Skin transcriptome analysis in Brangus cattle under heat stress.

Heat stress is a major factor that negatively affects animal welfare and production systems. Livestock should adapt to tropical and subtropical areas and to meet this, composite breeds have been developed. This work aimed to evaluate gene expression profiles in the skin of Brangus cattle under heat stress using a case-control design, and to correlate this with skin histological characteristics. Two groups of bulls were set using rectal temperature as a criterion to define stress conditions: stressed (N = 5) and non-stressed (N = 5) groups. Skin transcriptomics was performed and correlations between breed composition, phenotypic and skin histological traits were evaluated. Results showed 4309 differentially expressed genes (P < 0.01), 2113 downregulated and 2196 upregulated. Enrichment and ontology analyses revealed 132 GO terms and 67 pathways (P < 0.01), including thermogenesis, glycolysis, gluconeogenesis, mitochondrial activity, antioxidant and immune response, and apoptosis. The identity of the terms and pathways indicated the diversity of mechanisms directed to relieve the animals' suffering, acting from simple passive mechanisms (conduction, convection and radiation) to more complex active ones (behavioural changes, evaporation, vasodilation and wheezing). Furthermore, significant differences between phenotypic and skin histological traits and correlations between pairs of traits suggested a direction towards heat dissipation processes. In this sense, number of vessels was positively correlated with number of sweat glands (P < 0.001) and both were positively correlated with zebuine genetic content (P < 0.05 and P < 0.01, respectively), gland size was positively correlated with epidermal thickness and negatively with hair length (P < 0.05), and epidermal thickness was negatively correlated with gland-epidermis distance (P < 0.0005). These results support the notion that response to heat stress is physiologically complex, producing significant changes in the expression of genes involved in several biological pathways, while the animal's ability to face it depends greatly on their skin features.

Genetic evaluations of dairy goats with few pedigree data: different approaches to use molecular information.

One of the limitations of implementing animal breeding programs in small-scale or extensive production systems is the lack of production records and genealogical records. In this context, molecular markers could help to gain information for the breeding program. This study addresses the inclusion of molecular data into traditional genetic evaluation models as a random effect by molecular pedigree reconstruction and as a fixed effect by Bayesian clustering. The methods were tested for lactation curve traits in 14 dairy goat herds with incomplete phenotypic data and pedigree information. The results showed an increment of 37.3% of the relationships regarding the originals with MOLCOAN and clustering into five genetic groups. Data leads to estimating additive variance, error variance, and heritability with four different models, including pedigree and molecular information. Deviance Information Criterion (DIC) values demonstrate a greater fitting of the models that include molecular information either as fixed (genetic clusters) or as random (molecular matrix) effects. The molecular information of simple markers can complement genetic improvement strategies in populations with little information.

Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer.

BACKGROUND: Recent guidelines recommend consideration of the use of oral edoxaban or rivaroxaban for the treatment of venous thromboembolism in patients with cancer. However, the benefit of these oral agents is limited by the increased risk of bleeding associated with their use. METHODS: This was a multinational, randomized, investigator-initiated, open-label, noninferiority trial with blinded central outcome adjudication. We randomly assigned consecutive patients with cancer who had symptomatic or incidental acute proximal deep-vein thrombosis or pulmonary embolism to receive oral apixaban (at a dose of 10 mg twice daily for the first 7 days, followed by 5 mg twice daily) or subcutaneous dalteparin (at a dose of 200 IU per kilogram of body weight once daily for the first month, followed by 150 IU per kilogram once daily). The treatments were administered for 6 months. The primary outcome was objectively confirmed recurrent venous thromboembolism during the trial period. The principal safety outcome was major bleeding. RESULTS: Recurrent venous thromboembolism occurred in 32 of 576 patients (5.6%) in the apixaban group and in 46 of 579 patients (7.9%) in the dalteparin group (hazard ratio, 0.63; 95% confidence interval [CI], 0.37 to 1.07; P<0.001 for noninferiority). Major bleeding occurred in 22 patients (3.8%) in the apixaban group and in 23 patients (4.0%) in the dalteparin group (hazard ratio, 0.82; 95% CI, 0.40 to 1.69; P = 0.60). CONCLUSIONS: Oral apixaban was noninferior to subcutaneous dalteparin for the treatment of cancer-associated venous thromboembolism without an increased risk of major bleeding. (Funded by the Bristol-Myers Squibb-Pfizer Alliance; Caravaggio ClinicalTrials.gov number, NCT03045406.).

Ligelizumab impairs IgE-binding to plasmacytoid dendritic cells more potently than omalizumab and restores IFN-α production and FOXP3+ Treg generation.

BACKGROUND: Ligelizumab is an anti-IgE monoclonal antibody binding IgE with higher affinity than omalizumab that is under clinical investigation for several IgE-mediated diseases. We previously showed that omalizumab removes IgE bound to FcεRI on plasmacytoid dendritic cells (pDCs) and restores their ability to produce IFN-α and regulatory T cells (Tregs). The aim of this work is to investigate the capacity of ligelizumab to regulate functional properties of pDCs in comparison with omalizumab. METHODS: pDCs were isolated from atopic donors and IgE was detached from FcεRI on pDCs with designed ankyrin repeat protein (DARPin) bi53-79. pDCs were resensitized with IgE alone or in the presence of ligelizumab or omalizumab prior to IgE-FcεRI crosslinking and Toll-like receptor 9 (TLR9) stimulation. Flow cytometry, ELISA, coculture experiments and intranuclear staining were performed to determine cytokine production and Treg generation. An antigen-specific model of resensitization and IgE-crosslinking was also performed. RESULTS: The levels of serum total free IgE show a non-linear positive correlation with the frequency of IgE+ pDCs displaying IgE bound to FcεRI within the 43 individual donors included in the study. Ligelizumab displays stronger capacity than omalizumab to block the binding of free IgE to FcεRI on human pDCs, resulting in a greater restoration of TLR9-L-induced IFN-α production. Ligelizumab also restores the ability of pDCs to generate FOXP3+ Tregs as previously reported for omalizumab. CONCLUSIONS: The uncovered novel molecular mechanisms of ligelizumab to regulate functional properties of pDCs from atopic donors might have important clinical implications for anti-IgE treatments in different IgE-mediated diseases.

C-Type Lectin Receptor Mediated Modulation of T2 Immune Responses to Allergens.

PURPOSE OF REVIEW: Allergic diseases represent a major health problem of increasing prevalence worldwide. In allergy, dendritic cells (DCs) contribute to both the pathophysiology and the induction of healthy immune responses to the allergens. Different studies have reported that some common allergens contain glycans in their structure. C-type lectin receptors (CLRs) expressed by DCs recognize carbohydrate structures and are crucial in allergen uptake, presentation, and polarization of T cell responses. This review summarizes the recent literature regarding the role of CLRs in the regulation of type 2 immune responses to allergens. RECENT FINDINGS: In this review, we highlight the capacity of CLRs to recognize carbohydrates in common allergens triggering different signaling pathways involved in the polarization of CD4+ T cells towards specific Th2 responses. Under certain conditions, specific CLRs could also promote tolerogenic responses to allergens, which might well be exploited to develop novel therapeutic approaches of allergen-specific immunotherapy (AIT), the single treatment with potential disease-modifying capacity for allergic disease. At this regard, polymerized allergens conjugated to non-oxidized mannan (allergoid-mannan conjugated) are next-generation vaccines targeting DCs via CLRs that promote regulatory T cells, thus favoring allergen tolerance both in preclinical models and clinical trials. A better understanding of the role of CLRs in the development of allergy and in the induction of allergen tolerance might well pave the way for the design of novel strategies for allergic diseases.

Combinatorial protein-protein interactions on a polymerizing scaffold.

Scaffold proteins organize cellular processes by bringing signaling molecules into interaction, sometimes by forming large signalosomes. Several of these scaffolds are known to polymerize. Their assemblies should therefore not be understood as stoichiometric aggregates, but as combinatorial ensembles. We analyze the combinatorial interaction of ligands loaded on polymeric scaffolds, in both a continuum and discrete setting, and compare it with multivalent scaffolds with fixed number of binding sites. The quantity of interest is the abundance of ligand interaction possibilities-the catalytic potential Q-in a configurational mixture. Upon increasing scaffold abundance, scaffolding systems are known to first increase opportunities for ligand interaction and then to shut them down as ligands become isolated on distinct scaffolds. The polymerizing system stands out in that the dependency of Q on protomer concentration switches from being dominated by a first order to a second order term within a range determined by the polymerization affinity. This behavior boosts Q beyond that of any multivalent scaffold system. In addition, the subsequent drop-off is considerably mitigated in that Q decreases with half the power in protomer concentration than for any multivalent scaffold. We explain this behavior in terms of how the concentration profile of the polymer-length distribution adjusts to changes in protomer concentration and affinity. The discrete case turns out to be similar, but the behavior can be exaggerated at small protomer numbers because of a maximal polymer size, analogous to finite-size effects in bond percolation on a lattice.

Coat score. A possible explanation for the zebuine selective sweep located on bovine chromosome 5: 47,670,001-48,100,000 bp.

Over 65% of the world's cattle population resides in warm areas where heat stress conditions limit the breed of European taurine cattle. Composite breeds were developed to retain the main traits of both parental breeds. The skin plays a central role in animal response to heat stress. Research on the genetic architecture of skin traits has identified genes and regions related to warm resistance skin features. The aim of this study was to determine whether the indicine proportion accounted for coat type or whether there were genes of large effect segregating in Brangus. Bulls (n = 108) were genotyped using microarrays and their coat score and hair length were evaluated. Indicine-taurine genome-wide composition was estimated and GWAS was performed. Although significant correlations between indicine proportion and traits were not observed, four windows of SNPs on BTA4 and BTA5 explained more than 2% of the trait variance. The GWAS for coat score in summer showed the main peak on BTA5:46,941,446-48,030,219 bp, accounting for 4.65% of the variance. Our results suggest that the variation in coat score and undercoat hair length in Argentinian Brangus bulls is associated with the presence of some particular gene variants, rather than with the whole indicine genetic content.

Helios as a Potential Biomarker in Systemic Lupus Erythematosus and New Therapies Based on Immunosuppressive Cells.

The Helios protein (encoded by the IKZF2 gene) is a member of the Ikaros transcription family and it has recently been proposed as a promising biomarker for systemic lupus erythematosus (SLE) disease progression in both mouse models and patients. Helios is beginning to be studied extensively for its influence on the T regulatory (Treg) compartment, both CD4+ Tregs and KIR+/Ly49+ CD8+ Tregs, with alterations to the number and function of these cells correlated to the autoimmune phenomenon. This review analyzes the most recent research on Helios expression in relation to the main immune cell populations and its role in SLE immune homeostasis, specifically focusing on the interaction between T cells and tolerogenic dendritic cells (tolDCs). This information could be potentially useful in the design of new therapies, with a particular focus on transfer therapies using immunosuppressive cells. Finally, we will discuss the possibility of using nanotechnology for magnetic targeting to overcome some of the obstacles related to these therapeutic approaches.

2022 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer, including patients with COVID-19.

The International Initiative on Thrombosis and Cancer is an independent academic working group of experts aimed at establishing global consensus for the treatment and prophylaxis of cancer-associated thrombosis. The 2013, 2016, and 2019 International Initiative on Thrombosis and Cancer clinical practice guidelines have been made available through a free, web-based mobile phone application. The 2022 clinical practice guidelines, which are based on a literature review up to Jan 1, 2022, include guidance for patients with cancer and with COVID-19. Key recommendations (grade 1A or 1B) include: (1) low-molecular-weight heparins (LMWHs) for the initial (first 10 days) treatment and maintenance treatment of cancer-associated thrombosis; (2) direct oral anticoagulants for the initial treatment and maintenance treatment of cancer-associated thrombosis in patients who are not at high risk of gastrointestinal or genitourinary bleeding, in the absence of strong drug-drug interactions or of gastrointestinal absorption impairment; (3) LMWHs or direct oral anticoagulants for a minimum of 6 months to treat cancer-associated thrombosis; (4) extended prophylaxis (4 weeks) with LMWHs to prevent postoperative venous thromboembolism after major abdominopelvic surgery in patients not at high risk of bleeding; and (5) primary prophylaxis of venous thromboembolism with LMWHs or direct oral anticoagulants (rivaroxaban or apixaban) in ambulatory patients with locally advanced or metastatic pancreatic cancer who are treated with anticancer therapy and have a low risk of bleeding.

Access to Substituted Indenol Ethers via a Regioselective Intermolecular Carbopalladation Cascade.

Alkyne carbopalladation reactions can rapidly generate multiple new C-C bonds; however, regioselectivity is challenging for intermolecular variants. Using ynol ethers, we observe complete regiocontrol of migratory insertion followed by a second migratory insertion with a pendant alkene to turn-over the catalytic cycle. The resulting products are oligosubstituted 1-indenol ethers with defined stereochemistry based on the initial alkene geometry. Blocking ß-hydride elimination allowed for C-H and C-C reductive elimination steps for catalyst turnover.

Genome-wide scan for signatures of selection in the Brangus cattle genome.

Brangus is a composite cattle breed developed with the objective of combining the advantages of Angus and Zebuine breeds (Brahman, mainly) in tropical climates. The aim of this work was to estimate breed composition both genome-wide and locally, at the chromosome level, and to uncover genomic regions evidencing positive selection in the Argentinean Brangus population/nucleus. To do so, we analysed marker data from 478 animals, including Brangus, Angus and Brahman. Average breed composition was 35.0% ± 9.6% of Brahman, lower than expected according to the theoretical fractions deduced by the usual cross-breeding practice in this breed. Local ancestry analysis evidenced that breed composition varies between chromosomes, ranging from 19.6% for BTA26 to 56.1% for BTA5. Using approaches based on allelic frequencies and linkage disequilibrium, genomic regions with putative selection signatures were identified in several chromosomes (BTA1, BTA5, BTA6 and BTA14). These regions harbour genes involved in horn development, growth, lipid metabolism, reproduction and immune response. We argue that the overlapping of a chromosome segment originated in one of the parental breeds and over-represented in the sample with the location of a signature of selection constitutes evidence of a selection process that has occurred in the breed since its take off in the 1950s. In this regard, our results could contribute to the understanding of the genetic mechanisms involved in cross-bred cattle adaptation and productivity in tropical environments.

Nation-wide human mobility prediction based on graph neural networks.

Nowadays, the anticipation of human mobility flow has important applications in many domains ranging from urban planning to epidemiology. Because of the high predictability of human movements, numerous successful solutions to perform such forecasting have been proposed. However, most focus on predicting human displacements on an intra-urban spatial scale. This study proposes a predictor for nation-wide mobility that allows anticipating inter-urban displacements at larger spatial granularity. For this goal, a Graph Neural Network (GNN) was used to consider the latent relationships among large geographical regions. The solution has been evaluated with an open dataset including trips throughout the country of Spain and the current weather conditions. The results indicate a high accuracy in predicting the number of trips for multiple time horizons, and more important, they show that our proposal only needs a single model for processing all the mobility areas in the dataset, whereas other techniques require a different model for each area under study.

Long-term follow-up of a prospective phase 2 clinical trial of extended treatment with rituximab in patients with B cell post-transplant lymphoproliferative disease and validation in real world patients.

The purpose of this report is to provide long-term follow-up of 38 patients diagnosed of post-transplant lymphoproliferative disease (PTLD) included in a phase 2 clinical trial of first line therapy with rituximab and to evaluate the same therapy in a real world cohort of 21 consecutive patients treated once the trial was closed. Eligible patients were ≥ 18 years of age with a biopsy-proven CD20 positive B cell PTLD and treatment naive except for reduction of immunosuppression. Treatment consisted in four weekly infusions of rituximab at the standard dose of 375 mg/m2. Patients in complete remission (CR) were followed without further treatment, and those in partial remission (PR) were treated with another four cycles of weekly rituximab. Median follow-up in the clinical trial was 13.0 years. Disease-specific survival (DSS) at 10 years was 64.7% [95% confidence interval (CI) 48.2-81.2%]. For those patients who achieved CR (61%), DSS at 5 and 10 years was 94.4% (95% CI 83.8-100%) and 88.1% (95% CI 72.6-100%), respectively, and only 1 patient progressed beyond 5 years. The median follow-up of the real world patients was 6.5 years. DSS at 5 years was 75.2% (95% CI 56.4-94.0%). DSS at 5 years of patients who achieved CR (38%) was 87.5% (95% CI 64.6-100%). In conclusion, PTLD patients in CR after rituximab have an excellent long-term outcome. These results not only apply in the clinical trial setting but are also reproducible in the real world. However, those patients who do not respond represent an unmet clinical need and should be included in prospective clinical trials.

"Therapeutic uses of natural astaxanthin: An evidence-based review focused on human clinical trials".

Astaxanthin is a natural C40 carotenoid with numerous reported biological functions, most of them associated with its antioxidant and anti-inflammatory activity, standing out from other antioxidants as it has shown the highest oxygen radical absorbance capacity (ORAC), 100-500 times higher than ⍺-tocopherol and a 10 times higher free radical inhibitory activity than related antioxidants (α-tocopherol, α-carotene, ß -carotene, lutein and lycopene). In vitro and in vivo studies have associated astaxanthin's unique molecular features with several health benefits, including neuroprotective, cardioprotective and antitumoral properties, suggesting its therapeutic potential for the prevention or co-treatment of dementia, Alzheimer, Parkinson, cardiovascular diseases and cancer. Benefits on skin and eye health promotion have also been reported, highlighting its potential for the prevention of skin photo-aging and the treatment of eye diseases like glaucoma, cataracts and uveitis. In this review, we summarize and discuss the currently available evidence on astaxanthin benefits, with a particular focus on human clinical trials, including a brief description of the potential mechanisms of action responsible for its biological activities.

A Collaborative Application for Assisting the Management of Household Plastic Waste through Smart Bins: A Case of Study in the Philippines.

The management and collection of household waste often represents a demanding task for elderly or impaired people. In particular, the increasing generation of plastic waste at home may pose a problem for these groups, as this type of waste accumulates very rapidly and occupies a considerable amount of space. This paper proposes a collaborative infrastructure to monitor household plastic waste. It consists of simple smart bins using a weight scale and a smart application that forecasts the amount of plastic generated for each bin at different time horizons out of the data provided by the smart bins. The application generates optimal routes for the waste-pickers collaborating in the system through a route-planning algorithm. This algorithm takes into account the predicted amount of plastic of each bin and the waste-picker's location and means of transport. This proposal has been evaluated by means of a simulated scenario in Quezon City, Philippines, where severe problems with plastic waste have been identified. A set of 176 experiments have been performed to collect data that allow representing different user behaviors when generating plastic waste. The results show that our proposal enables waste-pickers to collect more than the 80% of the household plastic-waste bins before they are completely full.

MiR130b from Schlafen4+ MDSCs stimulates epithelial proliferation and correlates with preneoplastic changes prior to gastric cancer.

The myeloid differentiation factor Schlafen4 (Slfn4) marks a subset of myeloid-derived suppressor cells (MDSCs) in the stomach during Helicobacter-induced spasmolytic polypeptide-expressing metaplasia (SPEM). OBJECTIVE: To identify the gene products expressed by Slfn4+-MDSCs and to determine how they promote SPEM. DESIGN: We performed transcriptome analyses for both coding genes (mRNA by RNA-Seq) and non-coding genes (microRNAs using NanoString nCounter) using flow-sorted SLFN4+ and SLFN4- cells from Helicobacter-infected mice exhibiting metaplasia at 6 months postinfection. Thioglycollate-elicited myeloid cells from the peritoneum were cultured and treated with IFNα to induce the T cell suppressor phenotype, expression of MIR130b and SLFN4. MIR130b expression in human gastric tissue including gastric cancer and patient sera was determined by qPCR and in situ hybridisation. Knockdown of MiR130b in vivo in Helicobacter-infected mice was performed using Invivofectamine. Organoids from primary gastric cancers were used to generate xenografts. ChIP assay and Western blots were performed to demonstrate NFκb p65 activation by MIR130b. RESULTS: MicroRNA analysis identified an increase in MiR130b in gastric SLFN4+ cells. Moreover, MIR130b colocalised with SLFN12L, a human homologue of SLFN4, in gastric cancers. MiR130b was required for the T-cell suppressor phenotype exhibited by the SLFN4+ cells and promoted Helicobacter-induced metaplasia. Treating gastric organoids with the MIR130b mimic induced epithelial cell proliferation and promoted xenograft tumour growth. CONCLUSION: Taken together, MiR130b plays an essential role in MDSC function and supports metaplastic transformation.

Biochemical and structural analyses suggest that plasminogen activators coevolved with their cognate protein substrates and inhibitors.

Protein sequences of members of the plasminogen activation system are present throughout the entire vertebrate phylum. This important and well-described proteolytic cascade is governed by numerous protease-substrate and protease-inhibitor interactions whose conservation is crucial to maintaining unchanged protein function throughout evolution. The pressure to preserve protein-protein interactions may lead to either co-conservation or covariation of binding interfaces. Here, we combined covariation analysis and structure-based prediction to analyze the binding interfaces of urokinase (uPA):plasminogen activator inhibitor-1 (PAI-1) and uPA:plasminogen complexes. We detected correlated variation between the S3-pocket-lining residues of uPA and the P3 residue of both PAI-1 and plasminogen. These residues are known to form numerous polar interactions in the human uPA:PAI-1 Michaelis complex. To test the effect of mutations that correlate with each other and have occurred during mammalian diversification on protein-protein interactions, we produced uPA, PAI-1, and plasminogen from human and zebrafish to represent mammalian and nonmammalian orthologs. Using single amino acid point substitutions in these proteins, we found that the binding interfaces of uPA:plasminogen and uPA:PAI-1 may have coevolved to maintain tight interactions. Moreover, we conclude that although the interaction areas between protease-substrate and protease-inhibitor are shared, the two interactions are mechanistically different. Compared with a protease cleaving its natural substrate, the interaction between a protease and its inhibitor is more complex and involves a more fine-tuned mechanism. Understanding the effects of evolution on specific protein interactions may help further pharmacological interventions of the plasminogen activation system and other proteolytic systems.

Updated meta-analysis on prevention of venous thromboembolism in ambulatory cancer patients.

Randomized clinical trials have evaluated the role of anticoagulants in the prevention of venous thromboembolism (VTE) in ambulatory cancer patients treated with chemotherapy. This meta-analysis is aimed at providing an updated evaluation of the efficacy and safety of anticoagulant prophylaxis in this clinical setting. Medline and Scopus were searched to retrieve randomized controlled trials on the prevention of VTE in ambulatory cancer patients. Two groups of trials were identified with VTE or death as the primary outcome, respectively. VTE was the primary outcome of this analysis. Anticoagulant prophylaxis reduced the incidence of VTE in studies in which the primary outcome was VTE [14 studies, 8,226 patients; odds ratio (OR)=0.45; 95% confidence interval (95% CI): 0.36-0.56] or death (8 studies, 3,727 patients; OR=0.61; 95% CI: 0.47-0.81). When these studies were pooled together, VTE was reduced by 49% (95% CI: 0.43-0.61) with no significant increase in major bleeding (OR=1.30, 95% CI: 0.98-1.73). The risk of major bleeding was increased in studies with VTE as the primary outcome (OR=1.43, 95% CI: 1.01-2.04). Similar reductions of VTE were observed in studies with parenteral (OR=0.43, 95% CI: 0.33-0.56) or oral anticoagulants (OR=0.49, 95% CI: 0.33-0.74). The reduction in VTE was confirmed in patients with lung (OR=0.42, 95% CI: 0.26-0.67) or pancreatic cancer (OR=0.26, 95% CI: 0.14-0.48), in estimated high-risk patients, in high-quality studies and with respect to symptomatic VTE. In conclusion, prophylaxis with oral or parenteral anticoagulants reduces the risk of VTE in ambulatory cancer patients, with an acceptable increase in major bleeding.

Meta-analysis examining overall survival in patients with pancreatic cancer treated with second-line 5-fluorouracil and oxaliplatin-based therapy after failing first-line gemcitabine-containing therapy: effect of performance status and comparison with other regimens.

BACKGROUND: Pancreatic cancer has a poor prognosis and few choices of therapy. For patients with adequate performance status, FOLFIRINOX or gemcitabine plus nab-paclitaxel are preferred first-line treatment. 5-Fluorouracil (5-FU)-based therapy (e.g. FOLFIRI, OFF, or FOLFOX) are often used in patients who previously received gemcitabine-based regimens. A systematic review was conducted of the safety and efficacy of FOLFOX for metastatic pancreatic cancer following prior gemcitabine-based therapy. A Bayesian fixed-effect meta-analysis with adjustment of patient performance status (PS) was conducted to evaluate overall survival (OS) and compare outcomes with nanoliposomal irinotecan combination therapy. METHODS: PubMed.gov , FDA.gov , ClinicalTrials.gov , congress abstracts, Cochrane.org library, and EMBASE database searches were conducted to identify randomized controlled trials of advanced/metastatic disease, prior gemcitabine-based therapy, and second-line treatment with 5-FU and oxaliplatin. The database search dates were January 1, 1990-June 30, 2019. Endpoints were OS and severe treatment-related adverse events (TRAEs). Trial-level PS scores were standardized by converting Karnofsky grade scores to Eastern Cooperative Oncology Group (ECOG) Grade, and overall study-weighted PS was calculated based on weighted average of all patients. RESULTS: Of 282 studies identified, 11 randomized controlled trials (N = 454) were included in the meta-analysis. Baseline weighted PS scores predicted OS in 10 of the 11 studies, and calculated PS scores of 1.0 were associated with a median OS of 6.3 months (95% posterior interval, 5.4-7.4). After adjusting for baseline PS, FOLFOX had a similar treatment effect profile (median OS, range 2.6-6.7 months) as 5-FU/leucovorin plus nanoliposomal irinotecan therapy (median OS, 6.1 months; 95% confidence interval 4.8-8.9). Neutropenia and fatigue were the most commonly reported Grade 3-4 TRAEs associated with FOLFOX. CONCLUSIONS: Baseline PS is a strong prognostic factor when interpreting the efficacy of 5-FU and oxaliplatin-based therapy of pancreatic cancer after progression on first-line gemcitabine-based regimens. When baseline PS is considered, FOLFOX has a similar treatment effect as 5-FU and nanoliposomal irinotecan therapy and a comparable safety profile. These findings suggest that 5-FU and oxaliplatin-based therapies remain an acceptable and alternative second-line treatment option for patients with pancreatic cancer and adequate PS (e.g. ECOG 0-1) following gemcitabine treatment.