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Progesterone is a steroid hormone that is critical for implantation and maintenance of pregnancy, and low levels are associated with higher miscarriage risk. However, little is known about its trajectory during early pregnancy. We sought to determine the gestational age-specific normative values of serum progesterone on a week-by-week basis, and its associated maternal and fetal factors, during the first trimester of a viable low-risk pregnancy. A cross-sectional study was conducted at KK Women’s and Children’s Hospital from 2013 to 2018. 590 women with a single viable intrauterine low-risk pregnancy, between gestational weeks 5 and 12, were recruited. Serum progesterone showed an increasing trend during the first trimester, with a transient decline between gestational weeks 6–8, corresponding to the luteal–placental shift. Lowest levels were seen at week 7. Maternal age, BMI, parity, gestational age and outcome of pregnancy at 16 weeks’ gestation were found to be associated with progesterone levels. Normative values of serum progesterone for low-risk pregnancies would form the basis for future work on pathological levels of serum progesterone that may increase risk of miscarriage. Larger studies are required to validate these normative values, and personalize them to account for maternal age, BMI, parity and gestational age.

Progesterone-induced blocking factor (PIBF), which plays an important role in maintaining healthy pregnancies, has shown great promise as a prognostic biomarker for threatened miscarriage. To better characterise the physiological trends of progesterone and PIBF, we analysed serum progesterone and PIBF concentrations in healthy non-pregnant and pregnant women across trimesters. We saw increasing concentrations of progesterone and PIBF in pregnant women with advancing trimesters. The serum progesterone and PIBF percentiles across gestational age in healthy pregnancies can be used as a guide for the formulation of reference ranges. We also demonstrated a significant positive correlation between progesterone and PIBF levels. This study demonstrates increasing progesterone and PIBF concentrations in later trimesters and underscores the importance of progesterone and PIBF in healthy pregnancies. Characterisation of progesterone and PIBF across gestational age in healthy pregnant women may help to prognosticate pregnancy viability and support further research into the importance of progesterone and PIBF in the maintenance of healthy pregnancies.

The persistent inflammatory response at the wound site is a cardinal feature of nonhealing wounds. Prolonged neutrophil presence in the wound site due to failed clearance by reduced monocyte-derived macrophages delays the transition from the inflammatory to the proliferative phase of wound healing. Angiopoietin-like 4 protein (Angptl4) is a matricellular protein that has been implicated in many inflammatory diseases. However, its precise role in the immune cell response during wound healing remains unclear. Therefore, we performed flow cytometry and single-cell RNA sequencing to examine the immune cell landscape of excisional wounds from Angptl4 +/+ and Angptl4 −/− mice. Chemotactic immune cell recruitment and infiltration were not compromised due to Angptl4 deficiency. However, as wound healing progresses, Angptl4 −/− wounds have a prolonged neutrophil presence and fewer monocyte-derived macrophages than Angptl4 +/+ and Angptl4 LysM−/− wounds. The underlying mechanism involves a novel Angptl4-interferon activated gene 202B (ifi202b) axis that regulates monocyte differentiation to macrophages, coordinating neutrophil removal and inflammation resolution. An unbiased kinase inhibitor screen revealed an Angptl4-mediated kinome signaling network involving S6K, JAK, and CDK, among others, that modulates the expression of ifi202b. Silencing ifi202b in Angptl4 −/− monocytes, whose endogenous expression was elevated, rescued the impaired monocyte-to-macrophage transition in the in vitro reconstituted wound microenvironment using wound exudate. GSEA and IPA functional analyses revealed that ifi202b-associated canonical pathways and functions involved in the inflammatory response and monocyte cell fate were enriched. Together, we identified ifi202b as a key gatekeeper of monocyte differentiation. By modulating ifi202b expression, Angptl4 orchestrates the inflammatory state, innate immune landscape, and wound healing process.

Threatened miscarriage is a common gynaecological emergency, with up to 25% of women eventually progressing to spontaneous miscarriage. The uncertainty of pregnancy outcomes results in significant anxiety. However, there is currently no acceptable framework for triaging patients presenting with threatened miscarriage. We aim to evaluate the efficacy and safety of a novel clinical protocol using a single serum progesterone level to prognosticate and guide management of patients with threatened miscarriage. 1087 women presenting with threatened miscarriage were enrolled in the study. The primary outcome was spontaneous miscarriage by 16 weeks’ gestation. Among the 77.9% (847/1087) of study participants with serum progesterone ≥ 35 nmol/L who were not treated with oral dydrogesterone, the miscarriage rate was 9.6% (81/847). This did not differ significantly from the 8.5% (31/364) miscarriage rate observed in our prior studies; p  = 0.566. Among women with serum progesterone < 35 nmol/L who were treated with dydrogesterone, the miscarriage rate was 70.8% (170/240). Our novel clinical triage protocol using a single serum progesterone level allowed both effective risk stratification and a reduction in progestogen use with no significant adverse pregnancy outcomes. This protocol, based on a single serum progesterone cutoff, can be readily adapted for use in other healthcare institutions.

Field cancerization and metastasis are the leading causes for cancer recurrence and mortality in cancer patients. The formation of primary, secondary tumors or metastasis is greatly influenced by multifaceted tumor-stroma interactions, in which stromal components of the tumor microenvironment (TME) can affect the behavior of the cancer cells. Many studies have identified cytokines and growth factors as cell signaling molecules that aid cell to cell communication. However, the functional contribution of reactive oxygen species (ROS), a family of volatile chemicals, as communication molecules are less understood. Cancer cells and various tumor-associated stromal cells produce and secrete a copious amount of ROS into the TME. Intracellular ROS modulate cell signaling cascades that aid in the acquisition of several hallmarks of cancers. Extracellular ROS help to propagate, amplify, and effectively create a mutagenic and oncogenic field which facilitate the formation of multifoci tumors and act as a springboard for metastatic tumor cells. In this review, we summarize our current knowledge of ROS as atypical paracrine signaling molecules for field cancerization and metastasis. Field cancerization and metastasis are often discussed separately; we offer a model that placed these events with ROS as the focal instigating agent in a broader “seed-soil” hypothesis.

Although polyvinylidene fluoride (PVDF) is non-toxic and stable in vivo, its hydrophobic surface has limited its bio-applications due to poor cell-material interaction and thrombus formation when used in blood contacting devices. In this study, surface modification of PVDF using naturally derived non-mammalian collagen was accomplished via direct surface-initiated atom transfer radical polymerisation (SI-ATRP) to enhance its cytocompatibility and hemocompatibility. Results showed that Type I collagen was successfully extracted from fish scales and bullfrog skin. The covalent immobilisation of fish scale-derived collagen (FSCOL) and bullfrog skin-derived collagen (BFCOL) onto the PVDF surface improves the attachment and proliferation of human umbilical vein endothelial cells (HUVECs). Furthermore, both FSCOL and BFCOL had comparable anti-thrombogenic profiles to that of commercially available bovine collagen (BVCOL). Also, cell surface expression of the leukocyte adhesion molecule was lower on HUVECs cultured on non-mammalian collagen surfaces than on BVCOL, which is an indication of lower pro-inflammatory response. Overall, results from this study demonstrated that non-mammalian sources of collagen could be used to confer bioactivity to PVDF, with comparable cell-material interactions and hemocompatibility to BVCOL. Additionally, higher expression levels of Type IV collagen in HUVECs cultured on FSCOL and BFCOL were observed as compared to BVCOL, which is an indication that the non-mammalian sources of collagen led to a better pro-angiogenic properties, thus making them suitable for blood contacting applications.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development, and differentiation. Their crucial biological roles dictate the significance of PPAR-targeting synthetic ligands in medical research and drug discovery. Clinical implications of PPAR agonists span across a wide range of health conditions, including metabolic diseases, chronic inflammatory diseases, infections, autoimmune diseases, neurological and psychiatric disorders, and malignancies. In this review we aim to consolidate existing clinical evidence of PPAR modulators, highlighting their clinical prospects and challenges. Findings from clinical trials revealed that different agonists of the same PPAR subtype could present different safety profiles and clinical outcomes in a disease-dependent manner. Pemafibrate, due to its high selectivity, is likely to replace other PPARα agonists for dyslipidemia and cardiovascular diseases. PPARγ agonist pioglitazone showed tremendous promises in many non-metabolic disorders like chronic kidney disease, depression, inflammation, and autoimmune diseases. The clinical niche of PPARβ/δ agonists is less well-explored. Interestingly, dual- or pan-PPAR agonists, namely chiglitazar, saroglitazar, elafibranor, and lanifibranor, are gaining momentum with their optimistic outcomes in many diseases including type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease, and primary biliary cholangitis. Notably, the preclinical and clinical development for PPAR antagonists remains unacceptably deficient. We anticipate the future design of better PPAR modulators with minimal off-target effects, high selectivity, superior bioavailability, and pharmacokinetics. This will open new possibilities for PPAR ligands in medicine.

The liver is a vital organ that sustains multiple functions beneficial for the whole organism. It is sexually dimorphic, presenting sex-biased gene expression with implications for the phenotypic differences between males and females. Estrogens are involved in this sex dimorphism and their actions in the liver of several reptiles, fishes, amphibians, and birds are discussed. The liver participates in reproduction by producing vitellogenins (yolk proteins) and eggshell proteins under the control of estrogens that act via two types of receptors active either mainly in the cell nucleus (ESR) or the cell membrane (GPER1). Estrogens also control hepatic lipid and lipoprotein metabolisms, with a triglyceride carrier role for VLDL from the liver to the ovaries during oogenesis. Moreover, the activation of the vitellogenin genes is used as a robust biomarker for exposure to xenoestrogens. In the context of liver diseases, high plasma estrogen levels are observed in fatty liver hemorrhagic syndrome (FLHS) in chicken implicating estrogens in the disease progression. Fishes are also used to investigate liver diseases, including models generated by mutation and transgenesis. In conclusion, studies on the roles of estrogens in the non-mammalian oviparous vertebrate liver have contributed enormously to unveil hormone-dependent physiological and physiopathological processes.

Intratumoral heterogeneity is a hallmark of glioblastoma (GBM) tumors, thought to negatively influence therapeutic outcome. Previous studies showed that mesenchymal tumors have a worse outcome than the proneural subtype. Here we focus on STAT3 as its activation precedes the proneural-mesenchymal transition. We first establish a STAT3 gene signature that stratifies GBM patients into STAT3 -high and -low cohorts. STAT3 inhibitor treatment selectively mitigates STAT3 -high cell viability and tumorigenicity in orthotopic mouse xenograft models. We show the mechanism underlying resistance in STAT3 -low cells by combining STAT3 signature analysis with kinome screen data on STAT3 inhibitor-treated cells. This allows us to draw connections between kinases affected by STAT3 inhibitors, their associated transcription factors and target genes. We demonstrate that dual inhibition of IGF-1R and STAT3 sensitizes STAT3 -low cells and improves survival in mice. Our study underscores the importance of serially profiling tumors so as to accurately target individuals who may demonstrate molecular subtype switching. STAT3 activates distinct transcriptional programmes within cancer cells. In this study, the authors find that, in glioma, a STAT3-mediated expression signature can stratify patients for targeted precision therapy.

Achieving untargeted chemical identification, isomeric differentiation, and quantification is critical to most scientific and technological problems but remains challenging. Here, we demonstrate an integrated SERS-based chemical taxonomy machine learning framework for untargeted structural elucidation of 11 epimeric cerebrosides, attaining >90% accuracy and robust single epimer and multiplex quantification with <10% errors. First, we utilize 4-mercaptophenylboronic acid to selectively capture the epimers at molecular sites of isomerism to form epimer-specific SERS fingerprints. Corroborating with in-silico experiments, we establish five spectral features, each corresponding to a structural characteristic: (1) presence/absence of epimers, (2) monosaccharide/cerebroside, (3) saturated/unsaturated cerebroside, (4) glucosyl/galactosyl, and (5) GlcCer or GalCer’s carbon chain lengths. Leveraging these insights, we create a fully generalizable framework to identify and quantify cerebrosides at concentrations between 10 −4 to 10 −10  M and achieve multiplex quantification of binary mixtures containing biomarkers GlcCer 24:1 , and GalCer 24:1 using their untrained spectra in the models. SERS-based chemical taxonomy is attractive for practical SERS applications where the identity and concentration of analytes are unknown. Here, the authors demonstrate a machine learning framework for classifying “unknown” molecules that lie outside the boundaries of the models used.