Loss of SMAD4 Is Associated With Poor Tumor Immunogenicity and Reduced PD-L1 Expression in Pancreatic Cancer

Transforming Growth Factor β (TGFβ) is a key mediator of immune evasion in pancreatic ductal adenocarcinoma (PDAC), and the addition of TGFβ inhibitors in select immunotherapy regimens shows early promise. Though the TGFβ target SMAD4 is deleted in approximately 55% of PDAC tumors, the effects of SMAD4 loss on tumor immunity have yet to be fully explored. Using a combination of genomic databases and PDAC specimens, we found that tumors with loss of SMAD4 have a comparatively poor T-cell infiltrate. SMAD4 loss was also associated with a reduction in several chemokines with known roles in T-cell recruitment, which was recapitulated using knockdown of SMAD4 in PDAC cell lines. Accordingly, JURKAT T-cells were poorly attracted to conditioned media from PDAC cells with knockdown of SMAD4 and lost their ability to produce IFNγ. However, while exogenous TGFβ modestly reduced PD-L1 expression in SMAD4-intact cell lines, SMAD4 and PD-L1 positively correlated in human PDAC samples. PD-L1 status was closely related to tumor-infiltrating lymphocytes, particularly IFNγ-producing T-cells, which were more abundant in SMAD4-expressing tumors. Low concentrations of IFNγ upregulated PD-L1 in tumor cells in vitro, even when administered alongside high concentrations of TGFβ. Hence, while SMAD4 may have a modest inhibitory effect on PD-L1 in tumor cells, SMAD4 indirectly promotes PD-L1 expression in the pancreatic tumor microenvironment by enhancing T-cell infiltration and IFNγ biosynthesis. These data suggest that pancreatic cancers with loss of SMAD4 represent a poorly immunogenic disease subtype, and SMAD4 status warrants further exploration as a predictive biomarker for cancer immunotherapy

Defining cognitive impairment in people-living-with-HIV: the POPPY study

Background The reported prevalence of cognitive impairment (CI) varies widely in cohorts of people living with HIV (PLWH); this may partly be due to the use of different diagnostic criteria. Agreement between diagnostic criteria of CI, the optimal definition to use, and associations with patient-reported cognitive symptoms have not been fully investigated. Methods Two hundred ninety PLWH aged >50 years and 97 matched negative controls completed a detailed assessment of cognitive function and three questions regarding cognitive symptoms. Age- and education-adjusted test scores (T-scores) determined if subjects met the following definitions of CI: Frascati, global deficit score (GDS) and the multivariate normative comparison (MNC) method. Results PLWH were more likely than controls to meet each definition of CI (ORs were 2.17, 3.12 and 3.64 for Frascati, GDS and MNC, respectively). Agreement of MNC with Frascati and GDS was moderate (Cohen’s k = 0.42 and 0.48, respectively), whereas that between Frascati and GDS was good (k = 0.74). A significant association was found between all the three criteria and reporting of memory loss but not with attention and reasoning problems. The 41 (14 %) PLWH meeting all the three criteria had the lowest median global T-score (36.9) and highest rate of symptom reporting (42 %). Conclusions Different CI criteria show fair diagnostic agreement, likely reflecting their ability to exclude CI in the same group of individuals. Given the lower overall cognitive performance and higher rates of symptom reporting in those meeting all three criteria of CI, further work assessing this as a definition of CI in PLWH is justified

Dorsal muscle group area and surgical outcomes in liver transplantation

Introduction Better measures of liver transplant risk stratification are needed. Our previous work noted a strong relationship between psoas muscle area and survival following liver transplantation. The dorsal muscle group is easier to measure, but it is unclear if they are also correlated with surgical outcomes. Methods Our study population included liver transplant recipients with a preoperative CT scan. Cross‐sectional areas of the dorsal muscle group at the T12 vertebral level were measured. The primary outcomes for this study were one‐ and five‐yr mortality and one‐yr complications. The relationship between dorsal muscle group area and post‐transplantation outcome was assessed using univariate and multivariate techniques. Results Dorsal muscle group area measurements were strongly associated with psoas area ( r  = 0.72; p < 0.001). Postoperative outcome was observed from 325 patients. Multivariate logistic regression revealed dorsal muscle group area to be a significant predictor of one‐yr mortality (odds ratio [ OR ] = 0.53, p = 0.001), five‐yr mortality ( OR  = 0.53, p < 0.001), and one‐yr complications ( OR  = 0.67, p = 0.007). Conclusion Larger dorsal muscle group muscle size is associated with improved post‐transplantation outcomes. The muscle is easier to measure and may represent a clinically relevant postoperative risk factor.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109316/1/ctr12422.pd

Surgical resident experience with common bile duct exploration and assessment of performance and autonomy with formative feedback

Background Common bile duct exploration (CBDE) is safe and effective for managing choledocholithiasis, but most US general surgeons have limited experience with CBDE and are uncomfortable performing this procedure in practice. Surgical trainee exposure to CBDE is limited, and their learning curve for achieving autonomous, practice-ready performance has not been previously described. This study tests the hypothesis that receipt of one or more prior CBDE operative performance assessments, combined with formative feedback, is associated with greater resident operative performance and autonomy. Methods Resident and attending assessments of resident operative performance and autonomy were obtained for 189 laparoscopic or open CBDEs performed at 28 institutions. Performance and autonomy were graded along validated ordinal scales. Cases in which the resident had one or more prior CBDE case evaluations (n = 48) were compared with cases in which the resident had no prior evaluations (n = 141). Results Compared with cases in which the resident had no prior CBDE case evaluations, cases with a prior evaluation had greater proportions of practice-ready or exceptional performance ratings according to both residents (27% vs. 11%, p = .009) and attendings (58% vs. 19%, p &lt; .001) and had greater proportions of passive help or supervision only autonomy ratings according to both residents (17% vs. 4%, p = .009) and attendings (69% vs. 32%, p &lt; .01). Conclusions Residents with at least one prior CBDE evaluation and formative feedback demonstrated better operative performance and received greater autonomy than residents without prior evaluations, underscoring the propensity of feedback to help residents achieve autonomous, practice-ready performance for rare operations

Multidecadal High Mortality Disease Events in Australian Domestic Geese Associated with a Novel Alphaherpesvirus, Designated Anatid Alphaherpevirus 2

Herpesviruses are ubiquitous viruses which infect a wide range of hosts. Novel herpesviruses are being increasingly detected in free-ranging bird populations and there are growing concerns for cross-species infection and spillover events. Herein, multiple sporadic outbreaks of mortality caused by a herpesvirus are described in domestic geese in Queensland, Australia. Goose herpesvirus was initially detected in 1989 in south-east Queensland, and this article details four further recent outbreaks and reports novel genome sequencing and phylogeny of the preliminarily designated anatid alphaherpesvirus 2 (AnHV-2). Affected flocks were housed outdoors and comingled with other domesticated and wild anseriforms and other birds which were unaffected by disease. Affected geese displayed anorexia, lethargy, weakness, vomiting, and diarrhoea prior to death within 12–24 hr of the onset of clinical signs. Post-mortem examinations showed variable hepatic necrosis, splenic necrosis, fibrinonecrotising enteritis, lymphoid necrosis, necrotising thymitis, necrotising adrenalitis, and vasculitis. Intranuclear inclusion bodies were observed in hepatocytes, biliary epithelium, small intestinal mucosal epithelium, thymus, endothelial cells, ovarian stromal cells, adrenal cortical cells, and neuronal cell bodies in peripheral nerve ganglia. Transmission electron microscopy visualised herpesviral particles in virus culture supernatant, and within the nuclei of hepatocytes, biliary epithelium, and endothelial cells in case tissues. The genome sequence of this herpesvirus, designated anatid alphaherpesvirus 2 (AnHV-2), is described. While investigating goose mortalities, archived isolate from a swan with suspected herpesvirus infection was tested and genome sequencing identified a further novel herpesvirus, proposed anatid alphaherpesvirus 3 (AnHV-3). The AnHV-2 and AnHV-3 genomes were more similar to each other, with a nucleotide identity of 76.1%, than to reference genome sequences. Phylogenetically, the new genomes formed a distinct clade within the alphaherpesvirus genus Mardivirus. We sequenced four AnHV-2 genomes from different cases and these did not display consistent divergence over time or distance. Expanded surveillance and outbreak testing are recommended, facilitated by the development of a specific real-time PCR for the rapid detection of AnHV-2

Scintillation Observations and Response of The Ionosphere to Electrodynamics (SORTIE) Mission First Light

At low and middle latitudes, wave-like plasma perturbations are thought to provide the seeds for larger perturbations that may evolve non-linearly to produce irregularities, which in turn have deleterious effects on HF communications and global positioning systems. Unfortunately, there is currently no comprehensive atlas of measurements describing the global spatial or temporal distribution of wave-like perturbations in the ionosphere. The SORTIE mission, a CubeSat experiment with team members from ASTRA, AFRL, UTD, and Boston College, was designed to help map and further understand the wave-like plasma perturbation distributions throughout the ionosphere. The SORTIE 6U CubeSat sensor package measures key in-situ plasma parameters, and includes an ion velocity meter and a planar Langmuir probe. SORTIE will provide (1) the initial spectrum of wave perturbations which are the starting point for plasma instabilities; (2) measured electric fields which determine the magnitude of the instability growth rate near the region where plasma bubbles are generated; (3) initial observations of irregularities in plasma density which result from plasma instability growth. The SORTIE spacecraft was deployed from the ISS in February 2020 and began data collections shortly after orbit insertion. The measurements are expected to continue for at least a year. In this presentation we present the first light results of the SORTIE mission, as well as reviewing the science objectives and providing an overview of the spacecraft and instruments

16th Annual Environmental Law Institute

Materials from the 16th Annual Environmental Law Institute held by UK/CLE in May 2000

Defining cognitive impairment in people-living-with-HIV: the POPPY study

Background The reported prevalence of cognitive impairment (CI) varies widely in cohorts of people living with HIV (PLWH); this may partly be due to the use of different diagnostic criteria. Agreement between diagnostic criteria of CI, the optimal definition to use, and associations with patient-reported cognitive symptoms have not been fully investigated. Methods Two hundred ninety PLWH aged >50 years and 97 matched negative controls completed a detailed assessment of cognitive function and three questions regarding cognitive symptoms. Age- and education-adjusted test scores (T-scores) determined if subjects met the following definitions of CI: Frascati, global deficit score (GDS) and the multivariate normative comparison (MNC) method. Results PLWH were more likely than controls to meet each definition of CI (ORs were 2.17, 3.12 and 3.64 for Frascati, GDS and MNC, respectively). Agreement of MNC with Frascati and GDS was moderate (Cohen’s k = 0.42 and 0.48, respectively), whereas that between Frascati and GDS was good (k = 0.74). A significant association was found between all the three criteria and reporting of memory loss but not with attention and reasoning problems. The 41 (14 %) PLWH meeting all the three criteria had the lowest median global T-score (36.9) and highest rate of symptom reporting (42 %). Conclusions Different CI criteria show fair diagnostic agreement, likely reflecting their ability to exclude CI in the same group of individuals. Given the lower overall cognitive performance and higher rates of symptom reporting in those meeting all three criteria of CI, further work assessing this as a definition of CI in PLWH is justified

Long-Term Gemcitabine Treatment Reshapes the Pancreatic Tumor Microenvironment and Sensitizes Murine Carcinoma to Combination Immunotherapy

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death with a median survival time of 6–12 months. Most patients present with disseminated disease and the majority are offered palliative chemotherapy. With no approved treatment modalities for patients who progress on chemotherapy, we explored the effects of long-term Gemcitabine on the tumor microenvironment in order to identify potential therapeutic options for chemo-refractory PDAC. Using a combination of mouse models, primary cell line-derived xenografts, and established tumor cell lines, we first evaluated chemotherapy-induced alterations in the tumor secretome and immune surface proteins by high throughput proteomic arrays. In addition to enhancing antigen presentation and immune checkpoint expression, Gemcitabine consistently increased the synthesis of CCL/CXCL chemokines and TGFβ-associated signals. These secreted factors altered the composition of the tumor stroma, conferring Gemcitabine resistance to cancer-associated fibroblasts in vitro and further enhancing TGFβ1 biosynthesis. Combined Gemcitabine and anti-PD-1 treatment in transgenic models of murine PDAC failed to alter disease course unless mice also underwent genetic or pharmacologic ablation of TGFβ signaling. In the setting of TGFβ signaling deficiency, Gemcitabine and anti-PD-1 led to a robust CD8+ T-cell response and decrease in tumor burden, markedly enhancing overall survival. These results suggest that Gemcitabine successfully primes PDAC tumors for immune checkpoint inhibition by enhancing antigen presentation only following disruption of the immunosuppressive cytokine barrier. Given the current lack of third-line treatment options, this approach warrants consideration in the clinical management of Gemcitabine-refractory PDAC