancer Progression.

The periprostatic adipose tissue (PPAT) is a site of invasion of prostate cancer (PCa) and is part of the microenvironment. It was shown that PPAT secretes factors and fatty acids (FAs) that alter the microenvironment of the PCa. The PPAT secretome of patients with PCa-T3 stage (PPAT-T3) has a metabolic profile enriched in several pathways related to energy production, indicating a greater energy requirement by the tumor, when compared to that of patients in the PCa-T2 stage (PPAT-T2). PPAT-T3 also shows enrichment in pathways related to hormone response, polyamine synthesis, and control of protein synthesis, through amino acid, RNA, and nucleotide metabolism. PPAT-T2 and PPAT-BPH secretomes have less complex metabolic profile, both related with energy balance, while PPAT-BPH has hormone response through insulin pathway. Undoubtedly, a deeper characterization of the human PPAT will lead to a better understanding of the disease and possibly allow new stratification factors and the design of a specific therapy that targets crucial components of the tumor microenvironment as another way to treat or control the disease.

Successful invasion of Trypanosoma cruzi trypomastigotes is dependent on host cell actin cytoskeleton.

Cellular invasion by Trypanosoma cruzi metacyclic trypomastigotes (MTs) or tissue culture trypomastigotes (TCTs) is a complex process involving host–parasite cellular and molecular interactions. Particularly, the involvement of host cell actin cytoskeleton during trypomastigote invasion is poorly investigated, and still, the results are controversial. In the present work, we compare side by side both trypomastigote forms and employ state‐of‐the‐art live‐cell imaging showing for the first time the dynamic mobilization of host cell actin cytoskeleton to MT and TCT invasion sites. Moreover, cytochalasin D, latrunculin B, and jasplakinolide‐pretreated cells inhibited MT and TCT invasion. Furthermore, our results demonstrated that TCT invasion decreased in RhoA, Rac1, and Cdc‐42 GTPase‐depleted cells, whereas MT invasion decreased only in Cdc42‐and RhoA‐depleted cells. Interestingly, depletion of the three studied GTPases induced a scattered lysosomal distribution throughout the cytosol. These observations indicate that GTPase depletion is sufficient to impair parasite invasion despite the importance of lysosome spread in trypomastigote invasion. Together, our results demonstrate that the host cell actin cytoskeleton plays a direct role during TCT and MT invasion.

Neutrophils and aquatic pathogens.

IntroductionNeutrophilic granulocytes are short‐lived cells continuously circulating in the vascular system of vertebrates. They play a basic and decisive role in the innate immune defence of the hosts against all types of pathogenic microorganisms.MethodsBased on a literature study, the functions of neutrophils and cells with similar functions are described. The study places special emphasis on organisms in the aquatic environment and the pathogens occurring in that particular environment.ResultsThe evolutionary origin of this specific cell type is not clear, but its most basic traits (recognition of foreign elements, extracellular trap release, phagocytosis and elimination of ingested material) are found in phagocytes in members of evolutionary ancient invertebrate groups spanning from amoebae, sponges, sea‐anemones, mollusks (snails and mussels), arthropods (crustaceans and insects) to echinoderms (sea stars and sea urchins). Their functions as innate immune sentinels and effector cells in these groups are well described. Neutrophilic granulocytes with elongated and lobed nuclei (possibly allowing cell movements through narrow extracellular spaces and leaving space for phagosomes) occur in vertebrates including fish, amphibians, reptiles, birds and mammals although the morphology of the nucleus, stainability of cytoplasmic granula, and the antimicrobial armament vary among groups. Following the pathogen invasion of a fish host, the neutrophils migrates from the vascular system into the infection focus. They apply their PRRs (including TLRs) to recognize the invader as non‐self, produce netosis by casting extracellular chromatin containing traps in the microenvironment. These nets assist the immobilization of invading microbes and prevents their further spread. The cells attach to and engulf the microbes by phagocytosis, whereafter they eliminate the pathogen in phagolysosomes equipped with a range of killing mechanisms and attract, by release of chemokines, additional immune cells (monocytes, macrophages and lymphocytes) to the site of invasion. Their role in innate immunity of fish hosts towards aquatic pathogens has been elucidated by in vivo and in vitro studies. Neutrophils interact with virus (e.g. IPNV and VHSV), bacteria (e.g. Aeromonas, Vibrio, Edwardsiella, Mycobacterium and Renibacterium) and parasites, including monogeneans (Gyrodactylus), cestodes (Diphyllobothrium), trematodes (Diplostomum) and ciliates (Ichthyophthirius and Philasterides). Despite the decisive function of neutrophils in innate immunity and early protection, the excessive production of ROS, RNS and NETs may lead to pathological disturbances in the host, which are exacerbated if the pathogens evolve immune evasion mechanisms.ConclusionNeutrophils in aquatic organisms play a central role in innate immunity but may serve as a toll and a support in acquired protection. The strong impact of the cellular reactions not only on pathogen but also on host tissues emphasizes that an optimal immune reaction is balanced, involves targeted and specific effector mechanisms, which leaves a minimum of collateral damage in host organs.

Recruitment of LC3 by Campylobacter jejuni to Bacterial Invasion Site on Host Cells via the Rac1-Mediated Signaling Pathway.

Campylobacter jejuni is a leading cause of food-borne disease worldwide. The pathogenicity of C. jejuni is closely associated with the internalization process in host epithelial cells, which is related to a host immune response. Autophagy indicates a key role in the innate immune system of the host to exclude invasive pathogens. Most bacteria are captured by autophagosomes and degraded by autophagosome-lysosome fusion in host cells. However, several pathogens, such as Salmonella and Shigella, avoid and/or escape autophagic degradation to establish infection. But autophagy involvement as a host immune response to C. jejuni infection has not been clarified. This study revealed autophagy association in C. jejuni infection. During infection, C. jejuni activated the Rho family small GTPase Rac1 signaling pathway, which modulates actin remodeling and promotes the internalization of this pathogen. In this study, we found the LC3 contribution to C. jejuni invasion signaling via the Rac1 signaling pathway. Interestingly, during C. jejuni invasion, LC3 was recruited to bacterial entry site depending on Rac1 GTPase activation just at the early step of the infection. C. jejuni infection induced LC3-II conversion, and autophagy induction facilitated C. jejuni internalization. Also, autophagy inhibition attenuated C. jejuni invasion step. Moreover, Rac1 recruited LC3 to the cellular membrane, activating the invasion of C. jejuni. Altogether, our findings provide insights into the new function of LC3 in bacterial invasion. We found the interaction between the Rho family small GTPase, Rac1, and autophagy-associated protein, LC3.

Collaborative studies of U.S.-China neurologists on acute motor axonal neuropathy.

Collaborative studies of U.S.-China neurologists on acute motor axonal neuropathy.

Stroke induces disease-specific myeloid cells in the brain parenchyma and pia

Inflammation triggers secondary brain damage after stroke. The meninges and other CNS border compartments serve as invasion sites for leukocyte influx into the brain thus promoting tissue damage after stroke. However, the post-ischemic immune response of border compartments compared to brain parenchyma remains poorly characterized. Here, we deeply characterize tissue-resident leukocytes in meninges and brain parenchyma and discover that leukocytes respond differently to stroke depending on their site of residence. We thereby discover a unique phenotype of myeloid cells exclusive to the brain after stroke. These stroke-associated myeloid cells partially resemble neurodegenerative disease-associated microglia. They are mainly of resident microglial origin, partially conserved in humans and exhibit a lipid-phagocytosing phenotype. Blocking markers specific for these cells partially ameliorates stroke outcome thus providing a potential therapeutic target. The injury-response of myeloid cells in the CNS is thus compartmentalized, adjusted to the type of injury and may represent a therapeutic target.