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Methylthioadenosine phosphorylase, an essential enzyme for the adenine salvage pathway, is often deficient (MTAP def ) in tumors with 9p21 loss and hypothetically renders tumors susceptible to synthetic lethality by antifolates targeting de novo purine synthesis. Here we report our single arm phase II trial (NCT02693717) that assesses pemetrexed in MTAP def urothelial carcinoma (UC) with the primary endpoint of overall response rate (ORR). Three of 7 enrolled MTAP def patients show response to pemetrexed (ORR 43%). Furthermore, a historic cohort shows 4 of 4 MTAP def patients respond to pemetrexed as compared to 1 of 10 MTAP-proficient patients. In vitro and in vivo preclinical data using UC cell lines demonstrate increased sensitivity to pemetrexed by inducing DNA damage, and distorting nucleotide pools. In addition, MTAP-knockdown increases sensitivity to pemetrexed. Furthermore, in a lung adenocarcinoma retrospective cohort (N = 72) from the published BATTLE2 clinical trial (NCT01248247), MTAP def associates with an improved response rate to pemetrexed. Our data demonstrate a synthetic lethal interaction between MTAP def and de novo purine inhibition, which represents a promising therapeutic strategy for larger prospective trials. The deficiency of MTAP, an enzyme of the adenine salvage pathway, occurs in some cancers. Here the authors perform a small cohort phase II clinical trial with metastatic MTAP-deficient urothelial cancer (UC) and show an increased overall response when comparing to MTAP-proficient UC patients.

The role of combination chemotherapy with immune checkpoint inhibitors (ICI) (ICI-chemo) over ICI monotherapy (ICI-mono) in non-small cell lung cancer (NSCLC) remains underexplored. In this retrospective study of 1133 NSCLC patients, treatment with ICI-mono vs ICI-chemo associate with higher rates of early progression, but similar long-term progression-free and overall survival. Sequential vs concurrent ICI and chemotherapy have similar long-term survival, suggesting no synergism from combination therapy. Integrative modeling identified PD-L1, disease burden (Stage IVb; liver metastases), and STK11 and JAK2 alterations as features associate with a higher likelihood of early progression on ICI-mono. CDKN2A alterations associate with worse long-term outcomes in ICI-chemo patients. These results are validated in independent external ( n  = 89) and internal ( n  = 393) cohorts. This real-world study suggests that ICI-chemo may protect against early progression but does not influence overall survival, and nominates features that identify those patients at risk for early progression who may maximally benefit from ICI-chemo. Immune checkpoint inhibitors with or without chemotherapy are now standard of care for non-small cell lung cancer. However, the benefits of combination vs sequential therapy have not been fully explored. Here, the authors analysed 1,133 patient records and show combination therapy showed increased protection against early progression, but similar overall survival.

The Automated Planet Finder (APF) is a facility purpose-built for the discovery and characterization of extrasolar planets through high-cadence Doppler velocimetry of the reflex barycentric accelerations of their host stars. Located atop Mount Hamilton, the APF facility consists of a 2.4 m telescope and its Levy spectrometer, an optical echelle spectrometer optimized for precision Doppler velocimetry. APF features a fixed-format spectral range from 374-970 nm, and delivers a \"throughput\" (resolution × slit width product) of 114,000″, with spectral resolutions up to 150,000. Overall system efficiency (fraction of photons incident on the primary mirror that are detected by the science CCD) on blaze at 560 nm in planet-hunting mode is 15%. First-light tests on the radial-velocity (RV) standard stars HD 185144 and HD 9407 demonstrate sub-meter-per-second precision (rms per observation) held over a 3 month period. This paper reviews the basic features of the telescope, dome, and spectrometer, and gives a brief summary of first-light performance.

This study explores the development and dynamics of the Wales Collaborative for Learning Design (WCLD), a multidisciplinary network across eight Welsh universities. Funded by Welsh Government, the WCLD aimed to foster collaboration in digital learning design while supporting individual and collective academic growth. The study aimed to investigate what factors impact on the development and sustainability of a personal and professional, multidisciplinary Higher Education collaborative network. Using a collective autoethnographic approach, the research explored the network's evolution, highlighting the interplay of person attributes, facilitating conditions, and professional relationships. Findings revealed key factors including trust, open-mindedness, and consistent communication as essential to the network's sustainability and success. Further findings illustrate how positive constraints, diverse career stages, and interdisciplinary opportunities underpin growth and productivity. 'Outcomes' included enhanced institutional impact, significant personal and professional conversations, and the cross-pollination of ideas within and beyond the network. When considered as a process, the findings underscore the value of cultivating intentional, yet adaptable, collaborative networks to support higher education innovation and personal academic development. This culminates in the 'Roots/routes to Fruit' model. This original contribution builds on existing theory surrounding significant, collaborative networks and provides a process for future interdisciplinary, multi-institutional, collaborative networks to build upon.

Humans of the advanced world are the most violent beings of all times. This violence is evident in the conditions of perpetual warfare and the accumulation of the most powerful and destructive arsenal ever known to humankind. It is also evident in the devastating impact of advanced world economy and cultural practices which have led to ecological devastation and the current era of mass species extinction. —one of only six mass extinction events in planetary history and the only one caused by the actions of a single species, humans. This violence is manifest in our interpersonal relationships, and the ways in which we organize ourselves through hierarchical systems that ensure the wealth and privilege of some, against the penury and misery of others. In this new and highly original book, Jeff Lewis argues that violence is deeply inscribed in human culture, thinking and expressive systems (media). Lewis contends that violence is not an inescapable feature of an aggressive human nature. Rather, violence is laced through our desires and dispositions to communalism and expressive interaction. From the near extinction of all Homo sapiens, around 74,000 years ago, the invention of culture and media enabled humans to imagine and articulate particular choices and pleasures. Organized intergroup violence or warfare emerged through the exercise of these choices and their expression through larger and increasingly complex human societies. This agitation of amplified desire, hierarchical social organization and mediated knowledge systems has created a cultural volition of violent complexity which continues into the present. Media, Culture and Human Violence examines the current conditions of conflict and harm as an expression of our violent complexity.

With respect to salmonid aquaculture, one of the most important bacterial pathogens due to high mortality and antibiotic usage is the causative agent of typical furunculosis, spp. ( ). In Atlantic salmon, , the host response during infections with is well-documented, with furunculosis outbreaks resulting in significant mortality in commercial settings. However, less is known about the host-pathogen interactions in the emerging aquaculture species, Arctic charr . Furthermore, there is no data on the efficacy or response of this species after vaccination with commonly administered vaccines against furunculosis. To this end, we examined the immunological response of during infection with , with or without administration of vaccines (Forte Micro®, Forte Micro® + Renogen®, Elanco Animal Health). Artic charr (vaccinated or unvaccinated) were i.p.-injected with a virulent strain of (10 CFUs/mL) and tissues were collected pre-infection/post-vaccination, 8, and 29 days post-infection. Unvaccinated Arctic charr were susceptible to with 72% mortalities observed after 31 days. However, there was 72-82% protection in fish vaccinated with either the single or dual-vaccine, respectively. Protection in vaccinated fish was concordant with significantly higher serum IgM concentrations, and following RNA sequencing and transcriptome assembly, differential expression analysis revealed several patterns and pathways associated with the improved survival of vaccinated fish. Most striking was the dramatically higher basal expression of complement/coagulation factors, acute phase-proteins, and iron hemostasis proteins in pre-challenged, vaccinated fish. Remarkably, following infection, this response was abrogated and instead the transcriptome was characterized by a lack of immune-stimulation compared to that of unvaccinated fish. Furthermore, where pathways of actin assembly and FcγR-mediated phagocytosis were significantly differentially regulated in unvaccinated fish, vaccinated fish showed either the opposite regulation (ForteMicro®), or no impact at all (ForteMicro®Renogen®). The present data indicates that vaccine-induced protection against relies on the pre-activation and immediate control of humoral immune parameters that is coincident with reduced activation of apoptotic (e.g., NF-κB) and actin-associated pathways.

BackgroundWhile the clinical outcomes of immune checkpoint inhibitor (ICI) use in older adults with advanced-stage non-small cell lung cancer (NSCLC) have been described, the role of ICI use continued beyond disease progression (BDP) remains to be well defined for this population. This retrospective single-center study explored the clinical outcomes of continuing ICIs BDP among older adult patients with advanced NSCLC.MethodsUsing MD Anderson’s Gemini Lung Cancer database, we retrospectively reviewed the clinical outcomes of older adults (≥70 years) diagnosed with advanced-stage NSCLC treated with anti-PD-(L)1 monotherapy from March 2015 through April 2019 to correlate clinicopathologic features with clinical outcomes. Clinical therapy responses were evaluated by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Toxicities were assessed using Common Terminology Criteria for Adverse Events (CTCAE), version 5. Patients treated BDP were defined as individuals receiving ICIs for ≥8 weeks prior to documentation of progression who subsequently remained on ICIs for ≥6 weeks.ResultsOf the 159 older adults meeting the inclusion criteria, 33 (21%) received ICIs BDP (64% male, median age 74.9 years (70.1–82.0) at the start of ICI treatment, 3 received first-line ICI therapy). Most patients were former (85%) or current (6%) smokers. 79% had adenocarcinoma histology. The median duration of immunotherapy continued BDP was 7.1 months (95% CI: 3.0–8.2). After a follow-up of 30.1 months, the median overall survival (mOS) was 31.5 months (95% CI: 16.5-not reached). Eight (24%) received local consolidative radiotherapy with a median duration of ICI BDP of 8.2 months (95% CI: 1.9–13.3). Twenty-five (76%) did not receive local consolidative therapy and achieved a median duration of ICI BDP of 4.1 months (95% CI: 2.3–7.8). Six (18%) exhibited pseudo-progression (i.e. delayed response to immunotherapy with decreased tumor burden on subsequent radiologic studies), with 4 achieving ”stable disease” as best response and 2 achieving a partial response. The median duration of immunotherapy continued beyond pseudo-progression was 11.7 months (95% CI: 7.1–35.7), and the mOS was 26.2 months (95% CI: 16.5–40.0). Patients treated with ICI BDP most commonly experienced fatigue (18%), pneumonitis (12%), rash (9%), and hypothyroidism (9%). Three patients (9%) experienced grade 3 or higher toxicities (one grade 3 arthralgias and two grade 3 pneumonitis).ConclusionsICI-use BDP in older adults with advanced NSCLC may benefit a subset of patients. Additionally, local consolidative therapy with radiation may offer prolonged duration of ICI treatment.AcknowledgementsSupported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Moon Shot Program and the MD Anderson Cancer Center Support Grant P30 CA01667. Special acknowledgment to the GEMINI team.Ethics ApprovalThis study was approved and conducted in accordance with the institutional review board at the University of Texas MD Anderson Cancer Center; approval number (PA13-0589).

Language Wars is a fascinating account of the relationship between the media, culture and new forms of global, political violence. Using an innovative approach, Jeff Lewis shows how language and the media are implicated in global terrorism and the US-led reprisals in the war on terror. Through an examination of the language of terrorism and war, Lewis illuminates key events in the current wave of political violence - the 9/11 attacks on New York and the Pentagon, the Beslan siege, the invasion of Afghanistan and Iraq, the Bali bombings and the ongoing occupation in the Middle East. He argues that the language used to report incidents of violence has changed, not just in official channels but in wider cultural contexts, and shows the impact this has on social perceptions. Lewis deconstructs these new discourses to reveal how Islam has been construed as the antagonist of freedom, democracy and the rule of law. Ideal for students of media studies and cultural studies, this is a subtle account of the relation between language and culture that exposes a dangerous new east-west divide in popular discourse.