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Identifying tumor antigen-specific T cells from cancer patients has important implications for immunotherapy diagnostics and therapeutics. Here, we show that CD103 + CD39 + tumor-infiltrating CD8 T cells (CD8 TIL) are enriched for tumor-reactive cells both in primary and metastatic tumors. This CD8 TIL subset is found across six different malignancies and displays an exhausted tissue-resident memory phenotype. CD103 + CD39 + CD8 TILs have a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery. CD103 + CD39 + CD8 TILs also efficiently kill autologous tumor cells in a MHC-class I-dependent manner. Finally, higher frequencies of CD103 + CD39 + CD8 TILs in patients with head and neck cancer are associated with better overall survival. Our data thus describe an approach for detecting tumor-reactive CD8 TILs that will help define mechanisms of existing immunotherapy treatments, and may lead to future adoptive T-cell cancer therapies. Identifying and enumerating tumor-specific CD8 T cells are important for assessing cancer prognosis and therapy efficacy. Here the authors show that CD39 and CD103 mark a subset of tumor-infiltrating CD8 T cells that are tumor-reactive and exhibit characteristics of exhausted or tissue-resident memory T cells.

Identifying tumor antigen-specific T cells from cancer patients has been a goal of tumor immunologists for several decades. Here we show that co-expression of CD103 and CD39 on CD8 TIL highly enriched for tumor-reactive T cells. This cell population, which is only present in TIL from primary and metastatic tumors, exhibited features of exhausted cells and displayed characteristics of tissue-resident memory T cells. CD39+CD103+ CD8 TIL had a distinct TCR repertoire compared to other CD8 TIL subsets and were clonally expanded within the tumor. They were highly enriched for tumor antigen recognition and efficiently killed autologous tumor cells. Finally, patients with head and neck cancer whose CD8 TIL contained a higher frequency of CD39+CD103+ cells experienced a greater overall survival. This work describes a simple method for detecting tumor-reactive CD8 TIL, which should help define mechanisms of current immunotherapies and may lead to the development of future immunotherapies.

Glioblastoma (GBM) remains the most lethal primary brain cancer with a median survival of under 2 years despite current best treatment practices. Early immunotherapies, including checkpoint blockade and vaccines, showed safety and immunogenicity but no survival benefit. Chimeric antigen receptor (CAR) T treatments in GBM trials have yielded feasibility and antitumor signals but still lack long-term control. This review synthesizes recent clinical and mechanistic data to establish priorities for clinical trial design, patient selection, and treatment development aimed at achieving durable responses in GBM.Recent trials highlight two consistent observations regarding the delivery of CAR T treatment. First, that CAR T cells can be effectively delivered peripherally rather than requiring direct intracranial administration. And second, multi-antigen, regionally delivered products can induce measurable intracranial responses. These findings indicate that access across the blood-brain barrier is feasible, but persistent function is limited by tumor antigen heterogeneity and an immunosuppressive, myeloid-dominated microenvironment that accelerates T-cell exhaustion.Emerging development strategies reflect these constraints. Broader antigen recognition is being pursued through bivalent and engager-secreting constructs. Locoregional delivery through cerebrospinal fluid spaces enables repeated exposure at multifocal sites. Resistance modules targeting TGF-β (Transforming Growth Factor-beta) signaling and myeloid suppression are being investigated to prolong persistence. Cerebrospinal fluid pharmacodynamic monitoring, such as measuring cytokines, chemokines, and CAR cell kinetics, may support adaptive dosing and minimize corticosteroid use. Patient selection criteria increasingly favor individuals with confirmed target expression, sufficient intratumoral T-cell infiltration, and minimal steroid exposure.Advances in manufacturing, including point-of-care platforms, allogeneic products, and in vivo CAR engineering, aim to shorten production timelines and improve access. Collectively, regional delivery, multi-antigen recognition, and microenvironment resistance constitute the current framework for translating CAR T therapy in GBM from transient responses toward sustained benefit.

Small area estimation is a research area in official and survey statistics of great practical relevance for national statistical institutes and related organizations. Despite rapid developments in methodology and software, researchers and users would benefit from having practical guidelines for the process of small area estimation. We propose a general framework for the production of small area statistics that is governed by the principle of parsimony and is based on three broadly defined stages, namely specification, analysis and adaptation, and evaluation. Emphasis is given to the interaction between a user of small area statistics and the statistician in specifying the target geography and parameters in the light of the available data. Model-free and model-dependent methods are described with a focus on model selection and testing, model diagnostics and adaptations such as use of data transformations. Uncertainty measures and the use of model and design-based simulations for method evaluation are also at the centre of the paper. We illustrate the application of the proposed framework by using real data for the estimation of non-linear deprivation indicators. Linear statistics, e.g. averages, are included as special cases of the general framework.

An outbreak of fungal infections has been identified in patients who received epidural injections of methylprednisolone acetate that was contaminated with environmental molds. In this report, we present the mycological and histopathological findings in an index case of Exserohilum meningitis and vasculitis in an immunocompetent patient, who received a cervical spine epidural steroid injection for chronic neck pain 1 week before the onset of fulminant meningitis with subsequent multiple brain and spinal cord infarcts. The fungus was recovered from two separate cerebrospinal fluid specimens collected before initiation of antifungal therapy and at autopsy on standard bacterial and fungal culture media. The mold was identified phenotypically as Exserohilum species. DNA sequencing targeting the internal transcribed spacer region and D1/D2 region of 28S ribosomal DNA enabled further speciation as E. rostratum . Gross examination at autopsy revealed moderate brain edema with bilateral uncal herniation and a ventriculostomy tract to the third ventricle. The brainstem, cerebellum, and right orbitofrontal cortex were soft and friable, along with hemorrhages in the cerebellar vermis and thalamus. Microscopic examination demonstrated numerous fungi with septate hyphae invading blood vessel walls and inducing acute necrotizing inflammation. The leptomeninges were diffusely infiltrated by mixed inflammatory cells along with scattered foci of fungal elements. This is the first report of iatrogenic E. rostratum meningitis in humans. This report describes the microbiological procedures and histopathological features for the identification of E. rostratum (a pigmented vascularly invasive fungi), the cause of a current nationwide outbreak of fatal fungal meningitis.

Background Emerging evidence supports the diagnostic and prognostic utility of plasma biomarkers in Alzheimer’s disease (AD), particularly in early disease stages. We sought to extend these findings by evaluating the prognostic value of plasma biomarkers in a clinical trial of mild-to-moderate AD. Methods Post-hoc analyses investigated whether baseline concentrations of plasma biomarkers (Aβ42/Aβ40, T-tau, P-tau181, NfL, and GFAP) predicted change in ADAS-Cog11, CDR-SB, and volumetric MRI among participants in T2 Protect AD, a negative 48-week, phase-2, placebo-controlled trial of troriluzole in mild-to-moderate AD. All trial participants met diagnostic criteria for probable AD. Baseline concentrations of, and 48-week changes in, plasma biomarkers were assessed for association with 48-week change in outcomes using linear regression. Combinations of baseline biomarkers that best predicted change on the ADAS-Cog11 and CDR-SB were identified using least absolute shrinkage and selection operator (LASSO) regression. Biomarker-informed sample size calculations were modeled. Results Of 350 trial participants, 319 had all requisite biomarker and clinical outcome data for inclusion in these analyses (mean age 71.5, SD = 8.03; 58.6% female). Higher plasma NfL at baseline predicted worsening scores on the ADAS-Cog11 (effect size (ES) = 1.42, 95%CI = [0.43, 2.41], p  = 0.026) and CDR-SB (ES = 0.42, 95%CI = [0.10, 0.73], p  = 0.048). LASSO regression revealed that worsening on the ADAS-Cog11 was best predicted by the combination of baseline plasma NfL, T-tau, and Aβ42/40 ratio, whereas baseline NfL alone best predicted worsening on CDR-SB. Higher baseline NfL predicted increasing ventricular volume (ES = 1.30cm 3 , 95%CI = [0.43, 2.17], p  = 0.018) and decreasing mid-temporal cortical volume (ES = -0.47, 95%CI = [-0.74, -0.20], p  = 0.003). Increasing NfL over the 48-week trial was associated with worsening on CDR-SB but not ADAS-Cog11. Modeling of biomarker-informed power calculations revealed that including high NfL as a trial entry criterion could substantially reduce requisite trial sample size. Conclusions Elevated baseline plasma NfL predicted more rapid clinical decline and MRI volume loss. Furthermore, increasing plasma NfL concentration over time was associated with worsening on the CDR-SB. Plasma NfL is an easily accessible biomarker that may enhance the design of clinical trials in mild-to-moderate AD. Trial registration The T2 Protect AD trial was registered as NCT03605667 on clinicaltrials.gov on 2018-07-27.

The possible reemergence of smallpox through bioterrorism requires the preparation of adequate stockpiles of vaccine. Dryvax, the only US-licensed vaccinia virus smallpox vaccine, has an unacceptable safety profile in the pre-event setting. LC16m8 is a Japanese-licensed attenuated vaccinia virus strain that has been safely used in over 50,000 persons. Until now, efficacy of this vaccine was unproven. Using two animal models, we show that LC16m8 and Dryvax elicit comparable humoral immune responses after a single vaccination and equivalently protect against lethal poxvirus disease. Thus, LC16m8 shows promise as a safe and effective smallpox vaccine with the potential for replacing Dryvax.

8With the current state of the economy and the budget woes found in everyone's workplace, every extra dollar we can use to offset the cost of projects counts—and what if those extra dollars came with public relations opportunities at no cost to you? For the last several years, the Pennsylvania Bureau of Forestry has cultivated relationships with a variety of non-traditional partners. These relationships have not only provided additional funds for tree planting projects through our TreeVitalize program, but have also provided fantastic public relations exposure and access to new audiences. Come hear how we used a “win-win” approach with our new partners and be inspired to try some of these ideas in your “neck of the woods.”

Large-scale climate patterns influenced temperature and weather patterns around the globe in 2011. In particular, a moderate-to-strong La Nina at the beginning of the year dissipated during boreal spring but reemerged during fall. The phenomenon contributed to historical droughts in East Africa, the southern United States, and northern Mexico, as well the wettest two-year period (2010-11) on record for Australia, particularly remarkable as this follows a decade-long dry period. Precipitation patterns in South America were also influenced by La Nina. Heavy rain in Rio de Janeiro in January triggered the country's worst floods and landslides in Brazil's history. The 2011 combined average temperature across global land and ocean surfaces was the coolest since 2008, but was also among the 15 warmest years on record and above the 1981-2010 average. The global sea surface temperature cooled by 0.1 degrees C from 2010 to 2011, associated with cooling influences of La Nina. Global integrals of upper ocean heat content for 2011 were higher than for all prior years, demonstrating the Earth's dominant role of the oceans in the Earth's energy budget. In the upper atmosphere, tropical stratospheric temperatures were anomalously warm, while polar temperatures were anomalously cold. This led to large springtime stratospheric ozone reductions in polar latitudes in both hemispheres. Ozone concentrations in the Arctic stratosphere during March were the lowest for that period since satellite records began in 1979. An extensive, deep, and persistent ozone hole over the Antarctic in September indicates that the recovery to pre-1980 conditions is proceeding very slowly. Atmospheric carbon dioxide concentrations increased by 2.10 ppm in 2011, and exceeded 390 ppm for the first time since instrumental records began. Other greenhouse gases also continued to rise in concentration and the combined effect now represents a 30% increase in radiative forcing over a 1990 baseline. Most ozone depleting substances continued to fall. The global net ocean carbon dioxide uptake for the 2010 transition period from El Nino to La Nina, the most recent period for which analyzed data are available, was estimated to be 1.30 Pg C yr(-1), almost 12% below the 29-year long-term average. Relative to the long-term trend, global sea level dropped noticeably in mid-2010 and reached a local minimum in 2011. The drop has been linked to the La Nina conditions that prevailed throughout much of 2010-11. Global sea level increased sharply during the second half of 2011. Global tropical cyclone activity during 2011 was well-below average, with a total of 74 storms compared with the 1981-2010 average of 89. Similar to 2010, the North Atlantic was the only basin that experienced above-normal activity. For the first year since the widespread introduction of the Dvorak intensity-estimation method in the 1980s, only three tropical cyclones reached Category 5 intensity level-all in the Northwest Pacific basin. The Arctic continued to warm at about twice the rate compared with lower latitudes. Below-normal summer snowfall, a decreasing trend in surface albedo, and above-average surface and upper air temperatures resulted in a continued pattern of extreme surface melting, and net snow and ice loss on the Greenland ice sheet. Warmer-than-normal temperatures over the Eurasian Arctic in spring resulted in a new record-low June snow cover extent and spring snow cover duration in this region. In the Canadian Arctic, the mass loss from glaciers and ice caps was the greatest since GRACE measurements began in 2002, continuing a negative trend that began in 1987. New record high temperatures occurred at 20 m below the land surface at all permafrost observatories on the North Slope of Alaska, where measurements began in the late 1970s. Arctic sea ice extent in September 2011 was the second-lowest on record, while the extent of old ice (four and five years) reached a new record minimum that was just 19% of normal. On the opposite pole, austral winter and spring temperatures were more than 3 degrees C above normal over much of the Antarctic continent. However, winter temperatures were below normal in the northern Antarctic Peninsula, which continued the downward trend there during the last 15 years. In summer, an all-time record high temperature of -12.3 degrees C was set at the South Pole station on 25 December, exceeding the previous record by more than a full degree. Antarctic sea ice extent anomalies increased steadily through much of the year, from briefly setting a record low in April, to well above average in December. The latter trend reflects the dispersive effects of low pressure on sea ice and the generally cool conditions around the Antarctic perimeter.