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Aim Topographic complexity is widely accepted as a key driver of biodiversity, but at the patch‐scale, complexity–biodiversity relationships may vary spatially and temporally according to the environmental stressors complexity mitigates, and the species richness and identity of potential colonists. Using a manipulative experiment, we assessed spatial variation in patch‐scale effects of complexity on intertidal biodiversity. Location 27 sites within 14 estuaries/bays distributed globally. Time period 2015–2017. Major taxa studied Functional groups of algae, sessile and mobile invertebrates. Methods Concrete tiles of differing complexity (flat; 2.5‐cm or 5‐cm complex) were affixed at low–high intertidal elevation on coastal defence structures, and the richness and abundance of the colonizing taxa were quantified after 12 months. Results The patch‐scale effects of complexity varied spatially and among functional groups. Complexity had neutral to positive effects on total, invertebrate and algal taxa richness, and invertebrate abundances. However, effects on the abundance of algae ranged from positive to negative, depending on location and functional group. The tidal elevation at which tiles were placed accounted for some variation. The total and invertebrate richness were greater at low or mid than at high intertidal elevations. Latitude was also an important source of spatial variation, with the effects of complexity on total richness and mobile mollusc abundance greatest at lower latitudes, whilst the cover of sessile invertebrates and sessile molluscs responded most strongly to complexity at higher latitudes. Conclusions After 12 months, patch‐scale relationships between biodiversity and habitat complexity were not universally positive. Instead, the relationship varied among functional groups and according to local abiotic and biotic conditions. This result challenges the assumption that effects of complexity on biodiversity are universally positive. The variable effect of complexity has ramifications for community and applied ecology, including eco‐engineering and restoration that seek to bolster biodiversity through the addition of complexity.

A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers800 and peak antibody fold change8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.

Coastal systems such as estuaries are threatened by multiple anthropogenic stressors worldwide. However, how these stressors and estuarine hydrology shape benthic bacterial communities and their functions remains poorly known. Here, we surveyed sediment bacterial communities in poorly flushed embayments and well flushed channels in Sydney Harbour, Australia, using 16S rRNA gene sequencing. Sediment samples were collected monthly during the Austral summer-autumn 2014 at increasing distance from a large storm drain in each channel and embayment. Bacterial communities differed significantly between sites that varied in proximity to storm drains, with a gradient of change apparent for sites within embayments. We explored this pattern for embayment sites with analysis of RNA-Seq gene expression patterns and found higher expression of multiple genes involved in bacterial stress response far from storm drains, suggesting that bacterial communities close to storm drains may be more tolerant of localised anthropogenic stressors. Several bacterial groups also differed close to and far from storm drains, suggesting their potential utility as bioindicators to monitor contaminants in estuarine sediments. Overall, our study provides useful insights into changes in the composition and functioning of benthic bacterial communities as a result of multiple anthropogenic stressors in differing hydrological conditions.

We experimentally investigated the saturable absorption influence of graphene layers with natural stacking order in an erbium-doped fiber laser passive mode-locking. Mechanically exfoliated graphene saturable absorber (MEGSA) samples, ranging from 1 to 6 layers, were fabricated preserving their natural ABA stacking order and precisely characterized by 2D band profile from Raman spectroscopy. By incorporating the samples as saturable absorbers (SA) in the fiber laser, mode-locking performances with pulse duration from 670–780 fs and bandwidth from 3.8–4.6 nm could be generated. Also, we identified a transition in the mode-locking activation mechanism from non-self-starting, for monolayer and bilayer graphene, to self-starting, for trilayer and few-layer graphene, which is a strong indicative of fast-to-slow saturable absorption response dependence on the number of graphene layers.

Preserving biodiversity over time is a pressing challenge for conservation science. A key goal of marine protected areas (MPAs) is to maintain stability in species composition, via reduced turnover, to support ecosystem function. Yet, this stability is rarely measured directly under different levels of protection. Rather, evaluations of MPA efficacy generally consist of static measures of abundance, species richness, and biomass, and rare measures of turnover are limited to short-term studies involving pairwise (beta diversity) comparisons. Zeta diversity is a recently developed metric of turnover that allows for measurement of compositional similarity across multiple assemblages and thus provides more comprehensive estimates of turnover. We evaluated the effectiveness of MPAs at preserving fish zeta diversity across a network of marine reserves over 10 years in Batemans Marine Park, Australia. Snorkel transect surveys were conducted across multiple replicated and spatially interspersed sites to record fish species occurrence through time. Protection provided by MPAs conferred greater stability in fish species turnover. Marine protected areas had significantly shallower decline in zeta diversity compared with partially protected and unprotected areas. The retention of harvested species was four to six times greater in MPAs compared with partially protected and unprotected areas, and the stabilizing effects of protection were observable within 4 years of park implementation. Conversely, partial protection offered little to no improvement in stability, compared with unprotected areas. These findings support the efficacy of MPAs for preserving temporal fish diversity stability. The implementation of MPAs helps stabilize fish diversity and may, therefore, support biodiversity resilience under ongoing environmental change.Impactos de las Áreas Protegidas Marinas sobre la Estabilidad Temporal de la Diversidad de Especies de Peces Resumen A medida que avanza el tiempo, la conservación de la biodiversidad es un reto apremiante para las ciencias de la conservación. Un objetivo importante de las áreas marinas protegidas (AMP) es mantener la estabilidad de la composición de especies, por medio de rotaciones reducidas, para así ayudar a la función del ecosistema. Sin embargo, esta estabilidad casi no se mide directamente bajo diferentes niveles de protección. En su lugar, las evaluaciones de eficiencia de las AMP generalmente consisten en medidas estáticas de abundancia, riqueza de especies y biomasa, y las pocas medidas de la rotación están limitadas a los estudios a corto plazo que involucran comparaciones por pares (diversidad beta). La diversidad zeta es una medida recientemente desarrollada de la rotación, la cual permite la medición de las similitudes en la composición en múltiples ensamblajes, proporcionando así estimaciones más completas de la rotación. Evaluamos la efectividad que tienen las AMP en la conservación de la diversidad zeta de los peces en una red de reservas marinas durante diez años en el Parque Marino Bateman, Australia. Se realizaron censos en transecto con snorkel en varios sitios replicados e intercalados espacialmente para registrar la presencia de especies de peces a lo largo del tiempo. La protección proporcionada por las AMP otorgó una mayor estabilidad en la rotación de especies de peces. Las áreas marinas protegidas tuvieron una declinación significativamente más baja de la diversidad zeta que las áreas parcialmente protegidas o desprotegidas. La retención de especies pescadas fue 4-6 veces mayor en las AMP que en las áreas desprotegidas o parcialmente protegidas, y los efectos estabilizadores de la protección fueron observables a partir de cuatro años de la implementación del parque. De manera opuesta, la protección parcial ofreció poca o ninguna estabilidad, comparada con las áreas desprotegidas. Estos descubrimientos respaldan la eficiencia que tienen las AMP en la conservación de la estabilidad temporal de la diversidad de especies de peces. La implementación de las AMP ayuda a estabilizar la diversidad de peces y por lo tanto puede fomentar la resiliencia de la biodiversidad frente al cambio ambiental en curso.【摘要】对生物多样性的长期保护是保护科学面临的一项紧迫挑战。海洋保护区 (MPAs) 的一个关键目标是通过降低周转率来维持物种组成稳定, 以支持生态系统功能。然而, 很少有研究直接测量不同保护级别的海洋中的物种稳定性。相反, 海洋保护区的有效性评估则通常包括对丰度、物种丰富度和生物量的静态测量, 少有的周转率量度也仅限于涉及成对 (beta 多样性) 比较的短期研究。 Zeta 多样性是近期发展起来的周转率指标, 它可以测量多个群集的物种组成相似性, 从而提供更全面的周转率估计。本研究利用澳大利亚贝特曼海岸公园超过十年的海洋保护区网络, 估计了海洋保护区在保护鱼类 zeta 多样性方面的有效性。我们通过在空间上分散的多个位点进行重复的浮潜样带调查, 记录了不同时期鱼类物种的出现情况。结果发现, 海洋保护区提供的保护使鱼类物种周转更加稳定。相比于部分保护区和未保护位点, 海洋保护区 zeta 多样性下降明显更为缓和, 且对渔获物种的保留率高出 4-6 倍, 这种保护带来的稳定性成效可以在建立海岸公园的四年内观测到。相反, 部分保护区与未受保护位点相比, 在稳定性方面几乎没有改善。这些发现支持了海洋保护区在保护鱼类多样性时间稳定性方面的有效性。海洋保护区的建立有助于稳定鱼类多样性, 因此可以支持持续环境变化背景下的生物多样性恢复力。【翻译: 胡怡思; 审校: 聂永刚】.

INTRODUCTION AND OBJECTIVE:Nadofaragene firadenovec is a recombinant adenoviral vector-based intravesical therapeutic that delivers a copy of human IFNα2b gene to urothelial cells. A recent phase 3...

Objectives To evaluate the role of blue-light cystoscopy (BLC) in detecting invasive tumours that were not visible on white-light cystoscopy (WLC). Patients and methods Using the multi-institutional Cysview registry database, patients who had at least one white-light negative (WL-)/blue-light positive (BL+) lesion with invasive pathology (≥T1) as highest stage tumour were identified. All WL-/BL+ lesions and all invasive tumours in the database were used as denominators. Relevant baseline and outcome data were collected. Results Of the 3514 lesions (1257 unique patients), 818 (23.2%) lesions were WL-/BL+, of those, 55 (7%) lesions were invasive (48 T1, seven T2; 47 unique patients) including 28/55 (51%) de novo invasive lesions (26 unique patients). In all, 21/47 (45%) patients had WL-/BL+ concommitant carcinoma in situ and/or another T1 lesions. Of 22 patients with a WL-/BL+ lesion who underwent radical cystectomy (RC), high-risk pathological features leading to RC was only visible on BLC in 18 (82%) patients. At time of RC, 11/22 (50%) patients had pathological upstaging including four (18%) with node-positive disease. Conclusions A considerable proportion of invasive lesions are only detectable by BLC and the rate of pathological upstaging is significant. Our present findings suggest an additional benefit of BLC in the detection of invasive bladder tumours that has implications for treatment approach.

A number of immunotherapies have been developed and adopted for the treatment of urothelial cancer (encompassing cancers arising from the bladder, urethra, or renal pelvis). For these immunotherapies to positively impact patient outcomes, optimal selection of agents and treatment scheduling, especially in conjunction with existing treatment paradigms, is paramount. Immunotherapies also warrant specific and unique considerations regarding patient management, emphasizing both the prompt identification and treatment of potential toxicities. In order to address these issues, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts in the field of immunotherapy for urothelial cancer. The expert panel developed this clinical practice guideline (CPG) to inform healthcare professionals on important aspects of immunotherapeutic treatment for urothelial cancer, including diagnostic testing, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with urothelial cancer.

Administration of rabies postexposure prophylaxis (PEP) is expensive and time-consuming. In suburban Cook County, Illinois, USA, administration of 55.5% of PEP treatments did not follow Advisory Committee on Immunization Practices guidelines. Health department consultation lowered the odds of inappropriate PEP administration by 87%. Providers should consult their health department before prescribing PEP.

Non-muscle-invasive bladder cancer (NMIBC) is the most common form of bladder cancer, with frequent recurrences and risk of progression. Risk-stratified treatment and surveillance protocols are often used to guide management. In 2017, BJUI reviewed guidelines on NMIBC from four major organizations: the American Urological Association/Society of Urological Oncology, the European Association of Urology, the National Comprehensive Cancer Network, and the National Institute for Health and Care Excellence. The present update will review major changes in the guidelines and broadly summarize new recommendations for treatment of NMIBC in an era of bacillus Calmette-Guerin shortage and immense novel therapy development.

Current guidelines recommend confirming a negative urethral margin prior to orthotopic neobladder reconstruction. We investigated our rate of urethral positive margins and recurrence in the absence of intraoperative frozen section.We retrospectively reviewed clinical and pathological data on 357 patients who underwent radical cystectomy and orthotopic urinary diversion without intraoperative frozen section. At a median followup of 27 months the rates of positive urethral margins and urethral recurrence were tabulated. Differences in overall and recurrence-free survival in patients with a positive urethral margin were analyzed by Cox regression to generate the HR with the 95% CI.We identified 6 urethral recurrences (1.6%) during followup. The urethral recurrence rate was not higher in patients with a positive urethral margin (p=0.22). In the 15 patients with positive urethral margins overall survival was unchanged (HR 0.98, 95% CI 0.24-4.04). When accounting for lymph node staging, recurrence-free survival was not significantly worse in patients with positive urethral margins (HR 2.33, 95% CI 0.95-5.73).Omitting intraoperative frozen section prior to orthotopic neobladder reconstruction appears safe with a rate of urethral recurrence similar to that in historical series. It may allow for increased performance of orthotopic urinary diversions.

Background & Aims African American and European American individuals have a similar prevalence of gastroesophageal reflux disease (GERD), yet esophageal adenocarcinoma (EAC) disproportionately affects European American individuals. We investigated whether the esophageal squamous mucosa of African American individuals has features that protect against GERD-induced damage, compared with European American individuals. Methods We performed transcriptional profile analysis of esophageal squamous mucosa tissues from 20 African American and 20 European American individuals (24 with no disease and 16 with Barrett's esophagus and/or EAC). We confirmed our findings in a cohort of 56 patients and analyzed DNA samples from patients to identify associated variants. Observations were validated using matched genomic sequence and expression data from lymphoblasts from the 1000 Genomes Project. A panel of esophageal samples from African American and European American subjects was used to confirm allele-related differences in protein levels. The esophageal squamous-derived cell line Het-1A and a rat esophagogastroduodenal anastomosis model for reflux-generated esophageal damage were used to investigate the effects of the DNA-damaging agent cumene-hydroperoxide (cum-OOH) and a chemopreventive cranberry proanthocyanidin (C-PAC) extract, respectively, on levels of protein and messenger RNA (mRNA). Results We found significantly higher levels of glutathione S-transferase theta 2 (GSTT2) mRNA in squamous mucosa from African American compared with European American individuals and associated these with variants within the GSTT2 locus in African American individuals. We confirmed that 2 previously identified genomic variants at the GSTT2 locus, a 37-kb deletion and a 17-bp promoter duplication, reduce expression of GSTT2 in tissues from European American individuals. The nonduplicated 17-bp promoter was more common in tissue samples from populations of African descendant. GSTT2 protected Het-1A esophageal squamous cells from cum-OOH–induced DNA damage. Addition of C-PAC increased GSTT2 expression in Het-1A cells incubated with cum-OOH and in rats with reflux-induced esophageal damage. C-PAC also reduced levels of DNA damage in reflux-exposed rat esophagi, as observed by reduced levels of phospho-H2A histone family member X. Conclusions We found GSTT2 to protect esophageal squamous cells against DNA damage from genotoxic stress and that GSTT2 expression can be induced by C-PAC. Increased levels of GSTT2 in esophageal tissues of African American individuals might protect them from GERD-induced damage and contribute to the low incidence of EAC in this population.

Background Clinically localized renal cell carcinoma is treated primarily with surgery followed by observation or adjuvant sunitinib in selected high-risk patients. The checkpoint inhibitor immunotherapeutic agents nivolumab and ipilimumab have recently shown a survival benefit in the first-line metastatic setting. To date, there have been no reports on the response of localized renal cancer to modern immunotherapy. We report a remarkable response of an advanced tumor thrombus to combined immunotherapy which facilitated curative-intent resection of the non-responding primary renal tumor. We characterized the tumor microenvironment within the responding and non-responding tumors. Case presentation A 54-year-old female was diagnosed with a locally advanced clear cell renal cell carcinoma with a level IV tumor thrombus of the vena cava. She was initially deemed unfit for surgical resection due to poor performance status. She underwent neoadjuvant immunotherapy with nivolumab and ipilimumab with a complete response of the vena cava and renal vein tumor thrombus, but had stable disease within her renal mass. She underwent complete surgical resection with negative margins and remains disease-free longer than 1 year after her diagnosis with no further systemic therapy. Notably, pathologic analysis showed a complete response within the vena cava and renal vein, but substantial viable cancer remained in the kidney. Multichannel immunofluorescence was performed and showed marked infiltration of immune cells including CD8+ T cells and Batf3+ dendritic cells in the thrombus, while the residual renal tumor showed a non-T cell-inflamed phenotype. Conclusions Preoperative immunotherapy with nivolumab and ipilimumab for locally advanced clear cell renal cancer resulted in a complete response of an extensive vena cava tumor thrombus, which enabled curative-intent resection of a non-responding primary tumor. If validated in larger cohorts, preoperative immunotherapy for locally advanced renal cell carcinoma may ultimately impact surgical planning and long-term prognosis.

Background Bladder cancer is commonly diagnosed in patients ineligible for radical cystectomy or chemoradiotherapy (chemo-RT) with cisplatin or fluorouracil with mitomycin. We assessed tolerability, efficacy, and toxicity of hypofractionated radiotherapy with capecitabine in this challenging population. Patients and Methods Patients with high-grade urothelial bladder cancer ineligible for radical cystectomy or high-intensity chemo-RT underwent maximal transurethral resection of bladder tumor followed by capecitabine (median, 825 mg/m2 per day 2 times a day) and radiation (median, 55 Gy in 2.2 Gy per fraction). Patients underwent surveillance cystoscopy and imaging, and were evaluated for toxicity, freedom from local failure and freedom from distant metastasis, progression-free survival, and overall survival. Results Eleven patients (median age, 80 years) with localized disease (n = 7), locally advanced disease (n = 3), or local-only recurrence after cystectomy (n = 1) were treated. Four patients (35%) had an Eastern Cooperative Oncology Group performance status of 2; median Charlson comorbidity index was 5. There was 1 acute grade 3 genitourinary event (9%), 6 acute grade 3 hematologic events (55%) of lymphopenia, and no acute grade 4 or higher events or hospitalizations. Ten patients (91%) completed radiotherapy, while 4 patients (36%) temporarily discontinued capecitabine. The complete response rate in the bladder was 64%. Two patients (18%) experienced late grade 1/2 genitourinary toxicities, and 1 (9%) experienced a transient late grade 4 genitourinary toxicity. With a median follow-up of 16.6 months, overall survival, progression-free survival, freedom from local failure, and freedom from distant metastasis at 1 year were 82%, 55%, 100%, and 55%, respectively, and at 2 years were 61%, 41%, 80%, and 55%, respectively. Conclusion Hypofractionated chemo-RT was well tolerated and was associated with a high rate of local control in this comorbid population, thus providing a treatment option for select bladder cancer patients.

Our understanding of diseases has been transformed by the realisation that people are holobionts, comprised of a host and its associated microbiome(s). Disease can also have devastating effects on populations of marine organisms, including dominant habitat formers such as seaweed holobionts. However, we know very little about how interactions between microorganisms within microbiomes - of humans or marine organisms – affect host health and there is no underpinning theoretical framework for exploring this. We applied ecological models of succession to bacterial communities to understand how interactions within a seaweed microbiome affect the host. We observed succession of surface microbiomes on the red seaweed Delisea pulchra in situ, following a disturbance, with communities ‘recovering’ to resemble undisturbed states after only 12 days. Further, if this recovery was perturbed, a bleaching disease previously described for this seaweed developed. Early successional strains of bacteria protected the host from colonisation by a pathogenic, later successional strain. Host chemical defences also prevented disease, such that within-microbiome interactions were most important when the host’s chemical defences were inhibited. This is the first experimental evidence that interactions within microbiomes have important implications for host health and disease in a dominant marine habitat-forming organism.

Immune checkpoint inhibitors have revolutionized the treatment of patients with metastatic urothelial carcinoma. In cisplatin-eligible muscle-invasive bladder cancer (MIBC), cisplatin-based neoadjuvant chemotherapy (NAC) before radical cystectomy improves overall survival. Tumor PD-L1 expression increases in MIBC after NAC, suggesting potential synergy in combining PD1/PD-L1 inhibitors with NAC. IDO1 is overexpressed in bladder cancer and is associated with poor outcomes. Linrodostat mesylate (BMS-986205) – a selective, potent, oral IDO1 inhibitor – combined with nivolumab has demonstrated safety and preliminary evidence of clinical activity in metastatic urothelial carcinoma. Here, we discuss the rationale and trial design of the ENERGIZE, a Phase III trial investigating the efficacy of NAC in combination with nivolumab with or without linrodostat followed by postsurgery nivolumab or nivolumab with linrodostat in cisplatin-eligible patients with MIBC. Clinical trial registration number: NCT03661320

We present the design and pilot trial of near-field communication (NFC) sensors for the long-term preventive care of fine art objects. This work was undertaken to address the unmet need for a permanent and unified object specific sensory and digital data labelling system for fine art objects that does not require large-scale wireless infrastructure. The sensor-tags are demonstrated in a six-month pilot study to evaluate the temperature and humidity buffering performance of a microclimate enclosure (MCE) constructed to protect a late C16th panel painting. The framed painting fitted with NFC sensor-tags was hung in a busy, and environmentally uncontrolled, Cambridge college dining hall to mimic a typically large, semi-public exhibition space. The resulting visibility of climatic conditions and the detailed analytics made possible from the data sets harvested from the NFC sensor-tags have provided invaluable information to the painting conservators. This study provides the first steps in understanding how object specific electronic sensor-tags will play a critical role in improving the display management, storage and long-term preventive care of fine art objects.

Contains fulltext : 251844.pdf (Publisher’s version ) (Open Access) OBJECTIVES: Neoadjuvant chemotherapy and radical cystectomy (RC) are underutilized standards of care for the treatment of muscle-invasive bladder cancer (MIBC) due to high patient burden from systemic toxicities and postoperative complications, respectively. TAR-200 is a novel intravesical drug delivery system developed to release gemcitabine into the bladder urine continuously, resulting in distribution of drug into stromal layers of the bladder. The primary aim of the TAR-200-101 study was to evaluate the safety of TAR-200 in patients with MIBC prior to RC (NCT02722538). METHODS AND MATERIALS: This phase I, open-label study was conducted across 6 US and European sites. Eligible patients were aged ≥18 years with histologically confirmed T2a-T3b N0-N1 M0 urothelial cancer and had refusal or were ineligible to receive cisplatin-based combination chemotherapy. Two arms were enrolled serially. Patients in Arm 1 had residual tumor >3 cm after transurethral resection of bladder tumor (TURBT); those in Arm 2 had undergone maximal TURBT (residual tumor

Epiphytic microbial communities often have a close relationship with their eukaryotic host, assisting with defence, health, disease prevention and nutrient transfer. Shifts in the structure of microbial communities could therefore have negative effects on the individual host and indirectly impact the surrounding ecosystem, particularly for major habitat-forming hosts, such as kelps in temperate rocky shores. Thus, an understanding of the structure and dynamics of host-associated microbial communities is essential for monitoring and assessing ecosystem changes. Here, samples were taken from the ecologically important kelp, Ecklonia radiata, over a 17-month period, from six different sites in two distinct geographic regions (East and West coasts of Australia), separated by ∼3,300 kms, to understand variation in the kelp bacterial community and its potential environmental drivers. Differences were observed between kelp bacterial communities between the largely disconnected geographical regions. In contrast, within each region and over time the bacterial communities were considerably more stable, despite substantial seasonal changes in environmental conditions.

Improvement of risk stratification through prognostic biomarkers may enhance the personalization of cancer patient monitoring and treatment. We used Ancer, an immunoinformatic CD8, CD4, and regulatory T cell neoepitope screening system, to perform an advanced neoantigen analysis of genomic data derived from the urothelial cancer cohort of The Cancer Genome Atlas. Ancer demonstrated improved prognostic stratification and five-year survival prediction compared to standard analyses using tumor mutational burden or neoepitope identification using NetMHCpan and NetMHCIIpan. The superiority of Ancer, shown in both univariate and multivariate survival analyses, is attributed to the removal of neoepitopes that do not contribute to tumor immunogenicity based on their homology with self-epitopes. This analysis suggests that the presence of a higher number of unique, non-self CD8- and CD4-neoepitopes contributes to cancer survival, and that prospectively defining these neoepitopes using Ancer is a novel prognostic or predictive biomarker.

We report a case of a newborn with two synchronous tumors—sialoblastoma and hepatoblastoma—diagnosed at 20 weeks of gestation by magnetic resonance imaging (MRI) and ultrasonography (US). The aim of this study was to describe the management of this case together with a review of the literature. Our patient had a large facial tumor associated with extremely high alpha-fetoprotein levels. Diagnosis of the tumors was made by surgical biopsy, showing typical features in both. Sialoblastoma is a potentially aggressive tumor. In our case, the Ki67 index in the sialoblastoma was between 20 and 30%, indicating a possibly unfavorable behavior. The infant underwent surgery and chemotherapy in different steps. Complete surgical resection with clean margins is considered to be the best treatment option for sialoblastoma. Only four similar cases were previously reported. Timely management by a multidisciplinary team is essential in these difficult cases. In our patient, outcome was good at the time of this report.

Background: Hyperglycemia occurs in over 40% of ischemic stroke patients, which induces hemorrhagic transformation (HT) and worsens stroke outcomes. The management of hyperglycemia with insulin did not show favorable outcomes. Thus, strategies for managing hyperglycemia-exacerbated stroke injury are urgently needed. We previously demonstrated that ischemic postconditioning (IPostC) (repeated transient interruption of cerebral blood flow during reperfusion) can reduce brain infarct size and improve neurological outcomes. In this study, we hypothesized that IPostC can reduce HT in ischemic stroke with acute hyperglycemia. Method: Male mice were subjected to middle cerebral artery occlusion (MCAO) for 1 hour, followed by reperfusion to mimic ischemic stroke. Glucose was injected before MCAO to induce hyperglycemia. IPostC was initiated upon reperfusion with 3 cycles of 30-second reperfusion followed by 10 seconds of MCA occlusion. Brain infarct was visualized by TTC staining and quantitated using Image J. Hemorrhagic transformation was evaluated by hemorrhagic scores. Result: Acute hyperglycemia significantly increased the brain infarct size (by 25%, p Conclusion: Our findings suggest that IPostC can counteract the effects of acute hyperglycemia and reduce brain injury, edema and HT after stroke. Grant/Other Support: NIH Grant R01NS064136C

Background: Moyamoya disease (MMD) is a rare, progressive steno-occlusive cerebrovascular disorder of the internal carotid artery, leading to stroke. Affected arteries exhibited thickened intima with depleted elastic lamina and media, indicating a dysfunction of the vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). However, the pathogenesis of the disease is still unclear. We aim to address this gap in knowledge by using patient derived induced pluripotent stem cells (iPSCs), to generate VSMCs and ECs. Methods: Peripheral blood mononuclear cells (PBMCs) from controls and MMD patients (n=3 per group) were used for generating iPSCs. Functional properties of differentiated ECs and VSMCs in normoxia/hypoxia model (1%O 2 ) were assessed for cell proliferation by BrDU incorporation, migration by scratch assays and apoptosis by exposure to hydrogen peroxide (H2O2). In vitro angiogenic tube formation was assessed with ECs alone, as well as ECs and VSMCs as a co-culture. Hypoxia inducible factor 1α (HIF1α) and Intercellular adhesion molecule-1 (ICAM-1) activation was determined using qPCR and western blot in VSMCs. Results: Functional proliferative assays showed that MMD ECs proliferated faster than control ECs. Migration assays showed that MMD ECs migrate slower in response to VEGF after hypoxia. MMD ECs were found to be more sensitive to insults such as H2O2 treatment and exhibited more apoptosis. In contrast, MMD VSMCs proliferate and migrate similar to controls, but exhibited elevated levels of HIF1α, ICAM-1 mRNA and protein expression. MMD and control ECs showed similar levels of tube formation in single cultures, however, when co-culturing with VSMCs, MMD VSMCs failed to support EC tubes beyond 24 h, resulting in tube destabilization. Conclusions: Our preliminary results indicate that both MMD VSMCs and ECs are dysfunctional and may be related to the elevated expression of HIF1α and ICAM-1, possibly contributing to MMD pathology. Current ongoing studies include investigating the interactions between MMD VSMCs and ECs using co-cultures, as well as transcriptome analysis of these differentiated cells, which will provide important insights into the cellular and molecular mechanisms underlying MMD.

Stroke is a leading cause of long-term disability and death in the united states. The development of new therapies for stroke are sorely needed. There is great hope that stem cell therapy will create a paradigm shift in the treatment of stroke patients. A barrier to ensuring clinical success of stem cell therapy is the paucity of understanding of the mechanisms by which stem cells exert their beneficial effects. Using a novel mRNA purification method, we identified 50 genes encoding extracellular space proteins, expressed by human neural stem cells (hNSCs) whose expression positively correlated with functional recovery. In this study, we focus on one of the paracrine factors from grafted hNSCs that correlated best with functional recovery, to investigate its therapeutic potential in promoting recovery after stroke. Male nude rats underwent stroke using the distal middle cerebral artery occlusion (dMCAo) model. One week following stroke, osmotic pumps were prepared and loaded with recombinant MTN-2. The osmotic pumps were inserted into the peri-infarct area and infused recombinant MTN-2 for 5 days. Post-stroke, animals were assessed for functional recovery for 5 weeks using both the Montoya staircase test and the whisker-paw reflex test to assess for forelimb function, dexterity, side bias, and placing deficits. After 5 weeks, brain tissue was isolated to assess glial cell morphology. Brain sections were stained with GFAP and IBA1 to visualize astrocytes and microglia, respectively. Confocal images were processed and analyzed using the Bitplane Imaris image analysis software. Output measurements of number of cells/mm2, cell volume, cell branching, and process length and thickness were obtained to characterize the changes in astrocytic and microglial response to injury and paracrine factor treatment. By identifying paracrine factors that are responsible for the regeneration of brain tissue following implantation of hNSCs in stroke brain, this work will increase the likelihood of successful clinical translation of stem cell therapy for stroke. Moreover, elucidating these molecular pathways important for brain recovery may ultimately identify novel therapeutic targets and offer hope to millions of Americans who live with the devastating effects of stroke.

Moyamoya disease (MMD) is a progressive, occlusive disease of the internal carotid arteries and their proximal branches, with the subsequent development of an abnormal vascular network of small, weak blood vessels that are prone to rupture. Steno-occlusive changes in the posterior cerebral arteries (PCA) may contribute to worse outcomes in MMD patients, however, there is a paucity of information on the incidence and natural history of MMD patients with PCA disease. We retrospectively reviewed the charts of patients with MMD treated between 1987 and 2019. Demographics, peri-operative outcomes, and radiological phenotypes were recorded for 450 patients. PCA disease was scored as either 0 (no disease), 1 (mild), 2 (moderate), or 3 (severe, or occluded). Out of 450 patients, 164 (34.4%) had concurrent PCA disease. In patients with PCA disease, the extent of occlussion was mild in 56 (34%), moderate in 41 (25%), and severe in 67 (40.9%) patients. In total, there were 319 females (70.9%), with a higher proportion of female MMD patients having severe or moderate PCA disease (p=0.038). Patients with severe and moderate PCA disease had higher Suzuki grades (p Over a mean follow-up of 6.94±4.16 years, 28 patients (8.86%) developed new or progressive PCA disease. Bilateral disease was present in 66 patients (14.7%) and was associated with higher Suzuki grades (p PCA disease involvement is associated with higher rates of ischemic peri-operative complications and poor functional outcomes likely due to reduced collateral flow. Progression of PCA disease is not uncommon. Future studies are needed to assess the impact of PCA disease progression on long-term outcomes.

Purpose Smoking has a strong causal association with bladder cancer but the relationship with recurrence is not well established. We sought to assess the association of smoking status on recurrence of non-muscle invasive bladder cancer (NMIBC) in a contemporary cohort of patients with predominantly high-risk, recurrent NMIBC managed with photodynamic enhanced cystoscopy. Materials and methods We performed a retrospective study of patients with NMIBC included in a multi-institutional registry. Our primary exposure of interest was smoking status. Our primary outcome was first recurrence of NMIBC. Kaplan-Meier analysis was used to calculate recurrence free probabilities and Cox proportional hazards regression was used to evaluate the impact of smoking status on recurrence free survival. Results Our analytic cohort included 723 adults with bladder cancer, 11.5% with primary NMIBC and 88.5% with recurrent NMIBC. The majority of patients were white, male, and had high-risk NMIBC (72.6%). 52.6% of included patients were former smokers and 12.7% were current smokers. During the three-year study period, there was a NMIBC recurrence in 259 of the 723 patients (35.8%). The 1- and 3-year probability of recurrence was 19% and 44%, respectively. The grade and stage of recurrences were 28.9% LG Ta, 34.4% HG Ta, 15.8% pure CIS, 0.3% LG T1, 15.4% HG T1, and 5.4% unknown. After adjustment for a priori clinical and demographic factors, smoking status had no significant association with recurrence. Conclusion Smoking status was not significantly association with recurrence in a study of patients with predominantly high-risk recurrent NMIBC managed with photodynamic enhanced cystoscopy.

Contains fulltext : 237687.pdf (Publisher’s version ) (Open Access) Muscle-invasive bladder cancer (MIBC) is associated with high rates of recurrence and poor prognosis despite aggressive treatment. Neoadjuvant chemotherapy before radical cystectomy (RC) improves outcomes in cisplatin-eligible patients; however, the improvement in overall survival is modest. Standard of care for cisplatin-ineligible patients remains RC; more effective systemic therapies are needed. Recent Phase Ib/II studies suggest pembrolizumab monotherapy and combination therapy are effective neoadjuvant therapies for MIBC. The randomized Phase III KEYNOTE-866 and KEYNOTE-905/EV-303 studies are being conducted to evaluate efficacy and safety of perioperative pembrolizumab or placebo with chemotherapy in cisplatin-eligible patients with MIBC (KEYNOTE-866) and of pembrolizumab monotherapy versus pembrolizumab plus enfortumab vedotin versus RC plus pelvic lymph node dissection alone in cisplatin-ineligible patients with MIBC (KEYNOTE-905/EV-303). Clinical trial registration: NCT03924856 & NCT03924895 (ClinicalTrials.gov).