We propose a generalized linear low‐rank mixed model (GLLRM) for the analysis of both high‐dimensional and sparse responses and covariates where the responses may be binary, counts, or continuous. ...This development is motivated by the problem of identifying vaccine‐adverse event associations in post‐market drug safety databases, where an adverse event is any untoward medical occurrence or health problem that occurs during or following vaccination. The GLLRM is a generalization of a generalized linear mixed model in that it integrates a factor analysis model to describe the dependence among responses and a low‐rank matrix to approximate the high‐dimensional regression coefficient matrix. A sampling procedure combining the Gibbs sampler and Metropolis and Gamerman algorithms is employed to obtain posterior estimates of the regression coefficients and other model parameters. Testing of response‐covariate pair associations is based on the posterior distribution of the corresponding regression coefficients. Monte Carlo simulation studies are conducted to examine the finite‐sample performance of the proposed procedures on binary and count outcomes. We further illustrate the GLLRM via a real data example based on the Vaccine Adverse Event Reporting System.
Phillips Phillips R.F., 1991. A constrained maximum likelihood approach to estimating switching regressions.
Journal of Econometrics 48, 241–262 proposed a constrained maximum-likelihood approach to ...estimating the parameters in a switching regression model. In this note, we propose a new approach which leads to a proof of a more general result than Phillips’s. Specifically, we prove that the Constrained MLE (CMLE) is still strongly consistent when the constant
c
decreases to 0 at the rate of
exp
(
−
n
1
2
(
log
n
)
−
α
)
as
n
increases to
∞
, with
α
>
1
. We also suggest a suitable
α
, hence
c
n
, for practice based on simulation results.
An immunosuppressive tumour microenvironment is a major obstacle in the control of pancreatic and other solid cancers
. Agonists of the stimulator of interferon genes (STING) protein trigger ...inflammatory innate immune responses to potentially overcome tumour immunosuppression
. Although these agonists hold promise as potential cancer therapies
, tumour resistance to STING monotherapy has emerged in clinical trials and the mechanism(s) is unclear
. Here we show that the administration of five distinct STING agonists, including cGAMP, results in an expansion of human and mouse interleukin (IL)-35
regulatory B cells in pancreatic cancer. Mechanistically, cGAMP drives expression of IL-35 by B cells in an IRF3-dependent but type I interferon-independent manner. In several preclinical cancer models, the loss of STING signalling in B cells increases tumour control. Furthermore, anti-IL-35 blockade or genetic ablation of IL-35 in B cells also reduces tumour growth. Unexpectedly, the STING-IL-35 axis in B cells reduces proliferation of natural killer (NK) cells and attenuates the NK-driven anti-tumour response. These findings reveal an intrinsic barrier to systemic STING agonist monotherapy and provide a combinatorial strategy to overcome immunosuppression in tumours.
Despite perinatal depression (PND) being a common mental disorder affecting pregnant women and new mothers, limited attention has been paid to the heterogeneous nature of this disorder. We examined ...heterogeneity in PND symptom profiles and symptom trajectories. Literature searches revealed 247 studies, 23 of which were included in the final review. The most common statistical approaches used to explore symptom and trajectory heterogeneity were latent class model and growth mixture model. All but one study examined PND symptom trajectories and provided collective evidence of at least three heterogeneous patterns: low, medium, or chronic-high symptom levels. Social and psychological risk factors were the most common group of predictors related to a higher burden (high sum of score) of depressive symptoms. These studies were consistent in reporting poorer health outcomes for children of mothers assigned to high burden symptom trajectories. Only one study explored heterogeneity in symptom profile and was the only one to describe the specific constellations of depressive symptoms related to the PND heterogeneous patterns identified. Therefore, there is limited evidence on the specific symptoms and symptom configurations that make up PND heterogeneity. We suggest directions for future research to further clarify the PND heterogeneity and its related mechanisms.
Per‐ and polyfluoroalkyl substances (PFAS) are widespread environmental contaminants linked to adverse outcomes, including for female reproductive biology and related cancers. We recently reported, ...for the first time, that PFAS induce platinum resistance in ovarian cancer, potentially through altered mitochondrial function. Platinum resistance is a major barrier in the management of ovarian cancer, necessitating complementary therapeutic approaches. Photodynamic therapy (PDT) is a light‐based treatment modality that reverses platinum resistance and synergizes with platinum‐based chemotherapy. The present study is the first to demonstrate the ability of photodynamic priming (PDP), a low‐dose, sub‐cytotoxic variant of PDT, to overcome PFAS‐induced platinum resistance. Comparative studies of PDP efficacy using either benzoporphyrin derivative (BPD) or 5‐aminolevulinic acid‐induced protoporphyrin IX (PpIX) were conducted in two human ovarian cancer cell lines (NIH:OVCAR‐3 and Caov‐3). BPD and PpIX are clinically approved photosensitizers that preferentially localize to, or are partly synthesized in, mitochondria. PDP overcomes carboplatin resistance in PFAS‐exposed ovarian cancer cells, demonstrating the feasibility of this approach to target the deleterious effects of environmental contaminants. Decreased survival fraction in PDP + carboplatin treated cells was accompanied by decreased mitochondrial membrane potential, suggesting that PDP modulates the mitochondrial membrane, reducing membrane potential and re‐sensitizing ovarian cancer cells to carboplatin.
Select per‐ and polyfluoroalkyl substances (PFAS) have been shown to induce resistance to carboplatin, a platinum‐based chemotherapeutic agent, in two ovarian cancer cell lines. A concomitant increase in mitochondrial membrane potential was observed. In the present study, photodynamic priming (PDP) to overcome PFAS‐induced resistance was explored, using either benzoporphyrin derivative (BPD) or aminolevulinic acid‐induced protoporphyrin IX (ALA‐PpIX). PDP in combination with low‐dose carboplatin effectively reduced survival fraction in PFAS‐exposed cells. A decrease in mitochondrial membrane potential following PDP was observed, suggesting that PDP modulates mitochondrial health to re‐sensitize ovarian cancer cells to chemotherapy.
We propose a generalized linear low‐rank mixed model (GLLRM) for the analysis of both high‐dimensional and sparse responses and covariates where the responses may be binary, counts, or continuous. ...This development is motivated by the problem of identifying vaccine‐adverse event associations in post‐market drug safety databases, where an adverse event is any untoward medical occurrence or health problem that occurs during or following vaccination. The GLLRM is a generalization of a generalized linear mixed model in that it integrates a factor analysis model to describe the dependence among responses and a low‐rank matrix to approximate the high‐dimensional regression coefficient matrix. A sampling procedure combining the Gibbs sampler and Metropolis and Gamerman algorithms is employed to obtain posterior estimates of the regression coefficients and other model parameters. Testing of response‐covariate pair associations is based on the posterior distribution of the corresponding regression coefficients. Monte Carlo simulation studies are conducted to examine the finite‐sample performance of the proposed procedures on binary and count outcomes. We further illustrate the GLLRM via a real data example based on the Vaccine Adverse Event Reporting System.
Ionizing radiation causes acute radiation syndrome, which leads to hematopoietic, gastrointestinal, and cerebrovascular injuries. We investigated a population of mice that recovered from high-dose ...radiation to live normal life spans. These "elite-survivors" harbored distinct gut microbiota that developed after radiation and protected against radiation-induced damage and death in both germ-free and conventionally housed recipients. Elevated abundances of members of the bacterial taxa
and
were associated with postradiation restoration of hematopoiesis and gastrointestinal repair. These bacteria were also found to be more abundant in leukemia patients undergoing radiotherapy, who also displayed milder gastrointestinal dysfunction. In our study in mice, metabolomics revealed increased fecal concentrations of microbially derived propionate and tryptophan metabolites in elite-survivors. The administration of these metabolites caused long-term radioprotection, mitigation of hematopoietic and gastrointestinal syndromes, and a reduction in proinflammatory responses.
Irisin, an exercise-induced myokine, induces conversion of white into brown adipocytes, promoting mitochondrial biogenesis and energy expenditure. Irisin has a vascular protective effect on ...endothelial function in animals, including humans. Defects in irisin signaling pathways result in endothelial dysfunction in obesity and diabetes. However, the mechanisms underlying the effects of irisin on endothelial function have not been elucidated. Transient receptor potential vanilloid subtype 4 (TRPV4) channels are one of the most important Ca2+-permeable cation channels in vascular endothelial cells. In this study, we hypothesized that irisin may induce endothelium-dependent vasodilation by activating Ca2+ influx into endothelial cells via TRPV4 channels. In primary cultured rat mesenteric artery endothelial cells, irisin caused an increase in Ca2+i due to extracellular Ca2+ influx rather than release from Ca2+ stores. Moreover, irisin-induced increases in Ca2+i were completely abolished by a TRPV4 inhibitor. In addition, irisin induced endothelium-dependent vasodilation of rat mesenteric arteries. However, irisin had no effect on endothelium-independent vasodilation. Furthermore, irisin-induced vasodilation was fully abolished in the presence of a TRPV4 inhibitor, indicating the involvement of TRPV4 channels in endothelium-dependent vasodilation. This study provides the first evidence that irisin-induced endothelium-dependent vasodilation is related to the stimulation of extracellular Ca2+ influx via TRPV4 channels in rat mesenteric arteries.
•Irisin caused an increase in Ca2+i due to extracellular Ca2+ influx rather than Ca2+ release in endothelial cells.•Pretreatment with TRPV4 channel inhibitor completely abolished irisin-induced increases in Ca2+i.•Irisin induced endothelium-dependent vasodilation, however, it had no effect on endothelium-independent vasodilation.•Pretreatment with TRPV4 channel inhibitor fully abrogated irisin-induced vasodilation.
The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of through the induction of angiogenesis, tumor vascularization can ...occur through the nonangiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option is also prevalent in human breast cancer liver metastases, a setting in which results with anti-angiogenic therapy have been disappointing. In preclinical mechanistic studies, we found that cancer cell motility mediated by the actin-related protein 2/3 complex (Arp2/3) is required for vessel co-option in liver metastases in vivo and that, in this setting, combined inhibition of angiogenesis and vessel co-option is more effective than the inhibition of angiogenesis alone. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option might be a warranted therapeutic strategy.
PDF
