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Patients with advanced melanoma that is resistant to PD-1 blockade therapy have limited treatment options. Vidutolimod (formerly CMP-001), a virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist, may reverse PD-1 blockade resistance by triggering a strong IFN response to induce and attract antitumor T cells. In the dose-escalation part of this phase Ib study, vidutolimod was administered intratumorally at escalating doses with intravenous pembrolizumab to 44 patients with advanced melanoma who had progressive disease or stable disease on prior anti–PD-1 therapy. The combination of vidutolimod and pembrolizumab had a manageable safety profile, and durable responses were observed in 25% of patients, with tumor regression in both injected and noninjected lesions, including visceral lesions. Patients who responded to vidutolimod and pembrolizumab had noninflamed tumors at baseline and induction of an IFNγ gene signature following treatment, as well as increased systemic expression of the IFN-inducible chemokine CXCL10.Significance:In this phase Ib study in patients with advanced melanoma, intratumoral TLR9 agonist vidutolimod in combination with pembrolizumab had a manageable safety profile and showed promising clinical activity, supporting the further clinical development of vidutolimod to overcome PD-1 blockade resistance through induction of an IFN response.See related commentary by Sullivan, p. 2960.This article is highlighted in the In This Issue feature, p. 2945

Supplementary figures 1-6, supplementary tables 1-4

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Malignant glioma is an often fatal type of cancer. Aberrant activation of STAT3 leads to glioma tumorigenesis. STAT3-induced transcription of protein-coding genes has been extensively studied; however, little is known about STAT3-regulated miRNA gene transcription in glioma tumorigenesis. In this study, we found that abnormal activation or decreased expression of STAT3 promotes or inhibits the expression of miR-182-5p, respectively. Bioinformatics analyses determined that tumor suppressor protocadherin-8 (PCDH8) is a candidate target gene of miR-182-5p. miR-182-5p negatively regulated PCDH8 expression by directly targeting its 3′-untranslated region. PCDH8 knockdown induced the proliferative and invasive capacities of glioma cells. Silencing of PCDH8 or miR-182-5p mimics could reverse the inhibitory effect of WP1066, a STAT3 inhibitor, or STAT3 knockdown in vitro and in vivo on glioma progression. Clinically, expression levels of PCDH8 were inversely correlated with those of p-STAT3 or miR-182-5p in glioblastoma tissues. These findings reveal that the STAT3/miR-182-5p/PCDH8 axis has a critical role in glioma tumorigenesis and that targeting the axis may provide a new therapeutic approach for human glioma. Cancer Res; 76(14); 4293–304. ©2016 AACR.

By means of the direct simulation Monte Carlo method, the effect of rarefaction on the heat fluxes and the hydrodynamics of a granular gas bounded by thermal walls is investigated. The heat flux is found to evolve nonmonotonically with the particle inelasticity due to the competition between the particle inelasticity and rarefaction. The former enhances the heat flux, and the latter reduces the heat flux. As the particles become more inelastic, the onset of the heat flux diminishment due to rarefaction is found to be signaled by a temperature gradient collapse. The same temperature gradient convergence, which precedes the rarefied-reduced heat flux, is also found as the applied temperature gradient is increased.

3D scaffolds mimicking the environment in the primary tumor or metastatic organs can deconstruct complex niche signals and facilitate the study of cancer progression and metastasis. Here, we reported that a subcutaneous 3D scaffold implant acted as a lung-mimicking dormant metastatic niche in mouse models of metastatic breast cancer, recruiting lung-tropic circulating tumor cells yet suppressing their growth through potent in situ antitumor immunity. We compared it with the immunosuppressive lungs developing lethal metastases and the dormant lungs suppressing tumor growth derived from breast cancer models with varying tumor aggressiveness and host immunity. Our data suggested that breast cancer-induced Gr1+CD11b+Ly6G+ granulocytic myeloid cells (neutrophils) infiltrated the scaffold implants and lungs, secreting the same signal to facilitate the metastatic seeding of lung-tropic cancer cells in these two types of niches. However, circulating neutrophils with opposing phenotypes and functions (N1 and N2) were selectively recruited and enriched in the dormant scaffolds/lungs and immunosuppressive lungs, respectively, responding to two distinct groups of chemoattractants. N1 or N2 neutrophils established activated or suppressive immune environments in the metastatic niches, directing different fates of cancer cells. The clinical relevance of these scientific findings was validated by the strong positive correlation of a high N1-to-N2 neutrophil chemoattractant ratio with a low-grade primary tumor, a low metastases incidence, and a better prognosis in breast cancer patients. Overall, our study revealed the multifaceted roles of neutrophils in regulating lung metastasis and underscored the importance of N1 neutrophils in driving breast cancer metastatic dormancy in the lungs, inspiring next-generation immunotherapy. Citation Format: Jing Wang, Ramon Ocadiz-Ruiz, Matthew Hall, Grace Bushnell, Sophia Orbach, Joseph Decker, Ravi Raghani, Yining Zhang, Aaron Morris, Jacqueline Jeruss, Lonnie Shea. A lung-mimicking synthetic metastatic niche reveals N1 neutrophils drive breast cancer metastatic dormancy in the lungs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB347.

The SARS-CoV-2 main viral protease (Mpro) is an attractive target for antivirals given its distinctiveness from host proteases, essentiality in the viral life cycle and conservation across coronaviridae. We launched the COVID Moonshot initiative to rapidly develop patent-free antivirals with open science and open data. Here we report the use of machine learning for de novo design, coupled with synthesis route prediction, in our campaign. We discover novel chemical scaffolds active in biochemical and live virus assays, synthesized with model generated routes.

The immunologic and therapeutic effects of intratumoral (IT) delivery of a novel virus-like particle as a lymphoma immunotherapy were evaluated in preclinical studies with human cells and a murine model. CMP-001 is a virus-like particle composed of the Qβ bacteriophage capsid protein encapsulating an immunostimulatory CpG-A oligodeoxynucleotide TLR9 agonist. In vitro, CMP-001 induced cytokine production, including IFN-α from plasmacytoid dendritic cells, but only in the presence of anti-Qβ Ab. In vivo, IT CMP-001 treatment of murine A20 lymphoma enhanced survival and reduced growth of both injected and contralateral noninjected tumors in a manner dependent on both the ability of mice to generate anti-Qβ Ab and the presence of T cells. The combination of IT CMP-001 with systemic anti–PD-1 enhanced antitumor responses in both injected and noninjected tumors. IT CMP-001 alone or combined with anti–PD-1 augmented T cell infiltration in tumor-draining lymph nodes. We conclude IT CMP-001 induces a robust antitumor T cell response in an anti-Qβ Ab–dependent manner and results in systemic antitumor T cell effects that are enhanced by anti–PD-1 in a mouse model of B cell lymphoma. Early-phase clinical evaluation of CMP-001 and anti–PD-1 combination therapy in lymphoma will begin shortly, based in part on these results.

The pentafluorosulfanyl (-SF5) functional group is of increasing interest as a bioisostere in medicinal chemistry. A library of SF5-containing compounds, including amide, isoxazole, and oxindole derivatives, was synthesised using a range of solution-based and solventless methods, including microwave and ball-mill techniques. The library was tested against targets including human dihydroorotate dehydrogenase (HDHODH). A subsequent focused approach led to synthesis of analogues of the clinically used disease modifying anti-rheumatic drugs (DMARDs), Teriflunomide and Leflunomide, considered for potential COVID-19 use, where SF5 bioisostere deployment led to improved inhibition of HDHODH compared with the parent drugs. The results demonstrate the utility of the SF5 group in medicinal chemistry.

In the past two decades, three coronaviruses with ancestral origins in bats have emerged and caused widespread outbreaks in humans, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the first SARS epidemic in 2002–2003, the appreciation of bats as key hosts of zoonotic coronaviruses has advanced rapidly. More than 4,000 coronavirus sequences from 14 bat families have been identified, yet the true diversity of bat coronaviruses is probably much greater. Given that bats are the likely evolutionary source for several human coronaviruses, including strains that cause mild upper respiratory tract disease, their role in historic and future pandemics requires ongoing investigation. We review and integrate information on bat–coronavirus interactions at the molecular, tissue, host and population levels. We identify critical gaps in knowledge of bat coronaviruses, which relate to spillover and pandemic risk, including the pathways to zoonotic spillover, the infection dynamics within bat reservoir hosts, the role of prior adaptation in intermediate hosts for zoonotic transmission and the viral genotypes or traits that predict zoonotic capacity and pandemic potential. Filling these knowledge gaps may help prevent the next pandemic., Bats harbour a multitude of coronaviruses and owing to their diversity and wide distribution are prime reservoir hosts of emerging viruses. Ruiz-Aravena, McKee and colleagues analyse the currently available information on bat coronaviruses and discuss their role in recent and potential future spillovers.

Despite its general application, the Fourier's law of heat conduction is not always valid in dilute gases. One of the physical shortcomings of Fourier's law is the mismatch at the boundary; the temperature gradient in the Knudsen layer diverges in the boundary, but the heat flux does not. In this paper, we propose a more generalized constitutive relation for the heat flux to match the heat flux with the hydrodynamics in a rarefied granular gas. The proposed modified heat flux relation is then used to derive analytical solutions for the hydrodynamics of a granular gas bounded by equal and unequal temperature walls. The analytical solutions are then compared to direct simulation Monte Carlo simulations.

Background Prior retrospective and prospective studies suggest improved survival with the use of stereotactic radiosurgery (SRS) and bevacizumab in the treatment of limited-volume glioblastoma (GBM) recurrences. Methods We retrospectively reviewed our experience with gamma knife SRS in combination with bevacizumab for the treatment of focal GBM recurrence during 2009–2015. Outcomes include overall survival, progression free survival (PFS), and radiation-related adverse events. Kaplan–Meier methods and multivariable Cox proportional hazards models were performed for survival analysis. Results Within a median of 13.7 months after diagnosis, a total of 45 patients with GBM underwent gamma knife SRS and bevacizumab treatment. Median age was 57 years (range: 20–78 years) and 63.3% were women. The median Karnofsky Performance Score (KPS) at recurrence was 80 (range: 40–100). Sixty-four percent of patients had single radiosurgery target (range: 1–4) and median target volume and margin dose were 2.2 cm3 (range: 0.1–25.2 cm3) and 17.0 gray (Gy) (range: 13–24 Gy), respectively. Median PFS and overall survival were 9.3, 31.0 months following diagnosis, and 5.2, 13.3 months after SRS, respectively. Factors associated with poor outcomes were KPS ≤70, SRS dose Conclusions SRS in combination with bevacizumab can be safely used to treat focal GBM recurrence. KPS, radiation dose, and multi-agent chemotherapy usage prior to SRS demonstrated significant impact on PFS. Bevacizumab may provide clinically relevant radioprotection.

Patients with advanced melanoma that is resistant to PD-1 blockade therapy have limited treatment options. Vidutolimod (formerly CMP-001), a virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist, may reverse PD-1 blockade resistance by triggering a strong IFN response to induce and attract antitumor T cells. In the dose-escalation part of this phase Ib study, vidutolimod was administered intratumorally at escalating doses with intravenous pembrolizumab to 44 patients with advanced melanoma who had progressive disease or stable disease on prior anti–PD-1 therapy. The combination of vidutolimod and pembrolizumab had a manageable safety profile, and durable responses were observed in 25% of patients, with tumor regression in both injected and noninjected lesions, including visceral lesions. Patients who responded to vidutolimod and pembrolizumab had noninflamed tumors at baseline and induction of an IFNγ gene signature following treatment, as well as increased systemic expression of the IFN-inducible chemokine CXCL10. Significance: In this phase Ib study in patients with advanced melanoma, intratumoral TLR9 agonist vidutolimod in combination with pembrolizumab had a manageable safety profile and showed promising clinical activity, supporting the further clinical development of vidutolimod to overcome PD-1 blockade resistance through induction of an IFN response. See related commentary by Sullivan, p. 2960. This article is highlighted in the In This Issue feature, p. 2945

1. The COVID-19 pandemic has highlighted the importance of efficient sampling strategies and statistical methods for monitoring infection prevalence, both in humans and reservoir hosts. Pooled testing can be an efficient tool for learning pathogen prevalence in a population. Typically pooled testing requires a second phase follow up procedure to identify infected individuals, but when the goal is solely to learn prevalence in a population, such as a reservoir host, there are more efficient methods for allocating the second phase samples. 2. To estimate pathogen prevalence in a population, this manuscript presents an approach for data integration with two-phased testing of pooled samples that allows more efficient estimation of prevalence with less samples than traditional methods. The first phase uses pooled samples to estimate the population prevalence and inform efficient strategies for the second phase. To combine information from both phases, we introduce a Bayesian data integration procedure that combines pooled samples with individual samples for joint inferences about the population prevalence. 3. Data integration procedures result in more efficient estimation of prevalence than traditional procedures that only use individual samples or a single phase of pooled sampling. 4. The manuscript presents guidance on implementing the first phase and second phase sampling plans using data integration. Such methods can be used to assess the risk of pathogen spillover from reservoir hosts to humans, or to track pathogens such as SARS-CoV-2 in populations.

2020 saw the continuation of the second largest outbreak of Ebola virus disease (EVD) in history. Determining epidemiological links between cases is a key part of outbreak control. However, due to the large quantity of data and subsequent data entry errors, inconsistencies in potential epidemiological links are difficult to identify. We present chainchecker, an online and offline shiny application which visualises, curates and verifies transmission chain data. The application includes the calculation of exposure windows for individual cases of EVD based on user defined incubation periods and user specified symptom profiles. It has an upload function for viral hemorrhagic fever data and utility for additional entries. This data may then be visualised as a transmission tree with inconsistent links highlighted. Finally, there is utility for cluster analysis and the ability to highlight nosocomial transmission. chainchecker is a R shiny application which has an offline version for use with VHF (viral hemorrhagic fever) databases or linelists. The software is available at https://shiny.dide.imperial.ac.uk/chainchecker which is a web-based application that links to the desktop application available for download and the github repository, https://github.com/imperialebola2018/chainchecker.

As managers have scrambled to protect their declining revenue streams in recent years, they’ve found solace from courts, legislatures, and independent fund directors. While the market generally appears to be driving lower management fees, fund directors and judges have done little to aid the process, even in connection with transactions resulting in a change in a fund's investment adviser. This paper addresses developments in excessive management fee litigation as well as suboptimal board practices utilized in connection with asset manager mergers, which present fund directors with an opportunity to leverage lower fees and other improvements for the benefit of fund shareholders. Fund directors should take heed and obtain value for shareholders when such opportunities arise.

Herein we provide a living summary of the data generated during the COVID Moonshot project focused on the development of SARS-CoV-2 main protease (Mpro) inhibitors. Our approach uniquely combines crowdsourced medicinal chemistry insights with high throughput crystallography, exascale computational chemistry infrastructure for simulations, and machine learning in triaging designs and predicting synthetic routes. This manuscript describes our methodologies leading to both covalent and non-covalent inhibitors displaying protease IC50 values under 150 nM and viral inhibition under 5 uM in multiple different viral replication assays. Furthermore, we provide over 200 crystal structures of fragment-like and lead-like molecules in complex with the main protease. Over 1000 synthesized and ordered compounds are also reported with the corresponding activity in Mpro enzymatic assays using two different experimental setups. The data referenced in this document will be continually updated to reflect the current experimental progress of the COVID Moonshot project, and serves as a citable reference for ensuing publications. All of the generated data is open to other researchers who may find it of use.

Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human induced pluripotent stem cell-derived kidney organoids with SARS-CoV-2. Single cell RNA-sequencing indicated injury and dedifferentiation of infected cells with activation of pro-fibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in Long-COVID., Graphical Abstract, Jansen, Reimer, Nagai et al report that SARS-CoV-2 infects kidney cells and is associated with kidney fibrosis in patients. Using single cell transcriptomics of infected kidney organoids, they show that SARS-CoV-2 causes kidney injury and stimulates pro-fibrotic signaling. Viral infection in organoids was inhibited by a recently developed protease blocker.

Background Intratumoral (IT) injection of CMP-001, a CpG-A TLR9 agonist packaged within a virus-like particle, is designed to activate tumor-associated plasmacytoid dendritic cells, inducing an interferon-rich tumor microenvironment and anti-tumor CD8+ T cell responses. Methods CMP-001-001 is an ongoing Phase 1b trial evaluating the safety and efficacy of CMP-001 in combination with pembrolizumab (Part 1; N = 144) or alone (Part 2; N = 23) in patients with advanced melanoma resistant to prior anti-PD-1 therapy (Tables 1). CMP-001 is administered IT into accessible lesion(s) either with, or without on-site saline dilution (table 1), and response assessed by RECIST v1.1. Monotherapy patients who progress can be rolled over onto combination therapy and continue on study. Baseline and on-therapy serum is analyzed for cytokines, and immunohistochemistry and RNA-Seq are performed on available tumor biopsies. Results Adverse events (AEs) attributed to CMP-001 in combination with pembrolizumab or as monotherapy consisted predominately of transient low-Grade flu-like symptoms and injection site reactions: Grade 3+ related AEs were reported in 33% of patients treated with combination therapy and 22% of patients with monotherapy. The Objective Response Rate (ORR) with undiluted CMP-001 in combination with pembrolizumab was 24% (18/75; 95% confidence interval: 15%-35% (table 1); on-site dilution of CMP-001 was associated with a substantial decrease in ORR to 12% (7/61; 95% confidence interval: 5%-22% (table 1). Three additional patients had a delayed partial response after an initial period of disease progression. Anti-tumor response was comparable between injected and uninjected lesions. The median duration of response to combination therapy has not been reached. The ORR to CMP-001 monotherapy was 22% (5/23; 95% confidence interval: 7%-44% (table 1); time from last anti-PD-1 therapy before CMP-001 was 1.5 to >20 months in responders; 3 of the patients responding to CMP-001 monotherapy achieved PR at the first evaluation, but progressed by the second evaluation. Serum and tumor biopsy translational studies in the patients receiving combination therapy supported the proposed mechanism of TLR9 activation and identified a possible association between induction of serum CXCL10 and response. Conclusions IT CMP-001 alone and in combination with pembrolizumab appears well tolerated, can reverse resistance to anti-PD-1 therapy, and can produce deep and durable clinical responses in patients with advanced melanoma. Ethics Approval CMP-001-001 was centrally approved by the WCG-WIRB, WIRB approval tracking number 20152597.

Mutual fund investors pay over $100 billion every year in management fees to investment advisers. Throughout decades of litigation under Section 36(b) of the Investment Company Act, federal courts have yet to find that even a single management fee charged by an investment adviser for any period of time was excessive under the Section 36(b) standard. This paper argues that a combination of docile fund boards, hesitant federal courts, and a functioning, yet imperfect, market have allowed fund fees and expenses to decline in some areas, but not others. Outlier funds persist with unjustifiably high management fees, and have seemingly avoided market pressures. Fund boards and courts should play their legislatively assigned roles and check the ability of advisers to reap supracompetitive compensation.

Background In the treatment-naive setting, PD-1 blockade is associated with greater response in T cell-inflamed vs non-T cell-inflamed tumors. CMP-001 is a CpG-A oligonucleotide TLR9 agonist in a virus-like particle that is hypothesized to activate tumor-associated plasmacytoid dendritic cells (pDCs) to secrete type I interferons. Through this activity, CMP-001 may convert the tumor microenvironment to a Th1-like chemokine milieu (eg, increased CXCL10) and induce an antitumor CD8+ T-cell response. We have recently reported that intratumoral injection of CMP-001 + IV pembrolizumab (pembro) had an acceptable safety profile and can reverse PD-1 blockade resistance in patients (pts) with melanoma (Milhem et al, SITC 2019). Regression was observed in injected and uninjected lesions. Herein we report pharmacodynamic and translational data. Methods This 2-part, open-label, multicenter, phase 1b study (NCT02680184) enrolled pts with metastatic/unresectable melanoma and stable disease (SD) or progressive disease (PD) on/after anti−PD-1 therapy. In part 1 (3+3 dose-escalation and dose-expansion), pts received CMP-001 + pembro. In part 2, pts received CMP-001 monotherapy. Determination of safety and clinical activity were the study's main objectives. Prespecified pharmacodynamic and translational studies evaluated serum chemokines and evaluated tumor biopsies using RNA and/or whole exome sequencing and immunohistochemistry for PD-L1 (reported as H-score), CD8, and CD303 (pDC marker). Results As of September 30, 2020, 159 pts (part 1) and 40 pts (part 2) have been treated. A greater median fold increase of serum CXCL10 (a marker of innate immunity, n=40) was observed in responders (R) to CMP-001 + pembro (18.8x) vs nonresponders (NR) after treatment (9.9x in SD; 6.15x in PD; differences were not statistically significant). Preliminary analyses showed that interferon gene expression distinguished R vs NR. Tumor biopsy analyses (part 1, n=139; part 2, n=34) showed that pts with high PD-L1, high CD8+ T cells, or inflamed transcriptional signatures at baseline were less likely to respond to CMP-001 + pembro vs pts without inflammation markers at baseline. Baseline mean PD-L1 expression (H-score) was 8.1 in R (n=10) vs 21.8 in NR (n=49). Posttreatment biopsies generally showed increased PD-L1, CD8+ T cells, and inflamed transcriptional signatures in R vs NR. Neither tumor mutational burden nor baseline pDC density distinguished R vs NR. Conclusions In pts with anti-PD-1 refractory melanoma, intratumoral CMP-001 ± pembro appears to disproportionately induce antitumor responses in noninflamed tumors. Clinical response to CMP-001 ± pembro was associated with induction of markers of both innate and adaptive antitumor immunity. Citation Format: Jason John Luke, Riyue Bao, John M. Kirkwood, Yousef Zakharia, Diwakar Davar, Elizabeth Buchbinder, Theresa Medina, Adil Daud, Antoni Ribas, Jiaxin Niu, Geoffrey Gibney, Kim Margolin, Anthony J. Olszanski, Inderjit Mehmi, Takami Sato, Montaser Shaheen, Aaron Morris, Dmitri Bobilev, Katie Campbell, George Weiner, James E. Wooldridge, Arthur M. Krieg, Mohammed Milhem. CMP-001 demonstrates improved response in noninflamed anti-PD-1 refractory melanoma and response is associated with serum CXCL10 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT032.

Purpose To analyze the August 2016 court decision in Sivolella v. AXA Equitable Life Ins. Co. and its implications for cases concerning mutual fund advisory fees under Section 36(b) of the of the Investment Company Act of 1940. Design/methodology/approach Discusses Section 36(b), the plaintiffs’ arguments and the judge’s decision in favor of the mutual fund adviser. Provides insights from the judge’s analysis of the advisory fees at issue, including the independence of the mutual fund board and quality of the annual advisory contract renewal process, whether the language of the advisory and subadvisory agreements fully reflects the nature and extent of services provided, the board’s reliance on outside experts and advisers when considering the advisers’ fees and services, and continuous improvements in the boards’ annual advisory contract renewal process. Findings AXA was a decisive victory for the adviser, and serves as a reminder to boards and advisers alike that a diligent focus on board process and independence can pay twofold after litigation is filed. Practical implications Boards and advisers should consider AXA’s implications, and whether the decision raises issues that should be reviewed by independent counsel with experience advising funds and advisers with respect to the Investment Company Act. Originality/value Practical guidance from experienced financial services lawyers.

Malignant glioma is an often fatal type of cancer. Aberrant activation of STAT3 leads to glioma tumorigenesis. STAT3-induced transcription of protein-coding genes has been extensively studied; however, little is known about STAT3-regulated miRNA gene transcription in glioma tumorigenesis. In this study, we found that abnormal activation or decreased expression of STAT3 promotes or inhibits the expression of miR-182-5p, respectively. Bioinformatics analyses determined that tumor suppressor protocadherin-8 (PCDH8) is a candidate target gene of miR-182-5p. miR-182-5p negatively regulated PCDH8 expression by directly targeting its 3′-untranslated region. PCDH8 knockdown induced the proliferative and invasive capacities of glioma cells. Silencing of PCDH8 or miR-182-5p mimics could reverse the inhibitory effect of WP1066, a STAT3 inhibitor, or STAT3 knockdown in vitro and in vivo on glioma progression. Clinically, expression levels of PCDH8 were inversely correlated with those of p-STAT3 or miR-182-5p in glioblastoma tissues. These findings reveal that the STAT3/miR-182-5p/PCDH8 axis has a critical role in glioma tumorigenesis and that targeting the axis may provide a new therapeutic approach for human glioma. Cancer Res; 76(14); 4293–304. ©2016 AACR.

Objective Laser interstitial thermal therapy has become increasingly popular for targeting epileptic foci in a minimally invasive fashion. Despite its use in >1000 patients, the long-term effects of photothermal injury on brain physiology remain poorly understood. Methods We prospectively followed clinical and radiographic courses of 13 patients undergoing laser ablation for focal epilepsy by the senior author (N.T.). Only patients with nonenhancing lesions and patients who had a delayed postoperative magnetic resonance imaging (MRI) scan with gadolinium administration approximately 6 months after ablation were considered. Volumetric estimates of the amount of enhancement immediately after ablation and on the delayed MRI scan were made. Results Median interval between surgery and delayed postoperative MRI scan was 6 months (range, 5–8 months). In 12 of 13 cases, persistent enhancement was seen, consistent with prolonged blood-brain barrier dysfunction. Enhancement, when present, was 9%–67% (mean 30%). There was no correlation between the time from surgery and the relative percentage of postoperative enhancement on MRI. The blood-brain barrier remained compromised to gadolinium contrast for up to 8 months after thermal therapy. There were no adverse events from surgical intervention; however, 1 patient developed delayed optic neuritis. Conclusions Prolonged incompetence of the blood-brain barrier produced by thermal ablation may provide a path for delivery of macromolecules into perilesional tissue, which could be exploited for therapeutic benefit, but rarely it may result in autoimmune central nervous system inflammatory conditions.

Emerging infectious disease outbreaks are increasingly suspected to be a consequence of human pressures exerted on natural ecosystems. Previously, host taxonomic communities have been used as indicators of infectious disease emergence, and the loss of their diversity has been implicated as a driver of increased presence. The mechanistic details in how such pathogen-host systems function, however, may not always be explained by taxonomic variation or loss. Here we used machine learning and methods based on Gower's dissimilarity to quantify metrics of invertebrate functional diversity, in addition to functional groups and their taxonomic diversity at sites endemic and non-endemic for the model generalist pathogen Mycobacterium ulcerans, the causative agent of Buruli ulcer. Changes in these metrics allowed the rapid categorisation of the ecological niche of the mycobacterium's hosts and the ability to relate specific host traits to its presence in aquatic ecosystems. We found that taxonomic diversity of hosts and overall functional diversity loss and evenness had no bearing on the mycobacterium's presence, or whether the site was in an endemic area. These findings, however, provide strong evidence that generalist environmentally persistent bacteria such as M. ulcerans can be associated with specific functional traits rather than taxonomic groups of organisms, increasing our understanding of emerging disease ecology and origin.

An understanding of the patterns of animal contact networks provides essential information for the design of risk-based animal disease surveillance and control strategies. This study characterises pig movements throughout England and Wales between 2009 and 2013 with a view to characterising spatial and temporal patterns, network topology and trade communities. Data were extracted from the Animal and Plant Health Agency (APHA)’s RADAR (Rapid Analysis and Detection of Animal-related Risks) database, and analysed using descriptive and network approaches. A total of 61,937,855 pigs were moved through 872,493 movements of batches in England and Wales during the 5-year study period. Results show that the network exhibited scale-free and small-world topologies, indicating the potential for diseases to quickly spread within the pig industry. The findings also provide suggestions for how risk-based surveillance strategies could be optimised in the country by taking account of highly connected holdings, geographical regions and time periods with the greatest number of movements and pigs moved, as these are likely to be at higher risk for disease introduction. This study is also the first attempt to identify trade communities in the country, information which could be used to facilitate the pig trade and maintain disease-free status across the country in the event of an outbreak.

Objective Pyogenic cerebral abscesses are associated with high morbidity and mortality when treatment is delayed. Benign clinical presentation, as well as absence of restricted diffusion on MRI may contribute to missed diagnoses and delays. The authors sought to elucidate characteristics associated with facilitated diffusion on the MRIs of patients with pyogenic abscesses. Patients and methods The authors performed a 10-year retrospective review of prospectively attained data for patients undergoing mass resection by a single surgeon. Results Our findings show that 3/33 (9%) patients with microbiological diagnoses of cerebral abscesses with a thin ring of contrast enhancement but minimal or no restricted diffusion MRI imaging. All causative organisms were hemolytic streptococci and none of the subjects received antibiotic therapy prior to specimen collection. A trend in these patients was the presence of diabetes and in conjunction with other studies that cite incomplete treatment as being associated with facilitated diffusion, we conjecture that impaired inflammatory responses in some patients may be associated with the absence of restricted diffusion. Conclusion With this in mind, clinicians must maintain a high index of suspicion when assessing patients with cystic, contrast enhancing masses. A prospective multicenter study to compile imaging along with other patient characteristics may help refine the non-invasive diagnostic criteria for brain abscesses.

International audience; Generalist microorganisms are the agents of many emerging infectious diseases (EIDs), but their natural life cyclesare difficult to predict due to the multiplicity of potential hosts and environmental reservoirs. Among 250 knownhuman EIDs, many have been traced to tropical rain forests and specifically freshwater aquatic systems, which act asan interface between microbe-rich sediments or substrates and terrestrial habitats. Along with the rapid urbanizationof developing countries, population encroachment, deforestation, and land-use modifications are expected toincrease the risk of EID outbreaks. We show that the freshwater food-web collapse driven by land-use change has anonlinear effect on the abundance of preferential hosts of a generalist bacterial pathogen, Mycobacterium ulcerans.This leads to an increase of the pathogen within systems at certain levels of environmental disturbance. Thecomplex link between aquatic, terrestrial, and EID processes highlights the potential importance of species communitycomposition and structure and species life history traits in disease risk estimation and mapping. Mechanismssuch as the one shown here are also central in predicting how human-induced environmental change, for example,deforestation and changes in land use, may drive emergence.

Little is known about how often various prey animals are at risk of predation by Gray Wolves (Canis lupus). We used a system to monitor the presence during the day of two radio-collared Gray Wolves within 2 km of a radio-collared White-tailed Deer (Odocoileus virginianus) with a fawn or fawns in August 2013 in the Superior National Forest of northeastern Minnesota. We concluded that the fawn or fawns were at risk of predation by at least one wolf at least daily.