Search

Background: Predictive biomarkers for immune checkpoint blockade in the second-line treatment of metastatic renal cell carcinoma (mRCC) are lacking. Materials and methods: Patients with histologically confirmed RCC who started nivolumab after at least 4 months of tyrosine kinase inhibitors (TKIs) were recruited for this study. Serial tissue and blood samples were collected for immune biomarker evaluation. The primary endpoint was to determine the association of specific T-cell subsets with clinical outcomes tested using Wilcoxon rank sum for clinical benefit rate (CBR) and log-rank test for progression-free survival (PFS). Results: Twenty patients were included in this trial with a median age of 64 years and followed-up for a median of 12 months. The median PFS for patients who received TKI was 13.8 months, while for those subsequently treated with nivolumab following TKI therapy, the median PFS was 2.6 months. CBR of nivolumab was 20% with two partial responses. Functionally active programmed cell death protein 1+ CD4+ T cells were enriched in non-responders (q = 0.003) and associated with worse PFS on nivolumab (P = 0.04). Responders showed a significant reduction in the effector CD4+T-cell (TEF) fraction compared to non-responders at 3 months on nivolumab (0.40 versus 0.80, P = 0.0005). CD127+CD4+ T cells were enriched in patients who developed immune-related adverse effects (q = 0.003). Using in-house validated multiplex immunohistochemistry for six markers, we measured tumour-associated immune cell densities in tissue samples. Responders to nivolumab showed a significantly higher mean of immune cell densities in tissue samples compared to non-responders (346 versus 87 cells/mm2, P = 0.04). Conclusions: In this small study, analysis of tissue-based and peripheral blood immune cell subsets predicted clinical outcomes of nivolumab. Further studies are warranted with larger populations to validate these observations.

Gamma photons used in positron emission tomography are predicted to be produced in an entangled state. Here, the authors simulate the effects of entanglement and test them through comparison with experimental data from a PET demonstrator apparatus, showing the potential gains in background suppression.

Heavy weight gilts commonly show signs of oestrus during the late finishing phase, which results in a period of reduced feed intake and growth rate. Immunization against gonadotropin-releasing hormone (GnRH) (IM, immunocastration) was developed for finishing boars and recently extrapolated to females. Immunocastration acts by suppressing reproductive activity and improving the growth potential. The objective of this study was to evaluate the effects of IM on growth performance, reproductive activity and carcass characteristics of late finishing gilts. Seventy-two gilts (63.49 ± 0.39 kg) were either injected with saline (Intact) or immunized against GnRH (Immunized). The study consisted of three experimental periods: between the first to second immunization (V1 to V2, 15 to 19 weeks of age), from the second immunization to the beginning of daily boar exposure (DBE) (V2 to DBE, 19 to 21 weeks of age) and from the beginning of DBE to slaughter (S) (DBE to S, 21 to 25 weeks of age). Immunized gilts showed an overall increase (from 15 to 25 weeks) of 3.90 kg (P < 0.05) of live weight, 56 g (P < 0.05) of average daily gain (ADG) and 250 g (P < 0.001) of average daily feed intake (ADFI). Immunized gilts had a greater ADFI (+240 g, P < 0.05) and worse feed conversion ratio (+0.26, P < 0.05) from 19 (V2) to 21 weeks of age (before DBE). Furthermore, those females had higher feed intake (+410 g; P < 0.001) plus greater daily weight gain (+92 g; P < 0.05) from V2 to S, and from DBE to S (+470 g of ADFI, P < 0.001; +129 g of ADG, P < 0.01, respectively). Immunocastration had no effect on backfat thickness, lean meat percentage and weight, cold carcass yield or loin depth (P > 0.05). Immunized gilts showed 4.4% increased cold carcass weight (P < 0.01) and 10.6% greater gross flank weight (P < 0.001). Immunization against GnRH did not influence shoulder, collar, loin, belly or ham weights. Nor did it influence belly fat thickness, or meat, skin plus fat and bones yields of cold ham (P > 0.05). Immunocastration reduced ovarian and uterine weights by 82% (P < 0.001) and 93% (P < 0.001), respectively, and suppressed oestrus manifestation in all gilts in the immunized group (P < 0.001). These results indicate that immunization against GnRH is a promising tool for stimulating growth performance with no detrimental effects on carcass quality of heavy weight finishing gilts, by means of oestrus suppression.

We are living in a world of over seven billion people, with annual greenhouse gas emissions of approximately 50 billion tons a year and rising steadily. If continued unabated, the world is on target to warm by about 2 °C in less than 40 years, pushing the climate to a regime unlike any that has been witnessed in the last million years. Nonetheless, we still have time to avert such a catastrophic scenario, or delay its occurrence by several decades to provide human societies and the ecosystem with the time to adjust. In order to mitigate the possibility of climate disruption, we need to recognize that fossil fuel based technologies have become outdated and transform the energy system to that of low-carbon, sustainable and secure energy systems. In addition, we have to mitigate emissions of the four short-lived climate pollutants to bring immediate relief from climate change and protect vulnerable societies. Stability of the climate system involves not only the centrality of scientific and technological advancements and investments, but also necessary shifts in social structure and behavior by individuals, communities and societies worldwide as well as market based instruments, sub-national collaborations and governance structure. Fortunately, living laboratories—such as the State of California and the University of California system, which has pledged to become carbon neutral by 2025—provide demonstrable solutions which hold promise in alleviating the climate warming in the next generation. These jurisdictions are tiny emitters in the global picture, but they offer the potential for leverage through demonstrating (Figure 1) new technologies as well as workable institutions that cut emissions. We outline 10 pragmatic solutions—a “kit of parts” rooted in California but scalable to the world—that taken together, can “bend the curve” of the upward trajectory of human-caused warming trends. Wholesale transformation of our current fossil fuel based energy systems towards sustainable energy is among the greatest of societal challenges—and opportunities—faced in the 21st century.

Fetal growth restriction (FGR) increases the risk of cardiovascular disease. There are currently no treatment options available; however, antioxidants have shown potential to improve cardiovascular deficits associated with FGR. This systematic review aimed to determine whether antenatal antioxidant intervention can effectively protect the developing cardiovascular system in FGR. We searched for interventional studies that used an antenatal antioxidant intervention to improve cardiac and/or vascular outcomes in FGR published between 01/1946 and 09/2024 using MEDLINE and Embase (PROSPERO: CRD42024503756). The risk of bias was assessed with SYRCLE. The studies were assessed for cardiovascular protection based on the percentage of cardiac and/or vascular deficits that were restored with the antioxidant treatment. Studies were characterised as showing strong cardiovascular protection (≥50% restoration), mild cardiovascular protection (>0% but antioxidant-only effect (this did not include control group which showed a change with antioxidant intervention compared to FGR) or no cardiovascular protection (0% restoration). Thirty-eight publications met the inclusion criteria, encompassing 43 studies and investigating 15 antioxidant interventions. Moreover, 29/43 studies (71%) reported the restoration of at least one cardiac or vascular deficit with antioxidant intervention, and 21/43 studies (51%) were classified as strong cardiovascular protection. An ex vivo analysis of the arterial function in seven studies revealed endothelial dysfunction in growth-restricted offspring and antioxidant interventions restored the endothelial function in all cases. Additionally, four studies demonstrated that antioxidants reduced peroxynitrite-mediated oxidative stress. Notably, only 13/43 studies (32%) delayed antioxidant administration until after the induction of FGR. Antenatal antioxidant interventions show promise for providing cardiovascular protection in FGR. Melatonin was the most frequently studied intervention followed by nMitoQ, vitamin C and N-acetylcysteine, all of which demonstrated a strong capacity to reduce oxidative stress and improve nitric oxide bioavailability in the cardiovascular system of growth-restricted offspring; however, this systematic review highlights critical knowledge gaps and inconsistencies in preclinical research, which hinder our ability to determine which antioxidant treatments are currently suitable for clinical translation.