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Purpose: Current guidelines for the management of metastatic non-small cell lung cancer (NSCLC) without driver mutations recommend checkpoint immunotherapy with PD-1/PD-L1 inhibitors, either alone or in combination with chemotherapy. This approach fails to account for individual patient variability and host immune factors and often results in less-than-ideal outcomes. To address the limitations of the current guidelines, we developed and subsequently blindly validated a machine learning algorithm using pretreatment plasma proteomic profiles for personalized treatment decisions., Patients and Methods: We conducted a multicenter observational trial (ClinicalTrials.gov identifier: NCT04056247) of patients undergoing PD-1/PD-L1 inhibitor-based therapy (n = 540) and an additional patient cohort receiving chemotherapy (n = 85) who consented to pretreatment plasma and clinical data collection. Plasma proteome profiling was performed using SomaScan Assay v4.1., Results: Our test demonstrates a strong association between model output and clinical benefit (CB) from PD-1/PD-L1 inhibitor-based treatments, evidenced by high concordance between predicted and observed CB ( R 2 = 0.98, P < .001). The test categorizes patients as either PROphet-positive or PROphet-negative and further stratifies patient outcomes beyond PD-L1 expression levels. The test successfully differentiates between PROphet-negative patients exhibiting high tumor PD-L1 levels (≥50%) who have enhanced overall survival when treated with a combination of immunotherapy and chemotherapy compared with immunotherapy alone (hazard ratio [HR], 0.23 [95% CI, 0.1 to 0.51], P = .0003). By contrast, PROphet-positive patients show comparable outcomes when treated with immunotherapy alone or in combination with chemotherapy (HR, 0.78 [95% CI, 0.42 to 1.44], P = .424)., Conclusion: Plasma proteome-based testing of individual patients, in combination with standard PD-L1 testing, distinguishes patient subsets with distinct differences in outcomes from PD-1/PD-L1 inhibitor-based therapies. These data suggest that this approach can improve the precision of first-line treatment for metastatic NSCLC.

Desynchrony of phenological responses to climate change is a major concern for ecological communities. Potential uncoupling between one of the most fundamental divisions within populations, males and females, has not been well studied. To address this gap, we examined sex-specific plasticity in hibernation phenology in two populations of Columbian ground squirrels ( Urocitellus columbianus ). We find that both sexes display similar phenological plasticity to spring snowmelt dates in their timing of torpor termination and behavioural emergence from hibernation. As a result of this plasticity, the degree of protandry (i.e. males' emergences from hibernation preceding those of females) did not change significantly over the 27-year study. Earlier male behavioural emergence, relative to females, improved the likelihood of securing a breeding territory and increased annual reproductive success. Sexual selection favouring earlier male emergence from hibernation may maintain protandry in this population, but did not contribute to further advances in male phenology. Together, our results provide evidence that the sexes should remain synchronized, at least in response to the weather variation investigated here, and further support the role of sexual selection in the evolution of protandry in sexually reproducing organisms.

Foraging animals commonly choose whether to find new food (as 'producers') or scavenge from others (as 'scroungers'), and this decision has ecological and evolutionary consequences. Understanding these tactic decisions is particularly vital for naturally occurring producer-scrounger systems of economic importance, because they determine the system's productivity and resilience. Here, we investigate how individuals' traits predict tactic decisions, and the consistency and pay-offs of these decisions, in the remarkable mutualism between humans ( Homo sapiens ) and greater honeyguides ( Indicator indicator ). Honeyguides can either guide people to bees' nests and eat the resulting beeswax (producing), or scavenge beeswax (scrounging). Our results suggest that honeyguides flexibly switched tactics, and that guiding yielded greater access to the beeswax. Birds with longer tarsi scrounged more, perhaps because they are more competitive. The lightest females rarely guided, possibly to avoid aggression, or because genetic matrilines may affect female body mass and behaviour in this species. Overall, aspects of this producer-scrounger system probably increase the productivity and resilience of the associated human-honeyguide mutualism, because the pay-offs incentivize producing, and tactic-switching increases the pool of potential producers. Broadly, our findings suggest that even where tactic-switching is prevalent and producing yields greater pay-offs, certain phenotypes may be predisposed to one tactic.

Heat waves are predicted to be detrimental for organismal physiology with costs for survival that could be reflected in markers of biological state such as telomeres. Changes in early life telomere dynamics driven by thermal stress are of particular interest during the early post-natal stages of altricial birds because nestlings quickly shift from being ectothermic to endothermic after hatching. Telomeres of ectothermic and endothermic organisms respond differently to environmental temperature, but few investigations within species that transition from ectothermy to endothermy are available. Also, ambient temperature influences parental brooding behaviour, which will alter the temperature experienced by offspring and thereby, potentially, their telomeres. We exposed zebra finch nestlings to experimental heat waves and compared their telomere dynamics to that of a control group at 5, 12 and 80 days of age that encapsulate the transition from the ectothermic to the endothermic thermoregulatory stage; we also recorded parental brooding, offspring sex, mass, growth rates, brood size and hatch order. Nestling mass showed an inverse relationship with telomere length, and nestlings exposed to heat waves showed lower telomere attrition during their first 12 days of life (ectothermic stage) compared to controls. Additionally, parents of heated broods reduced the time they spent brooding offspring (at 5 days old) compared to controls. Our results indicate that the effect of heat waves on telomere dynamics likely varies depending on age and thermoregulatory stage of the offspring in combination with parental brooding behaviour during growth., (© 2023 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Telomere length and DNA methylation (DNAm) are two promising biomarkers of biological age. Environmental factors and life history traits are known to affect variation in both these biomarkers, especially during early life, yet surprisingly little is known about their reciprocal association, especially in natural populations. Here, we explore how variation in DNAm, growth rate, and early-life conditions are associated with telomere length changes during development. We tested these associations by collecting data from wild, nestling zebra finches in the Australian desert. We found that increases in the level of DNAm were negatively correlated with telomere length changes across early life. We also confirm previously documented effects of post hatch growth rate and clutch size on telomere length in a natural ecological context for a species that has been extensively studied in the laboratory. However, we did not detect any effect of ambient temperature during developmental on telomere length dynamics. We also found that the absolute telomere length of wild zebra finches, measured using the in-gel TRF method, was similar to that of captive birds. Our findings highlight exciting new opportunities to link and disentangle potential relationships between DNA based biomarkers of ageing, and of physiological reactions to environmental change., (© 2021 John Wiley & Sons Ltd.)

Maternal effects can induce adjustments in offspring phenotype to the environment experienced by the mother. Of particular interest is if mothers can programme their offspring to cope best under matching environmental conditions, but the evidence for such anticipatory maternal effects (AME) is limited. In this study, we manipulated experimentally the food availability experienced by mothers and their offspring in the European earwig (Forficula auricularia). Offspring produced by females that had access to high or low food quantities were cross-fostered to foster mothers experiencing matched or mismatched environments. Offspring experiencing food availability matching the one of their mothers had an increased survival to adulthood compared with offspring experiencing mismatched conditions. Females experiencing high food laid larger clutches. This clutch-size adjustment statistically explained the matching effect when offspring experienced high food, but not when experiencing low food conditions. There were no effects of matching on offspring growth and developmental rate. Overall, our study demonstrates that AME occurs in relation to food availability enhancing offspring survival to adulthood under matching food conditions., (© 2016 The Author(s).)

Pre-eclampsia, the development of hypertension and proteinuria or end-organ damage during pregnancy, is a leading cause of both maternal and fetal morbidity and mortality, and there are no effective clinical treatments for pre-eclampsia aside from delivery. The development of pre-eclampsia is characterized by maladaptation of the maternal immune system, excessive inflammation and endothelial dysfunction. We have reported that detection of extracellular RNA by the Toll-like receptors (TLRs) 3 and 7 is a key initiating signal that contributes to the development of pre-eclampsia. PLacental eXpanded (PLX-PAD) cells are human placenta-derived, mesenchymal-like, adherent stromal cells that have anti-inflammatory, proangiogenic, cytoprotective and regenerative properties, secondary to paracrine secretion of various molecules in response to environmental stimulation. We hypothesized that PLX-PAD cells would reduce the associated inflammation and tissue damage and lower blood pressure in mice with pre-eclampsia induced by TLR3 or TLR7 activation. Injection of PLX-PAD cells on gestational day 14 significantly decreased systolic blood pressure by day 17 in TLR3-induced and TLR7-induced hypertensive mice (TLR3 144-111 mmHg; TLR7 145-106 mmHg; both P<0.05), and also normalized their elevated urinary protein:creatinine ratios (TLR3 5.68-3.72; TLR7 5.57-3.84; both P<0.05). On gestational day 17, aortic endothelium-dependent relaxation responses improved significantly in TLR3-induced and TLR7-induced hypertensive mice that received PLX-PAD cells on gestational day 14 (TLR3 35-65%; TLR7 37-63%; both P<0.05). In addition, markers of systemic inflammation and placental injury, increased markedly in both groups of TLR-induced hypertensive mice, were reduced by PLX-PAD cells. Importantly, PLX-PAD cell therapy had no effects on these measures in pregnant control mice or on the fetuses. These data demonstrate that PLX-PAD cell therapy can safely reverse pre-eclampsia-like features during pregnancy and have a potential therapeutic role in pre-eclampsia treatment., (© 2016 Authors; published by Portland Press Limited.)

Parasites play an important role in the evolution of host traits via natural selection, coevolution and sexually selected ornaments used in mate choice. These evolutionary scenarios assume fitness costs for hosts. To test this assumption, we conducted an ectoparasite removal experiment in free-living Columbian ground squirrels (Urocittelus columbianus) in four populations over three years. Adult females were randomly chosen to be either experimentally treated with anti-parasite treatments (spot-on solution and flea powder, N = 61) or a sham treatment (control, N = 44). We expected that experimental females would show better body condition, increased reproductive success and enhanced survival. Contrary to our expectations, body mass was not significantly different between treatments at mating, birth of litter or weaning of young. Further, neither number nor size of young at weaning differed significantly between the two treatments. Survival to the next spring for adult females and juveniles was not significantly different between experimental and control treatments. Finally, annual fitness was not affected by the treatments. We concluded that females and their offspring were able compensate for the presence of ectoparasites, suggesting little or no fitness costs of parasites for females in the different colonies and during the years of our experiments., (© 2015 The Author(s) Published by the Royal Society. All rights reserved.)

The genetic conflict between parents and their offspring is a cornerstone of kin selection theory and the gene-centred view of evolution, but whether it actually occurs in natural systems remains an open question. Conflict operates only if parenting is driven by genetic trade-offs between offspring performance and the parent's ability to raise additional offspring, and its expression critically depends on the shape of these trade-offs. Here we investigate the occurrence and nature of genetic conflict in an insect with maternal care, the earwig Forficula auricularia. Specifically, we test for a direct response to experimental selection on female future reproduction and correlated responses in current offspring survival, developmental rate and growth. The results demonstrate genetic trade-offs that differ in shape before and after hatching. Our study not only provides direct evidence for parent-offspring conflict but also highlights that conflict is not inevitable and critically depends on the genetic trade-offs shaping parental investment.

Mesenchymal stem cells are potent candidates in stroke therapy due to their ability to secrete protective anti-inflammatory cytokines and growth factors. We investigated the neuroprotective effects of human placental mesenchymal-like adherent stromal cells (PLX) using an established ischemic model of nerve growth factor (NGF)-differentiated pheochromocytoma PC12 cells exposed to oxygen and glucose deprivation (OGD) followed by reperfusion. Under optimal conditions, 2 × 10⁵ PLX cells, added in a trans-well system, conferred 30-60% neuroprotection to PC12 cells subjected to ischemic insult. PC12 cell death, measured by LDH release, was reduced by PLX cells or by conditioned medium derived from PLX cells exposed to ischemia, suggesting the active release of factorial components. Since neuroprotection is a prominent function of the cytokine IL-6 and the angiogenic factor VEGF165, we measured their secretion using selective ELISA of the cells under ischemic or normoxic conditions. IL-6 and VEGF165 secretion by co-culture of PC12 and PLX cells was significantly higher under ischemic compared to normoxic conditions. Exogenous supplementation of 10 ng/ml each of IL-6 and VEGF165 to insulted PC12 cells conferred neuroprotection, reminiscent of the neuroprotective effect of PLX cells or their conditioned medium. Growth factors as well as co-culture conditioned medium effects were reduced by 70% and 20% upon pretreatment with 240 ng/ml Semaxanib (anti VEGF165) and/or 400 ng/ml neutralizing anti IL-6 antibody, respectively. Therefore, PLX-induced neuroprotection in ischemic PC12 cells may be partially explained by IL-6 and VEGF165 secretion. These findings may also account for the therapeutic effects seen in clinical trials after treatment with these cells., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Polyandry is common in many species and it has been suggested that females engage in multiple mating to increase the genetic diversity of their offspring (genetic diversity hypothesis). Multiple paternity occurs in 30% of litters in wild populations of house mice, Mus musculus musculus , and multiple-sired litters are genetically more diverse than single-sired ones. Here, we aimed to test whether female house mice produce multiple-sired litters when they have the opportunity to produce genetically diverse litters. We assessed the rates of multiple paternity when females could choose to mate with two males that were genetically dissimilar to each other (i.e. nonsiblings and MHC dissimilar) compared with when females could choose to mate with two males that were genetically similar to each other (i.e. siblings and shared MHC alleles). Multiple mating may depend upon a female's own condition, and, therefore, we also tested whether inbred (from full-sibling matings) females were more likely to produce multiple-sired progeny than outbred controls. Overall we found that 29% of litters had multiple sires, but we found no evidence that females were more likely to produce multiple-sired litters when they had the opportunity to mate with genetically dissimilar males compared with controls, regardless of whether females were inbred or outbred. Thus, our findings do not support the idea that female mice increase multiple paternity when they have the opportunity to increase the genetic diversity of their offspring, as expected from the genetic diversity hypothesis.

Background: It is often suggested that mate choice enhances offspring immune resistance to infectious diseases. To test this hypothesis, we conducted a study with wild-derived house mice (Mus musculus musculus) in which females were experimentally mated either with their preferred or non-preferred male, and their offspring were infected with a mouse pathogen, Salmonella enterica (serovar Typhimurium)., Results: We found that offspring sired by preferred males were significantly more likely to survive the experimental infection compared to those sired by non-preferred males. We found no significant differences in the pathogen clearance or infection dynamics between the infected mice, suggesting that offspring from preferred males were better able to cope with infection and had improved tolerance rather than immune resistance., Conclusion: Our results provide the first direct experimental evidence within a single study that partner preferences enhance offspring resistance to infectious diseases.

Scent marking is often assumed to be a secondary sexual trait that increases males' mating and reproductive success, although direct evidence for this hypothesis is lacking. We conducted a study with wild-derived house mice, Mus musculus musculus , to test whether scent marking increases males' reproductive success when females can freely choose between two territorial males. We also experimentally manipulated males' competitive scent marking by exchanging scent-marked tiles between the neighbouring males' territories (intrusion treatment) or relocating males' tiles within their own territory (control). Experimental animals were tested twice and we examined whether individual males were consistent in their marking. We found that males marked more in the intrusion treatment than controls and more at shared territorial borders than elsewhere. We found high day-to-day variation in most individuals' scent marking, and yet the sum of individuals' scent marking was consistent over time and across different social conditions. Genetic paternity analyses revealed that males' scent marking significantly increased their reproductive success in both the intrusion treatment and the controls. Surprisingly, however, female social preference was not positively correlated with male scent marking. These results provide direct evidence that scent marking increases males' reproductive success when females can choose their mates, even though it did not increase females' social preferences.

Females often show multi-male mating (MMM), but the adaptive functions are unclear. We tested whether female house mice ( Mus musculus musculus ) show MMM when they can choose their mates without male coercion. We released 32 females into separate enclosures where they could choose to mate with two neighboring males that were restricted to their own territories. We also tested whether females increase MMM when the available males appeared unable to exclude intruders from their territories. To manipulate territorial intrusion, we introduced scent-marked tiles from the neighboring males into males' territories, or we rearranged tiles within males' own territories as a control. Each female was tested in treatment and control conditions and we conducted paternity analyses on the 57 litters produced. We found that 46 % of litters were multiply sired, indicating that multiple paternity is common when females can choose their mates. Intrusion did not increase multiple paternity, though multiple paternity was significantly greater in the first trial when the males were virgins compared to the second trial. Since virgin male mice are highly infanticidal, this finding is consistent with the infanticide avoidance hypothesis. We also found that multiple paternity was higher when competing males showed small differences in their amount of scent marking, suggesting that females reduce MMM when they can detect differences in males' quality. Finally, multiple paternity was associated with increased litter size but only in the intrusion treatment, which suggests that the effect of multiple paternity on offspring number is dependent on male-male interactions.

We determined the sequence of the male-specific minor histocompatibility complex antigen (Smcy) from the Y chromosome of seven squirrel species (Sciuridae, Rodentia). Based on conserved regions inside the Smcy intron sequence, we designed PCR primers for sex determination in these species that can be co-amplified with nuclear loci as controls. PCR co-amplification yields two products for males and one for females that are easily visualized as bands by agarose gel electrophoresis. Our method provides simple and reliable sex determination across a wide range of squirrel species., (© 2012 Blackwell Publishing Ltd.)

The L1 cell adhesion molecule (L1CAM) belongs to the immunoglobulin superfamily and was originally identified in the nervous system. Recent studies demonstrated L1CAM expression in various types of cancer, predominantly at the invasive front of tumors and in metastases, suggesting its involvement in advanced stages of tumor progression. Overexpression of L1CAM in normal and cancer cells increased motility, enhanced growth rate and promoted cell transformation and tumorigenicity. Moreover, the expression of L1CAM in tumor cells conferred the capacity to form metastases. These properties of L1CAM, in addition to its cell surface localization, make it a potentially useful diagnostic marker for cancer progression and a candidate for anti-cancer therapy. We review the role of L1CAM in cancer progression with particular emphasis on colon cancer, and the potential of anti-L1CAM antibodies as a therapeutic tool for cancer.

A key step in human colon cancer development includes the hyperactivation of Wnt/beta-catenin signaling and the induction of beta-catenin-TCF target genes that participate in colon cancer progression. Recent studies identified members of the immunoglobulin-like cell adhesion molecules (IgCAM) of the L1CAM family (L1 and Nr-CAM) as targets of beta-catenin-TCF signaling in colon cancer cells. L1 was detected at the invasive front of colon cancer tissue and confers metastasis when overexpressed in cells. In contrast to L1, we did not detect in colon cancer cells significant levels of another IgCAM family of molecules, the nectin-like (Necl) receptors Necl1 and Necl4, while Necl4 was previously found in the normal small intestine and colon tissues. We studied the properties of colon cancer cells in which Necl4 and Necl1 were expressed either alone, or in combination, and found that such cells display a wide range of properties associated with tumor suppression. Expression of both Necl1 and Necl4 was the most efficient in suppressing the tumorigenicity of colon cancer cells. This was associated with enhanced rates of apoptosis and change in several apoptosis-related markers. In contrast to its capacity to suppress tumorigenesis, Necl4 was unable to affect the highly malignant and metastatic capacities of colon cancer cells in which L1 was overexpressed. Our results suggest that various IgCAM receptor families play different roles in affecting the tumorigenic function of the same cells, and that Necl1 and Necl4 can fulfill a tumor suppressive role., ((c) 2009 Wiley-Liss, Inc.)

Background: L1-cell adhesion molecule (L1-CAM) is a cell adhesion receptor of the immunoglobulin superfamily, known for its roles in nerve cell function. While originally believed to be present only in brain cells, in recent years L1-CAM has been detected in other tissues, and in a variety of cancer cells, including some common types of human cancer., Objective/methods: We review the prevalence of L1-CAM in human cancer, the possible mechanisms involved in L1-CAM-mediated tumorigenesis, and cancer therapies based upon L1-CAM antibody treatment., Results/conclusions: In colon cancer cells, the L1-CAM gene was identified as a target of the Wnt/beta-catenin-TCF signaling pathway, and L1-CAM was exclusively detected at the invasive front of colon and ovarian cancer tissue. The expression of L1-CAM in normal and cancer cells enhanced tumorigenesis and conferred metastasis in colon cancer cells. Antibodies against the L1-CAM ectodomain severely inhibited the proliferation of a variety of cancer cells in culture and reduced tumor burden when injected into mice harboring cancer cells expressing L1-CAM. These results, in addition to the presence of L1-CAM on the cell surface and its restricted distribution in normal tissues, make it an ideal target for tumor therapy.

L1-CAM, a neuronal cell adhesion receptor, is also expressed in a variety of cancer cells. Recent studies identified L1-CAM as a target gene of beta-catenin-T-cell factor (TCF) signaling expressed at the invasive front of human colon cancer tissue. We found that L1-CAM expression in colon cancer cells lacking L1-CAM confers metastatic capacity, and mice injected in their spleen with such cells form liver metastases. We identified ADAM10, a metalloproteinase that cleaves the L1-CAM extracellular domain, as a novel target gene of beta-catenin-TCF signaling. ADAM10 overexpression in colon cancer cells displaying endogenous L1-CAM enhanced L1-CAM cleavage and induced liver metastasis, and ADAM10 also enhanced metastasis in colon cancer cells stably transfected with L1-CAM. DNA microarray analysis of genes induced by L1-CAM in colon cancer cells identified a cluster of genes also elevated in a large set of human colon carcinoma tissue samples. Expression of these genes in normal colon epithelium was low. These results indicate that there is a gene program induced by L1-CAM in colon cancer cells that is also present in colorectal cancer tissue and suggest that L1-CAM can serve as target for colon cancer therapy.

Nr-CAM, a cell-cell adhesion molecule of the immunoglobulin-like cell adhesion molecule family, known for its function in neuronal outgrowth and guidance, was recently identified as a target gene of beta-catenin signaling in human melanoma and colon carcinoma cells and tissue. Retrovirally mediated transduction of Nr-CAM into fibroblasts induces cell motility and tumorigenesis. We investigated the mechanisms by which Nr-CAM can confer properties related to tumor cell behavior and found that Nr-CAM expression in NIH3T3 cells protects cells from apoptosis in the absence of serum by constitutively activating the extracellular signal-regulated kinase and AKT signaling pathways. We detected a metalloprotease-mediated shedding of Nr-CAM into the culture medium of cells transfected with Nr-CAM, and of endogenous Nr-CAM in B16 melanoma cells. Conditioned medium and purified Nr-CAM-Fc fusion protein both enhanced cell motility, proliferation, and extracellular signal-regulated kinase and AKT activation. Moreover, Nr-CAM was found in complex with alpha4beta1 integrins in melanoma cells, indicating that it can mediate, in addition to homophilic cell-cell adhesion, heterophilic adhesion with extracellular matrix receptors. Suppression of Nr-CAM levels by small interfering RNA in B16 melanoma inhibited the adhesive and tumorigenic capacities of these cells. Stable expression of the Nr-CAM ectodomain in NIH3T3 cells conferred cell transformation and tumorigenesis in mice, suggesting that the metalloprotease-mediated shedding of Nr-CAM is a principal route for promoting oncogenesis by Nr-CAM.

Isoform B of human NDP kinase (NDPK-B) was previously identified as a transcription factor stimulating in vitro and ex vivo the transcription of the c-myc oncogene, which involves this enzyme in carcinogenesis. We have studied the enzymatic properties of NDPK-B in the presence of several single-stranded oligonucleotides. We show that the oligonucleotides are competitive inhibitors of the catalytic activity, indicating that the active site acts as a binding template for the anchorage of the oligonucleotide. Furthermore, the presence of a guanine at the 3'-end of several different aptamers increases its affinity 10-fold. To define the surface of the protein contacting the DNA within the nucleoprotein complex, we used single nanosecond laser pulses as the cross-linking reagent and MALDI-TOF mass spectrometry to identify cross-linked peptides purified from proteolytic digests of the cross-linked complex. Using 11-mer and 30-mer single-stranded oligonucleotides, the same three different nucleopeptides were identified after irradiation of the complexes, indicating a common binding mode for these two aptamers. Taken together, these results allowed us to propose a structural model of NDPK-B bound to single-stranded DNA.

In this paper, we studied the interaction of the human isoform B of nucleoside diphosphate kinase (NDP kinase B) with the nuclease hypersensitive element (NHE) present in the promoter element of the c-myc oncogene. The DNA-binding properties of NDP kinase B and other NDP kinases are compared and the nucleotide requirement for binding are discussed. Using quantitative methods, we identified the DNA-binding sites on the protein and we proposed a structural model for a complex of one hexameric NDP kinase B with an oligonucleotide.