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The TLR7 and TLR9 signalings are implicated in the regulation of the immune system through type-I interferon induction. Preclinical studies have demonstrated the immunomodulatory and antitumor effects of TLR7 and TLR9 agonists in combination with cetuximab. We tested the hypothesis that genetic variations in TLR7 and TLR9 and their downstream molecules IRF5 and IRF7 were associated with outcomes in metastatic colorectal cancer (mCRC) patients receiving cetuximab-based chemotherapy. Six single nucleotide polymorphisms (SNPs) in TLR7, TLR9, IRF5 and IRF7 were tested for the association with RR, PFS, and OS in KRAS-wild type mCRC patients. Patients treated with FOLFIRI + cetuximab or FOLFIRI + bevacizumab in the FIRE-3 trial served as a discovery set ( FIRE3-Cet, n = 244) or a control set ( FIRE3-Bev, n = 246), respectively. Patients treated with FOLFOX or SOX + cetuximab in the JACCRO-CC05/06 trial served as a validation set ( JACCRO, n = 76). Genomic DNA isolated from tumor tissue samples was analyzed by PCR-based direct sequencing. In the discovery cohort, patients with the TLR7 rs3853839 G/G variant showed a trend toward longer PFS than those with any C variants (median 10.0 vs. 11.8 months, HR 1.39, p = 0.092). This preliminary association was confirmed in the validation cohort, and those with the G/G genotype showed a PFS benefit compared with others (univariate: 9.1 vs. 11.6 months, HR 2.04, p = 0.005, multivariate: HR 2.02, 95% CI: 1.14-3.55, p = 0.015). This association was not observed in the control cohort. Our findings suggest that TLR7 rs3853839 predicts the outcome of cetuximab-based chemotherapy in mCRC patients. [ABSTRACT FROM AUTHOR]

The Insulin-like growth factor (IGF)/IGF-receptor pathway with its scaffolding proteins Insulin Receptor Substrate (IRS)1 and IRS2 are crucial regulators of metabolism and progression in metastatic colorectal cancer (mCRC). The goal of the study was the identification of predictive and prognostic markers among IRS1, IRS2, IGF1 and IGF- 1R SNPs in mCRC patients enrolled in the FIRE-3 trial. Four SNPs of IRS ( IRS1 rs1801278, rs1801123; IRS2 rs1805097, rs2289046) and four SNPs of IGF1- IGFR1 (rs6214, rs6220, rs2946834, rs2016347) were analyzed by PCR/direct-sequencing in the FIRE-3 trial. The relation of SNPs with PFS and OS was evaluated through Kaplan-Meier method and log-rank test in the overall population and in subgroup according to RAS status and treatment arm. In the overall population IRS1 rs1801123 C/- carriers ( N= 105) achieved significantly worse OS compared to T/T ( N = 464) in univariate (HR = 1.32 [95%CI 1.03-1.70], p = 0.029) and in multivariable. Similar results were observed among RAS wild type. Patients with IGF1 rs2946834 T/- variant ( N= 280) achieved improved PFS compared to C/C ( N = 257) in univariate (HR = 0.77 [95%CI 0.64-0.92], p = 0.004) and in multivariable. In the RAS wild-type subgroup IGF1 rs2946834 T/- carriers showed better PFS and OS compared to C/C (univariate HR for PFS = 0.65 [95%CI 0.51-0.81], p < 0.001; multivariable HR for PFS = 0.63 [95%CI 0.50-0.81], p < 0.001). IRS1 rs1801123 SNP was identified as a new prognostic marker for mCRC. IGF1 rs2946834 was confirmed as prognostic factor in the overall population and in RAS wild type patients. Our findings underline the importance of IGF downstream signaling pathway in RAS wild-type mCRC patient. [ABSTRACT FROM AUTHOR]

Worldwide, many species are responding to ongoing climate change with shifts in distribution, abundance, phenology, or behavior. Consequently, natural-resource managers face increasingly urgent conservation questions related to biodiversity loss, expansion of invasive species, and deteriorating ecosystem services. We argue that our ability to address these questions is hampered by the lack of explicit consideration of species' adaptive capacity (AC). AC is the ability of a species or population to cope with climatic changes and is characterized by three fundamental components: phenotypic plasticity, dispersal ability, and genetic diversity. However, few studies simultaneously address all elements; often, AC is confused with sensitivity or omitted altogether from climate-change vulnerability assessments. Improved understanding, consistent definition, and comprehensive evaluations of AC are needed. Using classic ecological-niche theory as an analogy, we propose a new paradigm that considers fundamental and realized AC: the former reflects aspects inherent to species, whereas the latter denotes how extrinsic factors constrain AC to what is actually expressed or observed. Through this conceptualization, we identify ecological attributes contributing to AC, outline areas of research necessary to advance understanding of AC, and provide examples demonstrating how the inclusion of AC can better inform conservation and natural-resource management. [ABSTRACT FROM AUTHOR]

The massive scale of the 1997-1998 El Niño-associated coral bleaching event underscores the need for strategies to mitigate biodiversity losses resulting from temperature-induced coral mortality. As baseline sea surface temperatures continue to rise, climate change may represent the single greatest threat to coral reefs worldwide. In response, one strategy might be to identify (1) specific reef areas where natural environmental conditions are likely to result in low or negligible temperature-related bleaching and mortality (i.e., areas of natural "resistance" to bleaching) and (2) reef areas where environmental conditions are likely to result in maximum recovery of reef communities after bleaching mortality has occurred (i.e., areas of natural community "resilience"). These "target areas," where environmental conditions appear to boost resistance and resilience during and after large-scale bleaching events, could then be incorporated into strategic networks of marine protected areas designed to maximize conservation of global coral reef biodiversity. Based on evidence from the literature and systematically compiled observations from researchers in the field, this paper identifies likely environmental correlates of resistance and resilience to coral bleaching, including factors that reduce temperature stress, enhance water movement, decrease light stress, correlate with physiological tolerance, and provide physical or biological enhancement of recovery potential. As a tool for identifying reef areas that are likely to be most robust in the face of continuing climate change and for determining priority areas for reducing direct anthropogenic impacts, this information has important implications for coral reef conservation and management. [ABSTRACT FROM AUTHOR]

Wetlands are known to provide a myriad of vital ecosystem functions and services, which may be under threat from a changing climate. However, these effects may not be homogenous across ecosystem functions, wetland types, ecoregions, or meso‐scale watersheds, making broad application of the same management techniques inappropriate. Here, we present a relative wetland vulnerabilities framework, applicable across a range of spatial and temporal scales, to assist in identifying effective and robust management strategies in light of climate change. We deconstruct vulnerability into dimensions of exposure and sensitivity/adaptive capacity, and identify relevant measures of these as they pertain to the attributes of wetland extent and plant community composition. As a test of the framework, we populate it with data for three primary hydrogeomorphic wetland types (riverine, slope, and depression) in seven small watersheds across four ecoregions (Ridge and Valley, Piedmont, Unglaciated Plateau, and Glaciated Plateau) in the Susquehanna River watershed in Pennsylvania. We use data generated from the SRES A2 emissions experiment and MRI‐CGCM2.3.2 climate model as input to the Penn State Integrated Hydrologic Model to simulate future exposure to altered hydrologic conditions in our seven watersheds, as expressed in two hydrologic metrics: % time groundwater levels occur in the upper 30 cm (rooting zone) during the growing season, and median difference between spring and summer mean water levels. We then examine the spatial and temporal scales at which each of the components of vulnerability (exposure and sensitivity/adaptive capacity) shows significant relative differences. Overall, we find that relative differences in exposure persist at a very fine spatial grain, exhibiting high variability even among individual watersheds in a given ecoregion. For temporal scale, we find strong seasonal but weak annual relative differences in exposure resulting from a magnification of summer dry‐down combined with winter and spring wet periods becoming wetter. Sensitivities/adaptive capacities show significant differences among wetland types. A comparison between our anticipated hydrologic alterations under climate change and historical changes in hydrology due to anthropogenic disturbance indicates potential shifts in hydrologic patterns that are far beyond anything that wetland managers have experienced in the past. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the equivalence of immunogenicity, safety and efficacy of Gan & Lee (GL) Glargine (Basalin®; Gan & Lee Pharmaceutical) with that of the reference product (Lantus®) in adult participants with type 2 diabetes mellitus., Methods: This was a phase 3, multicenter, open-label, equivalence trial conducted across 57 sites. In total, 567 participants with type 2 diabetes mellitus were randomized in a 1:1 ratio to undergo treatment with either GL Glargine or Lantus® for 26 weeks. The primary endpoint was the proportion of participants in each treatment arm who manifested treatment-induced anti-insulin antibodies (AIA). Secondary endpoints included efficacy and safety metrics, changes in glycated haemoglobin levels, and a comparative assessment of adverse events. Results were analysed using an equivalence test comparing the limits of the 90% confidence interval (CI) for treatment-induced AIA development to the prespecified margins., Results: The percentages of participants positive for treatment-induced glycated haemoglobin by week 26 were similar between the GL Glargine (19.2%) and Lantus® (21.3%) treatment groups, with a treatment difference of -2.1 percentage points and a 90% CI (-7.6%, 3.5%) (predefined similarity margins: -10.7%, 10.7%). The difference in glycated haemoglobin was -0.08% (90% CI, -0.23, 0.06). The overall percentage of participants with any treatment-emergent adverse events was similar between the GL Glargine (80.1%) and Lantus® (81.6%) treatment groups., Conclusions: GL Glargine was similar to Lantus® in terms of immunogenicity, efficacy, and safety, based on the current study., (© 2024 John Wiley & Sons Ltd.)