Systemic Dissemination Research Articles

Buruli ulcer surveillance in south-eastern Australian possums: Infection status, lesion mapping and internal distribution of Mycobacterium ulcerans.

Buruli ulcer (BU) is a neglected tropical disease of skin and subcutaneous tissues caused by Mycobacterium ulcerans. BU-endemic areas are highly focal, and M. ulcerans transmission dynamics vary by setting. In Victoria, Australia, BU is an endemic vector-borne zoonosis, with mosquitoes and native possums implicated in transmission, and humans incidental hosts. Despite the importance of possums as wildlife reservoirs of M. ulcerans, knowledge of BU in these animals is limited. Opportunistic necropsy-based and active trap-and-release surveillance studies were conducted across Melbourne and Geelong, Victoria, to investigate BU in possums. Demographic data and biological samples were collected, and cutaneous lesions suggestive of BU were mapped. Samples were tested for the presence of M. ulcerans DNA by IS2404 qPCR. The final dataset included 26 possums: 20 necropsied; 6 trapped and released. Most possums (77%) were common ringtails from inner Melbourne. Nine had ulcers, ranging from single and mild, to multiple and severe, exposing bones and tendons in three cases. M. ulcerans was confirmed in 73% (19/26) of examined possums: 8 with lesions and 11 without. Oral swabs were most frequently indicative of M. ulcerans infection status. Severely ulcerated possums had widespread systemic internal bacterial dissemination and were shedding M. ulcerans in faeces. The anatomical distribution of ulcers and PCR positivity of biological samples suggests possums may contract BU from bites of M. ulcerans-harbouring mosquitoes, traumatic skin wounds, ingestion of an unknown environmental source, and/or during early development in the pouch. Ringtail possums appear highly susceptible to infection with M. ulcerans and are important bacterial reservoirs in Victoria. Oral swabs should be considered for diagnosis or surveillance of infected possums. A One Health approach is needed to design and implement integrated interventions that reduce M. ulcerans transmission in Victoria, thereby protecting wildlife and humans from this emerging zoonotic disease.

Hematogenous Brain Abscess Resulting from Prostatic Abscess Caused by <i>Klebsiella pneumoniae</i>

Brain abscess, a life-threatening infection, can result from hematogenous spread. Although uncommon, <i>Klebsiella pneumoniae</i> can lead to brain abscess and systemic dissemination. In this case report, <i>Klebsiella pneumoniae</i> brain abscess, linked with prostate abscess, in a 57-year-old diabetic male with liver cirrhosis and hepatitis B, resulted in fatal sepsis despite antibiotic therapy. This case underscores <i>Klebsiella</i>'s grave risk in immunocompromised patients, highlighting brain abscess and high mortality. Early diagnosis, treatment, and evaluation for multiple organ involvement are crucial.

Increased Susceptibility of Rousettus aegyptiacus Bats to Respiratory SARS-CoV-2 Challenge Despite Its Distinct Tropism for Gut Epithelia in Bats

Increasing evidence suggests bats are the ancestral hosts of the majority of coronaviruses. In general, coronaviruses primarily target the gastrointestinal system, while some strains, especially Betacoronaviruses with the most relevant representatives SARS-CoV, MERS-CoV, and SARS-CoV-2, also cause severe respiratory disease in humans and other mammals. We previously reported the susceptibility of Rousettus aegyptiacus (Egyptian fruit bats) to intranasal SARS-CoV-2 infection. Here, we compared their permissiveness to an oral infection versus respiratory challenge (intranasal or orotracheal) by assessing virus shedding, host immune responses, tissue-specific pathology, and physiological parameters. While respiratory challenge with a moderate infection dose of 1 × 104 TCID50 caused a systemic infection with oral and nasal shedding of replication-competent virus, the oral challenge only induced nasal shedding of low levels of viral RNA. Even after a challenge with a higher infection dose of 1 × 106 TCID50, no replication-competent virus was detectable in any of the samples of the orally challenged bats. We postulate that SARS-CoV-2 is inactivated by HCl and digested by pepsin in the stomach of R. aegyptiacus, thereby decreasing the efficiency of an oral infection. Therefore, fecal shedding of RNA seems to depend on systemic dissemination upon respiratory infection. These findings may influence our general understanding of the pathophysiology of coronavirus infections in bats.

Carcinoma colon masquerading as bleeding per vagina.

Isolated vaginal metastasis from colorectal cancer is a rare entity with very few reports in the literature. Here we report a patient who presented with bleeding per vagina from a vaginal mucosal lesion. Biopsy of the vaginal lesion indicated a metastatic adenocarcinoma from a colorectal primary. Further workup of the patient with colonoscopy and Positron emission tomography (PET CT) indicated a primary in the sigmoid colon. As the patient had a single site of metastasis, she was planned for definitive management. The colonic primary, as well as the vaginal deposit were managed surgically. Further, the patient received adjuvant chemotherapy as well as adjuvant external beam radiation to the site of the vaginal lesion. Vaginal metastases from colorectal primary are usually part of systemic dissemination with multiple metastatic sites and hence has poor prognosis. When the patient presents with an isolated metastasis in the vagina., the survival appears reasonable as per the few reports available in the literature. Due to the rarity of the presentation, there are no standard treatment guidelines available. Surgical management, radiation and adjuvant chemotherapy have been used in varying combinations in the reports available in the literature. To conclude, vaginal metastasis should be included in the differential diagnosis of patients presenting with vaginal bleeding, especially with a history of colorectal carcinoma. Available limited evidence suggests that isolated vaginal metastasis from colorectal cancer that is amenable to local surgical resection has a reasonable outcome. Hence, isolated vaginal metastasis should be treated with curative intent in a multidisciplinary context like other sites of oligometastatic disease.

Cold Atmospheric Pressure Plasma May Prevent Oral Mucositis-Related Candidemia in Chemotherapy-Treated Rats

Oral mucositis associated with candidiasis can causes systemic candidemia, posing a risk to cancer patients administered antineoplastic therapy. Cold atmospheric pressure plasma jets (CAPPJs) have antifungal and anti-inflammatory properties. This study evaluated the effects CAPPJs in preventing systemic fungal dissemination in a murine model of oral mucositis associated with candidiasis. Forty Wistar rats were divided into groups: CAPPJs (treated) and non-treated controls (for comparison), with subgroups subject to 24 and 72 h of treatment (n = 10 each). Four cycles of chemotherapy (cisplatin and 5-fluorouracil (5-FU)) were administered, followed by oral inoculation of Candida albicans for 3 days. Mucosal damage was induced on the lateral side of tongue with 50% acetic acid. CAPPJ treatment was performed on the lesion for 5 min (2 days). Body weight was assessed daily. Fungal dissemination was conducted using organ macerates and plated on Sabouraud Agar with chloramphenicol. Blood samples were obtained for blood count tests. Chemotherapy affected the general health of the animals, as evidenced by body weight loss. Treatment with CAPPJs showed an inhibitory effect on C. albicans, with a significant reduction in fungal recovery from the tongue after 24 h (p < 0.05). Interestingly, systemic fungal dissemination was significantly reduced after 24 and 72 h of treatment when compared to control (p < 0.05). Taken together, these results suggest that CAPPJs have potential for clinical application in patients with oral mucositis at risk of candidemia.

Primary Cutaneous Acral-type CD8-positive T-cell Lymphoproliferations: Widely Divergent Clinical Outcomes Despite Nearly Identical Histomorphology

Abstract Introduction/Objective Non-epidermotropic and acral CD8(+) T-cell proliferations have recently been reclassified as lymphoproliferative disorders (LPDs) due to their indolent course clinical. Here, we describe two cases with similar histomorphology but disparate clinical outcomes, highlighting the diagnostic challenges. Methods/Case Report Case 1: An 89-year-old male developed a 2 cm erythematous papule on the forehead. Biopsy showed a non-epidermotropic pan-dermal lymphocytic infiltrate, a distinct grenz zone, and areas of necrosis. Case 2: A 53-year-old male presented with a rapidly growing, ulcerating 8.9 cm scalp lesion. Biopsy showed a deep dermal lymphoid infiltrate with complete epidermal sparing. In both cases neoplastic cells were positive by immunohistochemistry for CD2, CD3, CD5, CD7 (partial), CD8, granzyme B, TIA-1, and CD68 (perinuclear dot-like pattern). The Ki-67 proliferation index varied modestly between cases (50% in case 1 and 70% in case 2, respectively). Despite treatment, within the span of a few months, case 2 developed adjacent, widely distributed scalp nodules with extensive local tissue destruction. Pathology was consistent with recurrent disease (flow cytometry demonstrating T-cells, co-expressing CD8, CD2, CD3, CD5, CD7 and monotypic TRBC1). Results (if a Case Study enter NA) NA Conclusion CD8+ T-cell lymphoproliferative disorders, specifically primary cutaneous acral CD8+ T-cell lymphoproliferative disorder, is a rare cutaneous T-cell disorder that was re-classified, owing to its indolent clinical course, low risk of systemic dissemination, and favorable prognosis. We report two cases of nearly identical isolated cutaneous lesions that demonstrated a CD8(+)-cytotoxic phenotype with CD68-dot-like positivity. Although all morphologic findings were supportive of the diagnosis, the aggressive clinical progression in case 2 highlights the potential for the disease to defy the classically described indolent behavior. Given that few cases with aggressive clinical courses have been published, we present these cases to underscore their complexity and propose that the classification incorporate clinicopathological correlation to guide management.

Vulvar Paget’s Disease with Inguinal Lymph Node Metastasis: A Case Report

Vulvar Paget's disease is a clinical condition with an invariable course affecting women of advanced age, and is associated with a significant rate of recurrence and dissemination, especially in its invasive form, which has a high metastatic potential. Here we present details of a unique case involving a 77-year-old woman with a history of disease progression over more than a decade. She initially presented with an erythematous lesion in the vulvar region, which was later diagnosed as adenocarcinoma in situ. During follow-up, the affected area extended to the perineal and gluteal regions, indicating an invasive aspect of the tumor. Due to surgical oncology recommendations, tissue resection was not feasible. The pacient experienced a significant worsening of symptoms, including local peeling of the affected region, and a biopsy confirmed Paget's disease in the vulvar region. Subsequently, imaging tests indicated changes in the volume of the inguinal lymph nodes. The patient underwent lymphadenectomy for histological analysis and to prevent systemic dissemination. Indicators of lymph node metastasis, suggestive of a gynecological primary site, were observed. Our case provides valuable insights for pathologists to consider the differential diagnosis of vulvar lesions.

Infection of Aspergillus fumigatus after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia: 2 cases report and literature review

Rare yeast infections have been slowly increasing, given the increasing numbers of patients who are immunocompromised after hematopoietic stem cell transplantation. A considered approach to the complex, multidisciplinary management of infections that are caused by these pathogens is essential to optimize patient outcomes. We reported the management of two patients with combined rare yeast Trichosporon asahii infections, that suggested we should perform timely multivisceral screening for systemic dissemination of infection, and early treatment and combination of medications may improve prognosis.

Impact of baseline SARS-CoV-2 load in plasma and upper airways on the incidence of acute extrapulmonary complications of COVID-19: a multicentric, prospective, cohort study.

Extrapulmonary complications (EPCs) are common in patients hospitalized for COVID-19, but data on their clinical consequences and association with viral replication and systemic viral dissemination is lacking. Patients hospitalized for COVID-19 and enrolled in the TICO (Therapeutics for Inpatients with COVID-19) platform trial at 114 international sites between August 2020 and November 2021 were included in a prospective cohort study. We categorized EPCs into 39 event types within 9 categories and estimated their frequency through day 28 and their association with clinical outcomes through day 90. We analyzed the association between baseline viral burden (plasma nucleocapsid antigen [N-Ag] and upper airway viral load [VL]) and EPCs, adjusting for other baseline factors. 2,625 trial participants were included in the study. The median age was 57 years (IQR 46-68), 57.7% were male, and 537 (20.5%) had at least one EPC. EPCs were associated with higher day-90 all-cause mortality (HR 9.6, 95% CI 7.3, 12.7) after adjustment for other risk factors. The risk of EPCs increased with increasing baseline plasma N-Ag (HR 1.21 per log10 ng/L increase, 95% CI 1.09, 1.34), and upper airway VL (HR 1.12 per log10 copies/mL increase, 95% CI 1.04, 1.19), after adjusting for comorbidities, disease severity, inflammatory markers, and other baseline factors. Trial treatment allocation had no effect on EPC risk. Systemic viral dissemination as evidenced by high plasma N-Ag and high respiratory viral burden are associated with development of EPCs in COVID-19, which in turn are associated with higher 90-day mortality.

Eosinophils respond to, but are not essential for control of an acute Salmonella enterica serovar Typhimurium infection in mice.

Eosinophils are a highly abundant cell type in the gastrointestinal tract during homeostatic conditions, where they have recently been reported to take on an activated phenotype following colonization by the bacterial microbiota. To date, there have been few studies investigating whether eosinophils respond to infection with enteric bacterial pathogens and/or investigating the requirements for eosinophils for effective bacterial pathogen control. In this study, we investigated the response of eosinophils to an acute enteric infection of mice with the bacterial pathogen Salmonella enterica serovar Typhimurium. We also assessed whether eosinophil deficiency impacted Salmonella burdens in the intestinal tract or impacted the systemic dissemination of Salmonella following an oral infection of littermate wild-type BALB/cJ and eosinophil-deficient ΔdblGATA BALB/cJ mice. We found comparable Salmonella burdens in the intestinal tract of wild-type and eosinophil-deficient mice and no significant differences in the levels of Salmonella disseminating to systemic organs within 3 days of infection. Despite our evidence suggesting that eosinophils are not an essential cell type for controlling bacterial burdens in this acute infection setting, we found higher levels of eosinophils in gut-draining lymph nodes following infection, indicating that eosinophils do respond to Salmonella infection. Our data contribute to the growing evidence that eosinophils are responsive to bacterial stimuli, yet the influence of and requirements for eosinophils during bacterial infection appear to be highly context-dependent.

Retrospective Analyses of Porcine Circovirus Type 3 (PCV-3) in Switzerland.

Porcine circovirus 3 (PCV-3) has emerged as a significant pathogen affecting global swine populations, yet its epidemiology and clinical implications remain incompletely understood. This retrospective study aimed to investigate the prevalence and histopathological features of PCV-3 infection in pigs from Switzerland, focusing on archival cases of suckling and weaner piglets presenting with suggestive lesions. An in-house qPCR assay was developed for detecting PCV-3 in frozen and formalin-fixed paraffin-embedded tissues, enhancing the national diagnostic capabilities. Histopathological reassessment identified PCV-3 systemic disease (PCV-3-SD) compatible lesions in 19 (6%) of archival cases, with 47% testing positive by qPCR across various organs. Notably, vascular lesions predominated, particularly in mesenteric arteries, heart, and kidneys. The study confirms the presence of PCV-3 in Switzerland since at least 2020, marking the first documented cases within the Swiss swine population. Despite challenges in in situ hybridization validation due to prolonged formalin fixation, the findings indicate viral systemic dissemination. These results contribute to the understanding of PCV-3 epidemiology in Swiss pigs, emphasizing the need for continued surveillance and further research on its clinical implications and interaction with host factors. Our study underscores the utility and limitations of molecular techniques in confirming PCV-3 infections.

Assessment of Immunoreactivity Patterns in the Excised Cervical Lymph Nodes of Oral Squamous Cell Carcinoma

Introduction: Epidermoid carcinoma (oral squamous cell carcinoma [OSCC]) comprises approximately 80% of the malignancies of the oral cavity, which is also responsible for the morbidity and mortality due to the distant spread of the neoplastic cells. The regional draining lymph node has been considered an anatomic barrier to the systemic dissemination of malignant cells. It has been postulated that the microscopic architectural pattern of a regional lymph node (RLn) represents the immunologic reactivity in that node and the host response. Morphological assessment of the regional nodes aids in a better understanding of the immune response and its correlation with the stage of the tumour. Materials and Methods: A total of 51 head-and-neck dissection cases were assessed for immunomorphological patterns and the degree of tumour involvement in positive lymph nodes. 49 lymph nodes were in the early stage (TNM Stage l and ll) and 71 lymph nodes were in the advanced stage(TNM stage lll and lV). A total of 595 lymph nodes were histologically evaluated and were categorised into metastatic and non-metastatic nodes showing four different patterns: lymphocyte predominance (LP) pattern, germinal centre predominance (GCP) pattern, sinus histiocytosis (SH) pattern and lymphocyte-depleted pattern. Results: The most frequently encountered pattern of lymph nodes was of LP (436 nodes), followed by GCP (61 nodes), SH (36 nodes) and lymphocyte depleted (18 nodes), respectively. Out of 595, 120 nodes were positive for metastasis, indicating that as the stage advances, the GCP type predominates (the predominant immunomorphological pattern shifts from LP to GCP), facilitating metastasis. Conclusion: Immunomorphological changes in the RLns of OSCCs seem to be pivotal factors that serve as an important prognostic indicator. Whereas the cell-mediated immune response represented by LP and SH appears to resist the metastasis process, the humoral response reflected by GCP favours metastasis.

802. TECHNICAL DETAILS: FREE JEJUNAL GRAFT AND REVERSE SAPHENOUS VEIN GRAFT FOR RECONSTRUCTION AFTER TOTAL PHARYNGO-LARYNGECTOMY AND PROXIMAL ESOPHAGECTOMY

Abstract Background We would like to show our tips for free jejunal graft and vascular reconstruction after pharyngo-laryngectomy and proximal esophagectomy. Methods 65 years-old man with history of hypopharynx squamous cell carcinoma cT3 cN0 cM0 who underwent radical Qt/Rt with initially complete response. After 2 years follow-up, he presented dysphagia and recurrence of squamous cell carcinoma proven by histology. Upper endoscopy shows cervical esophageal stenosis due to tumor infiltration. Rescue surgery was decided after systemic dissemination was ruled out with PET-CT. Results Pharyngo-laryngectomy, total thyroidectomy and proximal esophagectomy was performed. Free margin tumor was confirmed by frozen section. Jejunal segment with adequate vascular supply is selected, preferable with a single artery and vein. Peristaltic direction of the jejunum is marked to avoid mistakes during graft transposition. Division of mesenteric branches to prevent postoperative bleeding. Before jejunal section we recommend administration of hyoscine butilbromide 20 mg iv to avoid jejunal spams. Measuring the length graft needed before dividing the jejunum to avoid redundant or short graft is recommended. We must carefully isolate the pedicle avoiding damaging blood supply. To reduce time of ischemia, jejunal graft pedicle should not be ligated until cervical dissection is completed and we have ruled out if venous graft may be needed. After cervical artery and vein dissection, we ensure adequate blood flow and heparinize vessels before clipping. When dividing the pedicle, artery should be divided before the vein to avoid venous congestion, posteriorly we must heparinize the vessels. Povidone-iodine intraluminal washing is recommended. Jejuno-jejunal anastomosis for GI tract restoration. GI reconstruction first is recommended to avoid unnecessary traction on the vascular anastomosis. After ensuring adequate direction of the jejunal graft jejuno-esophageal anastomosis is performed with interrupted suture. Pharyngo-jejunal anastomosis is performed with barbed 3-0 running suture for anterior and posterior layer. Methylene blue test is performed for check the anastomosis. Vascular reconstruction technique depends on the vascular anatomical variations and availability. In this case, superior thyroid artery and sublingual vein were available. Saphenous vein graft might be needed, this graft must be used in reverse way to avoid the vein valves and length must be adjusted. Venous anastomosis should be performed before than arterial reconstruction after heparinize solution in both vessels to avoid thrombosis. Conclusion Free jejunal graft is a highly complex procedure that must be extremely coordinated and protocolized to avoid longer time of ischemia and risk of thrombosis that might compromise the graft viability. https://1drv.ms/v/s!AmFrct07P6MP1Fbyh_7Ce_OK5bB8?e=OMSjsK

Comparative genome analysis and the genome-shaping role of long terminal repeat retrotransposons in the evolutionary divergence of fungal pathogens Blastomyces dermatitidis and Blastomyces gilchristii.

Blastomyces dermatitidis and Blastomyces gilchristii are cryptic species of fungi that cause blastomycosis, an often severe disease involving pulmonary infection capable of systemic dissemination. While these species appear morphologically identical, differences exist in the genetic makeup, geographical range, and possibly the clinical presentation of infection. Here, we show genetic divergence between the cryptic species through both a Blastomyces species tree constructed from orthologous protein sequences and whole genome single nucleotide variant phylogenomic analysis. Following linked-read sequencing and de novo genome assembly, we characterized and compared the genomes of 3 B. dermatitidis and 3 B. gilchristii isolates. The B. gilchristii genomes (73.25-75.4 Mb), were ∼8 Mb larger than the B. dermatitidis genomes (64.88-66.61 Mb). Average nucleotide identity was lower between genomes of different species than genomes of the same species, yet functional classification of genes suggested similar proteomes. The most striking difference involved long terminal repeat retrotransposons. Although the same retrotransposon elements were detected in the genomes, the quantity of elements differed between the two species. Gypsy retrotransposon content was significantly higher in B. gilchristii (38.04-39.26 Mb) than in B. dermatitidis (30.85-32.40 Mb), accounting for the majority of genome size difference between species. Age estimation and phylogenetic analysis of the reverse transcriptase domains suggested that these retrotransposons are relatively ancient, with genome insertion predating the speciation of B. dermatitidis and B. gilchristii. We postulate that different trajectories of genome contraction led to genetic incompatibility, reproductive isolation and speciation, highlighting the role of transposable elements in fungal evolution.

Commensal Yeast Promotes Salmonella Typhimurium Virulence.

Enteric pathogens engage in complex interactions with the host and the resident microbiota to establish gut colonization. Although mechanistic interactions between enteric pathogens and bacterial commensals have been extensively studied, whether and how commensal fungi affect pathogenesis of enteric infections remains largely unknown. Here we show that colonization with the common human gut commensal fungus Candida albicans worsened infections with the enteric pathogen Salmonella enterica serovar Typhimurium. Presence of C. albicans in the mouse gut increased Salmonella cecum colonization and systemic dissemination. We investigated the underlying mechanism and found that Salmonella binds to C. albicans via Type 1 fimbriae and uses its Type 3 Secretion System (T3SS) to deliver effector proteins into C. albicans . A specific effector, SopB, was sufficient to manipulate C. albicans metabolism, triggering increased arginine biosynthesis in C. albicans and the release of millimolar amounts of arginine into the extracellular environment. The released arginine, in turn, induced T3SS expression in Salmonella , increasing its invasion of epithelial cells. C. albicans deficient in arginine production was unable to increase Salmonella virulence in vitro or in vivo . In addition to modulating pathogen invasion, arginine also directly influenced the host response to infection. Arginine-producing C. albicans dampened the inflammatory response during Salmonella infection, whereas C. albicans deficient in arginine production did not. Arginine supplementation in the absence of C. albicans increased the systemic spread of Salmonella and decreased the inflammatory response, phenocopying the presence of C. albicans . In summary, we identified C. albicans colonization as a susceptibility factor for disseminated Salmonella infection, and arginine as a central metabolite in the cross-kingdom interaction between fungi, bacteria, and host.

Perivascular B cells link intestinal angiogenesis to immunity and to the gut-brain axis during neuroinflammation

Disruption of gut barrier function and intestinal immune cell homeostasis are increasingly considered critical players in pathogenesis of extra-intestinal inflammatory diseases, including multiple sclerosis (MS) and its prototypical animal model, the experimental autoimmune encephalomyelitis (EAE). Breakdown of epithelial barriers increases intestinal permeability and systemic dissemination of microbiota-derived molecules. However, whether the gut-vascular barrier (GVB) is altered during EAE has not been reported. Here, we demonstrate that endothelial cell proliferation and vessel permeability increase before EAE clinical onset, leading to vascular remodeling and expansion of intestinal villi capillary bed during disease symptomatic phase in an antigen-independent manner. Concomitant to onset of angiogenesis observed prior to neurological symptoms, we identify an increase of intestinal perivascular immune cells characterized by the surface marker lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1). LYVE-1+ is expressed more frequently on B cells that show high levels of CD73 and have proangiogenic properties. B cell depletion was sufficient to mitigate enteric blood endothelial cell proliferation following immunization for EAE. In conclusion, we propose that altered intestinal vasculature driven by a specialized LYVE-1+ B cell subset promotes angiogenesis and that loss of GVB function is implicated in EAE development and autoimmunity.

Phaseolotoxin: Environmental Conditions and Regulatory Mechanisms Involved in Its Synthesis.

Phaseolotoxin is an antimetabolite toxin produced by diverse pathovars of Pseudomonas syringae which affects various plants, causing diseases of economic importance. Phaseolotoxin contributes to the systemic dissemination of the pathogen in the plant, therefore it is recognized as a major virulence factor. Genetic traits such as the Pht cluster, appear defining to the toxigenic strains phaseolotoxin producers. Extensive research has contributed to our knowledge concerning the regulation of phaseolotoxin revealing a complex regulatory network that involves processes at the transcriptional and posttranscriptional levels, in which specific and global regulators participate. Even more, significant advances in understanding how specific signals, including host metabolites, nutrient sources, and physical parameters such as the temperature, can affect phaseolotoxin production have been made. A general overview of the phaseolotoxin regulation, focusing on the chemical and physical cues, and regulatory pathways involved in the expression of this major virulence factor will be given in the present work.

Viral modulation of type II interferon increases T cell adhesion and virus spread

During primary varicella zoster virus (VZV) infection, infected lymphocytes drive primary viremia, causing systemic dissemination throughout the host, including the skin. This results in cytokine expression, including interferons (IFNs), which partly limit infection. VZV also spreads from skin keratinocytes to lymphocytes prior to secondary viremia. It is not clear how VZV achieves this while evading the cytokine response. Here, we show that VZV glycoprotein C (gC) binds IFN-γ and modifies its activity, increasing the expression of a subset of IFN-stimulated genes (ISGs), including intercellular adhesion molecule 1 (ICAM1), chemokines and immunomodulatory genes. The higher ICAM1 protein level at the plasma membrane of keratinocytes facilitates lymphocyte function-associated antigen 1-dependent T cell adhesion and expression of gC during infection increases VZV spread to peripheral blood mononuclear cells. This constitutes the discovery of a strategy to modulate IFN-γ activity, upregulating a subset of ISGs, promoting enhanced lymphocyte adhesion and virus spread.

Highly pathogenic avian influenza A(H5N1) virus infections on fur farms connected to mass mortalities of black-headed gulls, Finland, July to October 2023.

Highly pathogenic avian influenza (HPAI) has caused widespread mortality in both wild and domestic birds in Europe 2020-2023. In July 2023, HPAI A(H5N1) was detected on 27 fur farms in Finland. In total, infections in silver and blue foxes, American minks and raccoon dogs were confirmed by RT-PCR. The pathological findings in the animals include widespread inflammatory lesions in the lungs, brain and liver, indicating efficient systemic dissemination of the virus. Phylogenetic analysis of Finnish A(H5N1) strains from fur animals and wild birds has identified three clusters (Finland I-III), and molecular analyses revealed emergence of mutations known to facilitate viral adaptation to mammals in the PB2 and NA proteins. Findings of avian influenza in fur animals were spatially and temporally connected with mass mortalities in wild birds. The mechanisms of virus transmission within and between farms have not been conclusively identified, but several different routes relating to limited biosecurity on the farms are implicated. The outbreak was managed in close collaboration between animal and human health authorities to mitigate and monitor the impact for both animal and human health.

The role of neoadjuvant clinical trials in patients with newly diagnosed glioblastoma.

e14022 Background: Novel cytotoxic drugs are commonly first studied in patients with solid tumors who have recurrent disease. If high response rates and durable remissions are observed, further studies are conducted in previously untreated cancers where the novel agent can be combined with radiation or administered as neoadjuvant therapy (NAT) to reduce tumor size before surgery or radiation and to limit systemic dissemination. While NAT can provide critical information on response rates and survival in previously untreated patients, it can add toxicities and delay the administration of standard therapies. Neoadjuvant chemotherapy is now standard-of-care in many systemic cancers but is rarely considered in patients with glioblastoma (GBM). This literature review was conducted to describe factors leading to NAT playing an increasingly important role in systemic cancers and a diminishing role in patients with GBM. Methods: Prospective trials published between 1980 and 2023 where patients with newly diagnosed systemic cancers and GBM received NAT prior to radiation were identified in PubMed. Results: During these 43 years, over 5,000 NAT trials in patients with systemic cancers were published. As a result of these studies, NAT is now considered standard therapy for 28 different cancers. In contrast, during the same years only 51 prospective studies were reported evaluating the efficacy of NAT in newly diagnosed GBM. These clinical trials accrued a total of 2,047 patients and evaluated the efficacy of nitrosoureas, temozolomide, platinum-based agents, and targeted therapies. These studies peaked before 2005, when combining temozolomide and radiation was shown to improve survival, and declined thereafter. NAT temozolomide was studied in 12 trials (641 patients) resulting in a median response rate of 35% (range 8.7-51%) and a median overall survival of 12.5 (range 6-22) months. NAT trials in patients with GBM were not associated with unexpected toxicities, major reductions in survival, or poor patient accrual. Conclusions: As in other solid tumors, NAT in patients with GBM is relatively safe and feasible. Enthusiasm for this approach has been limited by the paucity of active agents in recurrent glioblastoma that could be subsequently evaluated in newly diagnosed patients. However, the neoadjuvant setting is ideally suited to rapidly screening novel cytotoxic agents for efficacy as it allows: 1) radiographic response rates in previously untreated patients to be the primary endpoint, 2) small sample sizes, and 3) efficacy results in 2-3 months when patients are transitioned to standard care. Given the well documented safety and feasibility history of using NAT in patients with solid tumors and GBM, this approach has the ability to rapidly identify potentially active, novel cytotoxic agents, especially in patients with MGMT unmethylated, IDH wildtype GBM who are unlikely to benefit from temozolomide.