41 research outputs found
Challenges to curing primary brain tumours.
Despite decades of research, brain tumours remain among the deadliest of all forms of cancer. The ability of these tumours to resist almost all conventional and novel treatments relates, in part, to the unique cell-intrinsic and microenvironmental properties of neural tissues. In an attempt to encourage progress in our understanding and ability to successfully treat patients with brain tumours, Cancer Research UK convened an international panel of clinicians and laboratory-based scientists to identify challenges that must be overcome if we are to cure all patients with a brain tumour. The seven key challenges summarized in this Position Paper are intended to serve as foci for future research and investment
State of the climate in 2018
In 2018, the dominant greenhouse gases released into Earth’s atmosphere—carbon dioxide, methane, and nitrous oxide—continued their increase. The annual global average carbon dioxide concentration at Earth’s surface was 407.4 ± 0.1 ppm, the highest in the modern instrumental record and in ice core records dating back 800 000 years. Combined, greenhouse gases and several halogenated gases contribute just over 3 W m−2 to radiative forcing and represent a nearly 43% increase since 1990. Carbon dioxide is responsible for about 65% of this radiative forcing. With a weak La Niña in early 2018 transitioning to a weak El Niño by the year’s end, the global surface (land and ocean) temperature was the fourth highest on record, with only 2015 through 2017 being warmer. Several European countries reported record high annual temperatures. There were also more high, and fewer low, temperature extremes than in nearly all of the 68-year extremes record. Madagascar recorded a record daily temperature of 40.5°C in Morondava in March, while South Korea set its record high of 41.0°C in August in Hongcheon. Nawabshah, Pakistan, recorded its highest temperature of 50.2°C, which may be a new daily world record for April. Globally, the annual lower troposphere temperature was third to seventh highest, depending on the dataset analyzed. The lower stratospheric temperature was approximately fifth lowest. The 2018 Arctic land surface temperature was 1.2°C above the 1981–2010 average, tying for third highest in the 118-year record, following 2016 and 2017. June’s Arctic snow cover extent was almost half of what it was 35 years ago. Across Greenland, however, regional summer temperatures were generally below or near average. Additionally, a satellite survey of 47 glaciers in Greenland indicated a net increase in area for the first time since records began in 1999. Increasing permafrost temperatures were reported at most observation sites in the Arctic, with the overall increase of 0.1°–0.2°C between 2017 and 2018 being comparable to the highest rate of warming ever observed in the region. On 17 March, Arctic sea ice extent marked the second smallest annual maximum in the 38-year record, larger than only 2017. The minimum extent in 2018 was reached on 19 September and again on 23 September, tying 2008 and 2010 for the sixth lowest extent on record. The 23 September date tied 1997 as the latest sea ice minimum date on record. First-year ice now dominates the ice cover, comprising 77% of the March 2018 ice pack compared to 55% during the 1980s. Because thinner, younger ice is more vulnerable to melting out in summer, this shift in sea ice age has contributed to the decreasing trend in minimum ice extent. Regionally, Bering Sea ice extent was at record lows for almost the entire 2017/18 ice season. For the Antarctic continent as a whole, 2018 was warmer than average. On the highest points of the Antarctic Plateau, the automatic weather station Relay (74°S) broke or tied six monthly temperature records throughout the year, with August breaking its record by nearly 8°C. However, cool conditions in the western Bellingshausen Sea and Amundsen Sea sector contributed to a low melt season overall for 2017/18. High SSTs contributed to low summer sea ice extent in the Ross and Weddell Seas in 2018, underpinning the second lowest Antarctic summer minimum sea ice extent on record. Despite conducive conditions for its formation, the ozone hole at its maximum extent in September was near the 2000–18 mean, likely due to an ongoing slow decline in stratospheric chlorine monoxide concentration. Across the oceans, globally averaged SST decreased slightly since the record El Niño year of 2016 but was still far above the climatological mean. On average, SST is increasing at a rate of 0.10° ± 0.01°C decade−1 since 1950. The warming appeared largest in the tropical Indian Ocean and smallest in the North Pacific. The deeper ocean continues to warm year after year. For the seventh consecutive year, global annual mean sea level became the highest in the 26-year record, rising to 81 mm above the 1993 average. As anticipated in a warming climate, the hydrological cycle over the ocean is accelerating: dry regions are becoming drier and wet regions rainier. Closer to the equator, 95 named tropical storms were observed during 2018, well above the 1981–2010 average of 82. Eleven tropical cyclones reached Saffir–Simpson scale Category 5 intensity. North Atlantic Major Hurricane Michael’s landfall intensity of 140 kt was the fourth strongest for any continental U.S. hurricane landfall in the 168-year record. Michael caused more than 30 fatalities and 6 billion (U.S. dollars) in damages across the Philippines, Hong Kong, Macau, mainland China, Guam, and the Northern Mariana Islands. Tropical Storm Son-Tinh was responsible for 170 fatalities in Vietnam and Laos. Nearly all the islands of Micronesia experienced at least moderate impacts from various tropical cyclones. Across land, many areas around the globe received copious precipitation, notable at different time scales. Rodrigues and Réunion Island near southern Africa each reported their third wettest year on record. In Hawaii, 1262 mm precipitation at Waipā Gardens (Kauai) on 14–15 April set a new U.S. record for 24-h precipitation. In Brazil, the city of Belo Horizonte received nearly 75 mm of rain in just 20 minutes, nearly half its monthly average. Globally, fire activity during 2018 was the lowest since the start of the record in 1997, with a combined burned area of about 500 million hectares. This reinforced the long-term downward trend in fire emissions driven by changes in land use in frequently burning savannas. However, wildfires burned 3.5 million hectares across the United States, well above the 2000–10 average of 2.7 million hectares. Combined, U.S. wildfire damages for the 2017 and 2018 wildfire seasons exceeded $40 billion (U.S. dollars)
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Dysregulation of pre-B cell development by autoantibodies derived from New Zealand Black mice
Autoimmune New Zealand Black (NZB) mice exhibit a dramatic age-dependent loss of bone marrow pre-B cells by a mechanism which has not been fully delineated, but may be related to increasing titers of autoantibody in aging NZB mice. In this investigation, we show that there is an extensive loss of B cell precursors in the bone marrow of aged NZB mice. These include precursors which, both by surface phenotype and function, are responsive to IL-7. To determine if antibodies in the repertoire of aged NZB mice contributed to a down-regulation of B lymphopoiesis, sera of NZB mice were assayed for reactivity with B cell precursor cells. NZB sera exhibited an age-related increase in reactivity with pre-B cell lines and inhibited the IL-7 stimulated in vitro proliferation and survival of bone marrow pro-B/pre-B cells. Of three IgM monoclonal antibodies (mAb) produced by fusion of 10 month old NZB splenocytes with SP2/0 cells and selected for reactivity with pre-B cell lines, two mAbs (2F5, 5G9) inhibited bone marrow IL-7 CFU in a concentration dependent manner. The inhibitory mAbs were reactive with a 210kDa protein on the surface of pre-B cell lines and IL-7 expanded pre-B cells. Both the binding of these mAbs and their inhibition of IL-7 CFU were dependent upon expression of the 5 surrogate light chain. The inhibition of IL-7 CFU by NZB antibodies was mediated by soluble cofactors ubiquitously produced by adherent bone marrow cells. In summary, these studies suggest that aging NZB mice produce autoantibodies which inhibit pre-B cell expansion. A fraction of these autoantibodies recognize cell surface antigens on IL-7 stimulated pre-B cells and render developing pre-B cells sensitive to negative regulation by cytokines produced by bone marrow adherent cells. These autoantibodies may contribute to the down-regulation of pre-B cell development in vivo seen in aging NZB mice
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Autoantibodies Inhibit Interleukin-7-Mediated Proliferation and Are Associated With the Age-Dependent Loss of Pre-B Cells in Autoimmune New Zealand Black Mice
Surface lgM+B220+ B cell precursors can be categorized as either leukosialin (CD43/S7) negative (late stage pre-B cells) or positive (pro-B/early pre-B cells). In autoimmune New Zealand Black (NZB) mice, bone marrow small pre-B cells (lgM-CD43-B220+) and pro-B/early pre-B cells (lgM-CD43+B220+) declined significantly with age. In particular, subpopulations of pro-B/early pre-B cells expressing the heat stable antigen (HSA) were found in lower proportions with age. Significant decreases in interleukin-7 (IL-7) colony forming units (CFU) were also seen in NZB mice by 6 to 8 months of age and accompanied alterations in the numbers of pro-B and pre-B cells in bone marrow. Concomitant with reduced numbers of B lineage precursor cells and IL-7 CFU in vivo, NZB mice produced serum IgM antibodies that strongly inhibited IL-7 CFU responses in vitro. Two monoclonal IgM antibodies (5G9, 2F5) derived from LPS stimulated 10-month-old NZB splenocytes recognized pre-B cell surface antigens on both pre-B cell lines and on IL-7 stimulated bone marrow pro-B/pre-B cells. However, these monoclonal antibodies (MoAb) failed to significantly stain ex vivo bone marrow cells. The 5G9 and 2F5 MoAbs also partially inhibited IL-7 CFU in vitro. These results suggest that NZB bone marrow becomes increasingly deficient in B cell precursors and especially in IL-7 responsive pre-B cells with age. IgM serum antibodies and monoclonal IgM antibodies derived from older NZB mice inhibit pre-B cell growth to IL-7. The production of such autoantibodies may interfere with B cell development in aging NZB mice by preventing IL-7-mediated proliferation
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A phase 1 trial of combined MEK, STAT3 and PD-1 inhibition in metastatic pancreatic ductal adenocarcinoma (PDAC)
TPS713 Background: PDAC is characterized by its innate and acquired resistance to both MAPK pathway inhibition and immune checkpoint (e.g. PD-1/PD-L1) inhibition (ICI) via multiple mechanisms. In preclinical models of PDAC, combined MEK and STAT3 inhibition (MEKi+STAT3i) uncovers stromal plasticity by attenuating cancer-associated fibroblasts (CAF) with IL-6/CXCL1-secretory phenotypes while enriching for Ly6a/CD34-expressing CAF phenotypes with mesenchymal stem cell-like features. This remodeling of CAF heterogeneity is associated with a striking attenuation in and reprogramming of tumor-associated macrophages (TAMs) as well as enhanced trafficking of CD8 T cells, which exhibit a distinct effector and anti-apoptotic transcriptional program. The addition of MEKi+STAT3i to PD-1 blockade overcomes ICI resistance by significantly enhancing the recruitment, degranulating capacity, and functional cytotoxicity of CD8 + T-cells, thereby augmenting antitumor responses and dramatically improving survival in these models. Furthermore, a patient with refractory PDAC treated off-label with this combination achieved a meaningful response. Based on this strong rationale, a phase 1 trial was initiated to test the combination of MEKi+STAT3 and PD1 inhibition in patients with metastatic PDAC. Methods: NCT05440942 is an open-label, prospective, single-institution phase 1 trial testing the safety, preliminary efficacy, and biomarkers of response to the combination of trametinib (MEKi), ruxolitinib (JAK2/STAT3 inhibitor) and retifanlimab (PD-1 inhibitor) in patients with metastatic PDAC. Patients with metastatic PDAC who have had disease progression on at least one line of prior therapy, with good organ function, preserved performance status, and without major intercurrent illness are eligible. Patients must have an accessible lesion for biopsy and must be willing to undergo this research biopsy at baseline and on treatment. Part 1 of the study is a dose-escalation phase with 3 dose levels and a target dose of trametinib 2mg orally daily, ruxolitinib 15mg orally twice daily, and retifanlimab 500mg intravenously every 28 days. The dose escalation is being done using the novel Bayesian keyboard design and 9-15 patients will be treated to get to the potential maximum tolerated dose (MTD). Dose level 1 has been completed without any dose-limiting toxicities seen. Part 2 is an expansion phase which will accrue an additional 20 patients. All patients in part 1 and 2 will have core-needle biopsies pre-treatment and after 4 weeks. Serial blood samples will be collected at baseline and on treatment. Biopsies are being analyzed by multiparameter immune profiling using mass cytometry and bulk RNA sequencing; blood is being analyzed for circulating tumor DNA and immune profiling. These results will be correlated with clinical response to therapy to determine biomarkers of response and resistance. Clinical trial information: NCT05440942
A Case Study of a Multi-Institution Replication of a Comprehensive GTA Teacher Training Program
A comprehensive graduate teaching assistant (GTA) training program in mathematical sciences designed at one institution is being adapted and replicated at two peer institutions. Using a case study approach, this paper outlines the development of the program components, which include a first-year teaching seminar, peer mentoring and support from a peer TA Coach, a Critical Issues in STEM Education seminar, and K–12 outreach to inform understanding of the pipeline. Additionally, adaptations due to institutional context and the impact of the Covid-19 pandemic are described. Implications for components of the comprehensive program, based on GTA-provided feedback, are discussed