The risk of endocrine immune-related adverse events induced by PD-1 inhibitors in cancer patients: a systematic review and meta-analysis

ObjectiveEndocrinopathies are the most common immune-related adverse events (irAEs) observed during therapy with PD-1 inhibitors. In this study, we conducted a comprehensive systematic review and meta-analysis to evaluate the risk of immune-related endocrinopathies in patients treated with PD-1 inhibitors.MethodsWe performed a systematic search in the PubMed, Embase, and Cochrane Library databases to retrieve all randomized controlled trials (RCTs) involving PD-1 inhibitors, spanning from their inception to November 24, 2023. The comparative analysis encompassed patients undergoing chemotherapy, targeted therapy, or receiving placebo as control treatments. This study protocol has been registered with PROSPERO (CRD42023488303).ResultsA total of 48 clinical trials comprising 24,514 patients were included. Compared with control groups, patients treated with PD-1 inhibitors showed an increased risk of immune-related adverse events, including hypothyroidism, hyperthyroidism, hypophysitis, thyroiditis, diabetes mellitus, and adrenal insufficiency. Pembrolizumab was associated with an increased risk of all aforementioned endocrinopathies (hypothyroidism: RR=4.76, 95%CI: 3.55-6.39; hyperthyroidism: RR=9.69, 95%CI: 6.95-13.52; hypophysitis: RR=5.47, 95%CI: 2.73-10.97; thyroiditis: RR=5.95, 95%CI: 3.02-11.72; diabetes mellitus: RR=3.60, 95%CI: 1.65-7.88; adrenal insufficiency: RR=4.80, 95%CI: 2.60-8.88). Nivolumab was associated with an increased risk of hypothyroidism (RR=7.67, 95%CI: 5.00-11.75) and hyperthyroidism (RR=9.22, 95%CI: 4.71-18.04). Tislelizumab and sintilimab were associated with an increased risk of hypothyroidism (RR=19.07, 95%CI: 5.46-66.69 for tislelizumab and RR=18.36, 95%CI: 3.58-94.21 for sintilimab). For different tumor types, both hypothyroidism and hyperthyroidism were at high risks. Besides, patients with non-small cell lung cancer were at a higher risk of thyroiditis and adrenal insufficiency. Patients with melanoma were at a higher risk of hypophysitis and diabetes mellitus. Both low- and high-dose group increased risks of hypothyroidism and hyperthyroidism.ConclusionRisk of endocrine irAEs may vary in different PD-1 inhibitors and different tumor types. Increased awareness and understanding of the risk features of endocrine irAEs associated with PD-1 inhibitors is critical for clinicians.Systematic review registrationcrd.york.ac.uk/prospero, identifier PROSPERO (CRD42023488303)

Pharmacokinetics, Bioavailability, and Tissue Distribution Study of Angoroside C and Its Metabolite Ferulic Acid in Rat Using UPLC-MS/MS

Angoroside C is a phenylpropanoid glycoside compound isolated from the dried root of Scrophularia ningpoensis Hemsl., which possesses the effects of preventing ventricular remodeling, reducing pulmonary oedema, and reducing blood pressure, as well as having the properties of anti-platelet aggregation, hepatoprotection and anti-nephritis, etc. However, few investigations have been conducted on the absorption, distribution, metabolism, and excretion (ADME) study of angoroside C. Thus, a fast ultra-high performance liquid chromatography-tandem quadrupole mass spectrometry (UPLC-MS/MS) method was established for the determination of angoroside C and its metabolite ferulic acid in rat plasma and tissue homogenate. The two analytes were extracted from the biosamples using a simple protein precipitation with acetonitrile. The developed method was validated and successfully applied to the pharmacokinetics, bioavailability and tissue distribution study after the intragastric administration of angoroside C (100 mg/kg) or the intravenous administration of angoroside C (5 mg/kg), respectively. The results showed that angoroside C can be absorbed extremely quickly (Tmax = 15 min), can be eliminated very rapidly (t1/2 = 1.26 h), and its oral bioavailability is only about 2.1%. Furthermore, angoroside C was extensively distributed in all main organs (liver, heart, spleen, lung, kidney, and brain), and the highest concentration was detected in the lung 15 min after oral administration. This paper also indicated that angoroside C could be converted to the active metabolite ferulic acid in vivo. The maximum concentrations of ferulic acid in the kidney occurred at 6 h after oral administration. In summary, this study explored some of the pharmacokinetic characteristics of angoroside C in vivo, and the data produced could provide a basis for the further investigation of angoroside C

From Helping Hand to Invisible Hand: Social Enterprise Models in Poverty-Reduction

This paper profiles and analyzes the efforts of social enterprises engaged in international development. It traces the historical roots of the movement back to the neoliberal movement in academia and politics, which championed free markets and their ability to address economic and social ills. It showcases the present poverty-reduction models, many of which focus on empowering the poor as consumers and fulfilling their basic material needs through market provision. Practitioners see such models as more financially sustainable and accountable to needs of aid recipients. However, all social enterprises surveyed experience trade-offs in terms of financial and social return. Although social enterprises are best suited for problems caused by individual information or behavioral failures, many situations of poverty are caused by systemic failures. Moving forward, social enterprise should recognize the systemic causes of poverty and market failures, which are best addressed by regulation and government involvement. Without such recognition from social enterprises and development institutions, social enterprise poverty reduction efforts can only address symptoms or sections of the bigger problem

Assessment of a Novel Flow Visualization Technique Using Photodissociation Spectroscopy

The study of complicated flows continuously calls for new nonintrusive flow diagnostics. A novel flow visualization technique based on photodissociation spectroscopy (PDS) is described, demonstrated, and assessed in this paper. This technique is centered around the creative use of photodissociation (PD). A PD precursor is seeded in the flow of interest, either passive or reactive. A laser pulse is then generated to completely and rapidly photodissociate both the precursor and the products formed from the precursor (if it reacts) into photofragments. A target photofragment is then imaged to obtain multidimensional information about the flow. An analytical methodology was developed to assess the feasibility of the PDS-based technique. This analytical method was applied to the case where molecular iodine was used as an example PD precursor, and the results were validated by experimental data. Both the analytical and experimental findings provided a promising outlook for this new technique as a practical flow visualization technique. With a properly chosen PD precursor, the PDS-based technique provides an attractive alternative for imaging several critical flow properties, including the mixture fraction and temperature field. This technique shares some key advantages with established techniques, e.g., a high spatial and temporal resolution comparable to the planar laser-induced fluorescence (PLIF) technique. Meanwhile, this technique offers several unique advantages to overcome the limitations of existing techniques, including enhancing the signal level and simplifying the interpretation of the signal. </jats:p

Demonstration of a New Laser Diagnostic Based on Photodissociation Spectroscopy for Imaging Mixture Fraction in a Non-Premixed Jet Flame

The study of turbulent combustion calls for new diagnostics that can measure multidimensional mixture fraction under a wide range of flame conditions. A laser diagnostic technique based on photodissociation spectroscopy (PDS) is proposed to address this need. This paper describes the concept of the PDS-based diagnostic, reports its experimental demonstration in a non-premixed jet flame, and assesses its performance and applicable range. This new technique is centered around the creative use of photodissociation (PD) for flow visualization. A carefully chosen PD precursor is seeded into the flow of interest to measure mixture fraction. The precursor is chosen such that (1) both the precursor itself and the products formed from the precursor (if it reacts) can be completely and rapidly photodissociated; thus, the concentration of one of the photofragments forms a conserved scalar and can be used to infer the mixture fraction, and (2) the target photofragment offers friendly spectroscopic properties (e.g., strong laser-induced fluorescence signals and/or simple signal interpretation) so multidimensional imaging can be readily obtained. Molecular iodine (I2) was identified as a precursor satisfying both requirements and was seeded into a carbon monoxide (CO)–air jet flame for single-shot two-dimensional imaging of mixture fraction. This demonstration illustrates the potential of the PDS-based technique to overcome the limitations of existing techniques and to provide multidimensional measurements of mixture fraction in a variety of reactive flows. </jats:p

Hydrologic-environmental effects of sponge city under different spatial scales

Abstract The storm water management models were established at three spatial scales (large, medium, and small) based on a sponge city pilot area in China to explore the hydrological and environmental effects of rainfall conditions and development modes. Results showed the following. (1) Total runoff reduction rates increased from 26.7% to 53.9% for the rainfall event of a 2-year recurrence period as the scale increased. For 5-year and above recurrence periods, total runoff reduction rates were 19.5–49.4%. These rates increased from the small to medium scale and slightly decreased from the medium to large scale. (2) The runoff coefficients were 0.87–0.29, which decreased from the small to medium scale and were basically constant from the medium to large scale. (3) The peak flow reduction rates decreased with increased recurrence periods. The rates increased initially and then decreased at the small scale, whereas the opposite trend occurred at the medium scale. (4) The reduction rates of pollutants were negatively correlated with recurrence periods under the three spatial scales. The pollution load reduction rates were 19.5–54.7%, which increased from the small to medium scale and were basically constant from the medium to large scale.</jats:p