First-line penpulimab (an anti-PD1 antibody) and anlotinib (an angiogenesis inhibitor) with nab-paclitaxel/gemcitabine (PAAG) in metastatic pancreatic cancer: a prospective, multicentre, biomolecular exploratory, phase II trial.

Metastatic pancreatic cancer (mPC) has a dismal prognosis. Herein, we conducted a prospective, multicentre, single-arm, phase II trial evaluating the efficacy and safety of penpulimab and anlotinib in combination with nab-paclitaxel/gemcitabine (PAAG) in patients with first-line mPC (NCT05493995). The primary endpoints included the objective response rate (ORR) and disease control rate (DCR), while secondary endpoints encompassed progression-free survival (PFS), overall survival (OS), and safety. In 66 patients analysed for efficacy, the best response, indicated by the ORR, was recorded at 50.0% (33/66) (95% CI, 37.4-62.6%), with 33 patients achieving partial response (PR). Notably, the DCR was 95.5% (63/66, 95% CI, 87.3-99.1%). The median PFS (mPFS) and OS (mOS) were 8.8 (95% CI, 8.1-11.6), and 13.7 (95% CI, 12.4 to not reached) months, respectively. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 39.4% of patients (26/66). In prespecified exploratory analysis, patients with altered SWI/SNF complex had a poorer PFS. Additionally, low serum CA724 level, high T-cell recruitment, low Th17 cell recruitment, and high NK CD56dim cell scores at baseline were potential predicative biomarkers for more favourable efficacy. In conclusion, PAAG as a first-line therapy demonstrated tolerability with promising clinical efficacy for mPC. The biomolecular findings identified in this study possess the potential to guide the precise clinical application of the triple-combo regimen.

A mandibular advancement device attenuates the abnormal morphology and function of mitochondria from the genioglossus in obstructive sleep apnea-hypopnea syndrome rabbits.

BACKGROUND: Obstructive sleep apnea hypopnea syndrome (OSAHS) is a serious and potentially life-threatening disease. Mandibular advancement device (MAD) has the characteristics of non-invasive, comfortable, portable and low-cost, making it the preferred treatment for mild-to-moderate OSAHS. Our previous studies found that abnormal contractility and fibre type distribution of the genioglossus could be caused by OSAHS. However, whether the mitochondria participate in these tissue changes is unclear. The effect of MAD treatment on the mitochondria of the genioglossus in OSAHS is also uncertain. OBJECTIVE: To examine the morphology and function of mitochondria from the genioglossus in a rabbit model of obstructive sleep apnea-hypopnea syndrome (OSAHS), as well as these factors after insertion of a mandibular advancement device (MAD). METHODS: Thirty male New Zealand white rabbits were randomised into three groups: control, OSAHS and MAD, with 10 rabbits in each group. Animals in Group OSAHS and Group MAD were induced to develop OSAHS by injection of gel into the submucosal muscular layer of the soft palate. The rabbits in Group MAD were fitted with a MAD. The animals in the control group were not treated. Further, polysomnography (PSG) and cone-beam computed tomography (CBCT) scan were used to measure MAD effectiveness. CBCT of the upper airway and PSG suggested that MAD was effective. Rabbits in the three groups were induced to sleep for 4-6 h per day for eight consecutive weeks. The genioglossus was harvested and detected by optical microscopy and transmission electron microscopy. The mitochondrial membrane potential was determined by laser confocal microscopy and flow cytometry. Mitochondrial complex I and IV activities were detected by mitochondrial complex assay kits. RESULTS: OSAHS-like symptoms were induced successfully in Group OSAHS and rescued by MAD treatment. The relative values of the mitochondrial membrane potential, mitochondrial complex I activity and complex IV activity were significantly lower in Group OSAHS than in the control group; however, there was no significant difference between Group MAD and the control group. The OSAHS-induced injury and the dysfunctional mitochondria of the genioglossus muscle were reduced by MAD treatment. CONCLUSION: Damaged mitochondrial structure and function were induced by OSAHS and could be attenuated by MAD treatment.

Quantitative evaluation of factors influencing the 3 Hz repetitive nerve stimulation test in patients with amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Previous studies have suggested that treatments targeting the neuromuscular junction (NMJ) may play a role in the treatment of amyotrophic lateral sclerosis (ALS). However, factors impacting repetitive nerve stimulation (RNS), a technique to evaluate NMJ function, have yet to be fully elucidated. We aimed to identify independent factors contributing to the decremental response of the accessory nerve and evaluated its value in ALS clinical practice. METHODS: A total of 626 patients who were diagnosed with ALS and underwent 3 Hz RNS tests on the accessory nerve were enrolled. Data on their clinical and electrophysiological indicators were divided into a training set (collected from June 2016 to December 2022) and a test set (collected from January to August 2023). Stepwise regression was used in independent variable selection and model building. RESULTS: Forty-two percent of patients had a decrement larger than 10% and 24% had a decrement larger than 15%. Onset age, sex, onset site, forced vital capacity (FVC) and motor unit potential (MUP) duration were independent factors contributing to the results of the RNS test. MUP duration had the greatest impact on decremental response, followed by FVC and onset age. The decremental response in females was larger than in males. Upper limb onset was found to contribute more to the decrement than lower limb or bulbar onset. DISCUSSION: In patients with ALS, NMJ safety factor is reduced during re-innervation. Decremental response is affected by multiple factors, which needs to be considered in clinical trials targeting the NMJ in these patients.

Causal association between obstructive sleep apnea and amyotrophic lateral sclerosis: a Mendelian randomization study.

Background: Obstructive sleep apnea (OSA) had a high prevalence in the population. Whether OSA increases the risk of amyotrophic lateral sclerosis (ALS) is unknown. Our aim was to clarify this issue using two-sample Mendelian randomization (MR) analysis in a large cohort. Methods: Two-sample MR was used to evaluate the potential causality between OSA and ALS by selecting single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) from genome-wide association studies (GWAS). The inverse-variance weighted (IVW) method was chosen as the primary method to estimate causal association. Weighted median, weighted mode and simple mode methods were used as sensitivity analyses to ensure the robustness of the results. Results: In MR analysis, IVW mode showed genetic liability to OSA was found to be significantly associated with a higher ALS risk (OR, 1.220; 95% confidence interval, 1.031-1.443; p = 0.021). No evidence of heterogeneity and horizontal pleiotropy were suggested. Conclusion: We found potential evidence for a causal effect of OSA on an increased risk of ALS.

Crosstalk between metabolism and cell death in tumorigenesis.

It is generally recognized that tumor cells proliferate more rapidly than normal cells. Due to such an abnormally rapid proliferation rate, cancer cells constantly encounter the limits of insufficient oxygen and nutrient supplies. To satisfy their growth needs and resist adverse environmental events, tumor cells modify the metabolic pathways to produce both extra energies and substances required for rapid growth. Realizing the metabolic characters special for tumor cells will be helpful for eliminating them during therapy. Cell death is a hot topic of long-term study and targeting cell death is one of the most effective ways to repress tumor growth. Many studies have successfully demonstrated that metabolism is inextricably linked to cell death of cancer cells. Here we summarize the recently identified metabolic characters that specifically impact on different types of cell deaths and discuss their roles in tumorigenesis.

Developing a novel immune infiltration-associated mitophagy prediction model for amyotrophic lateral sclerosis using bioinformatics strategies.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which leads to muscle weakness and eventual paralysis. Numerous studies have indicated that mitophagy and immune inflammation have a significant impact on the onset and advancement of ALS. Nevertheless, the possible diagnostic and prognostic significance of mitophagy-related genes associated with immune infiltration in ALS is uncertain. The purpose of this study is to create a predictive model for ALS using genes linked with mitophagy-associated immune infiltration. Methods: ALS gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) database. Univariate Cox analysis and machine learning methods were applied to analyze mitophagy-associated genes and develop a prognostic risk score model. Subsequently, functional and immune infiltration analyses were conducted to study the biological attributes and immune cell enrichment in individuals with ALS. Additionally, validation of identified feature genes in the prediction model was performed using ALS mouse models and ALS patients. Results: In this study, a comprehensive analysis revealed the identification of 22 mitophagy-related differential expression genes and 40 prognostic genes. Additionally, an 18-gene prognostic signature was identified with machine learning, which was utilized to construct a prognostic risk score model. Functional enrichment analysis demonstrated the enrichment of various pathways, including oxidative phosphorylation, unfolded proteins, KRAS, and mTOR signaling pathways, as well as other immune-related pathways. The analysis of immune infiltration revealed notable distinctions in certain congenital immune cells and adaptive immune cells between the low-risk and high-risk groups, particularly concerning the T lymphocyte subgroup. ALS mouse models and ALS clinical samples demonstrated consistent expression levels of four mitophagy-related immune infiltration genes (BCKDHA, JTB, KYNU, and GTF2H5) with the results of bioinformatics analysis. Conclusion: This study has successfully devised and verified a pioneering prognostic predictive risk score for ALS, utilizing eighteen mitophagy-related genes. Furthermore, the findings indicate that four of these genes exhibit promising roles in the context of ALS prognostic.

Engineering of Pore Design and Oxygen Vacancy on High-Entropy Oxides by a Microenvironment Tailoring Strategy.

High-entropy oxides (HEOs) exhibit abundant structural diversity due to cationic and anionic sublattices with independence, rendering them superior in catalytic applications compared to monometallic oxides. Nevertheless, the conventional high-temperature calcination approach undermines the porosity and reduces the exposure of active sites (such as oxygen vacancies, OVs) in HEOs, leading to diminished catalytic efficiency. Herein, we fabricate a series of HEOs with a large surface area utilizing a microenvironment modulation strategy (m-NiMgCuZnCo: 86 m2/g, m-MnCuCoNiFe: 67 m2/g, and m-FeCrCoNiMn: 54 m2/g). The enhanced porosity in m-NiMgCuZnCo facilitates the presentation of numerous OVs, exhibiting an exceptional catalytic performance. This tactic creates inspiration for designing HEOs with rich porosity and active species with vast potential applications.

Efficacy and safety of second-line therapy by S-1 combined with sintilimab and anlotinib in pancreatic cancer patients with liver metastasis: a single-arm, phase II clinical trial.

Background: Pancreatic adenocarcinoma carries a grim prognosis, and there are few recognized effective second-line treatment strategies. We attempted to evaluate the efficacy and safety of a combination of S-1, sintilimab, and anlotinib as a second-line treatment in pancreatic cancer patients with liver metastasis. Methods: Pancreatic cancer patients with liver metastases were recruited. S-1 was administered orally at 25 mg/m2 bid, anlotinib was administered orally at 12 mg qd from day 1 to day 14, and sintilimab was administered intravenously at 200 mg on day 1. This method was repeated every 21 days, and the therapeutic effect was evaluated every 3 cycles. The primary outcome was the objective response rate (ORR). Results: Overall, 23 patients were enrolled in this study of whom 19 patients had objective efficacy evaluation. The ORR was 10.5% (95% CI 0.4%-25.7%) in the evaluable population. The progression-free survival (PFS) was 3.53 (95% CI 2.50-7.50) months, and the overall survival (mOS) was 8.53 (95% CI 4.97-14.20) months. Grade 3 adverse events were 26.1%, and no grade 4 or above adverse events occurred. High-throughput sequencing was performed on the tumor tissues of 16 patients; patients with HRD-H (n = 10) had shorter PFS than those with HRD-L (n = 6) (2.43 vs. 5.45 months; P = 0.043), but there was no significant difference in OS between the two groups (4.43 vs. 9.35 months; P = 0.11). Conclusions: This study suggests the advantage of S-1 combined with sintilimab and anlotinib in extending OS as a second-line therapy in pancreatic cancer patients with liver metastasis. Clinical Trial Registration: ChiCTR2000030659.

Serum Cystatin C is a potential biomarker for predicting amyotrophic lateral sclerosis survival.

OBJECTIVE: Currently, it is unclear whether serum Cystatin C can be used to evaluate the prognosis of ALS. We aim to study the relationship between serum Cystatin C and survival in ALS. METHODS: Sporadic ALS patients diagnosed at the Department of Neurology, the First Medical Center, and the Chinese PLA General Hospital from January 2016 to December 2019 were enrolled in this study. Experienced neurologists followed up the participants regularly every 6 months until January 2022. According to the levels of serum Cystatin C, the participants were divided into high and low Cystatin C levels groups. The comparison between groups was performed with parametric or non-parametric test. Kaplan-Meier method and Cox regression model were used to calculate survival analysis. RESULTS: Three hundred fifty-six sporadic ALS patients were enrolled in this study, including 203 males and 153 females. Among all ALS patients, 26 cases (7.3%) were lost to follow-up, 226 cases (63.5%) died, and 104 cases (29.2%) were still alive at the last follow-up. The median survival time of all ALS patients was 42.0 months. Patients with high Cystatin C levels had shorter median survival than those with lower Cystatin C levels (38.0 months vs. 48.0 months, P = 2.58 × 10-4). In multivariate Cox regression analysis, onset form, age of onset, diagnostic delay, disease progression rate, creatinine, and serum Cystatin C levels were associated with ALS survival. CONCLUSIONS: Our study found that serum Cystatin C was associated with ALS survival, and serum Cystatin C level might be an independent predictor of ALS survival.

Mendelian Randomization Identifies Genetically Supported Drug Targets for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

Currently, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have no effective treatments. Drug repurposing offers a rapid method to meet therapeutic need for ALS and FTD. To identify therapeutic targets associated with ALS and FTD, Mendelian randomization (MR) analysis and colocalization were performed. Genetic instruments were based on transcriptomic and proteomic data for 422 actionable proteins targeted by approved drugs or clinical drug candidates. The publicly available ALS GWAS summary data (including a total of 20,806 ALS cases and 59,804 controls) and FTD GWAS summary data (including a total of 2154 patients with FTD and 4308 controls) were used. Using cis-expression quantitative trait loci and cis-protein quantitative trait loci genetic instruments, we identified several drug targets for repurposing (ALS: MARK3, false-discovery rate (FDR) = 0.043; LTBR, FDR = 0.068) (FTD: HLA-DRB1, FDR = 0.083; ADH5, FDR = 0.056). Our MR study analyzed the actionable druggable proteins and provided potential therapeutic targets for ALS and FTD. Future studies should further elucidate the underlying mechanism of corresponding drug targets in the pathogenesis of ALS and FTD.

Investigation into the Relationship between Spermidine Degradation and Phenolic Compounds Biosynthesis in Barley Seedlings under Ultraviolet B Stress.

Barley germination under ultraviolet B (UV-B) illumination stress induces effective accumulation of phenolic compounds in the barley. Spermidine can enhance the biosynthesis of phenolic compounds and alleviate the oxidative damage caused by UV-B. To better understand the function of spermidine, inhibitors of enzymes that are involved in the degradation of spermidine and the synthesis of gamma-aminobutyric acid (GABA), the product of spermidine degradation, were applied to barley germinated under UV-B treatment. The results showed a more severe oxidative damage, and a decrease in phenolic acid contents were observed when spermidine degradation was inhibited. However, GABA application did attenuate an increase in electrolyte permeability and MDA content caused by UV-B induced oxidative damage and improved the respiration rate. Meanwhile, GABA application can elevate the accumulation of phenolic compounds by ca. 20%, by elevating the activities of some key enzymes. Furthermore, the application of GABA, together with the inhibitor of spermidine degradation, can alleviate its suppression of the synthesis of phenolic acids, and resistance to UV-B stress. In conclusion, spermidine alleviated oxidative damage and enhanced the accumulation of phenolic compounds using its degradation product.

Focus on Co-digestion of waste activated sludge and food waste via yeast pre-fermentation and biochar supplementation: The optimization and mechanism.

Anaerobic digestion is a promising method to recover energy from waste, but the slow rate of fermentation hinders its application. Yeast pre-fermentation has been reported to enhance organic matter solubilization and ethanol production to promote syntrophic metabolism and methanogenesis. However, the pre-fermentation with yeast has not been optimized so far. In this study, the lab-scale experiment was conducted to optimize operational conditions, and a pilot-scale study was conducted to evaluate the combined strategy of yeast pre-fermentation and biochar supplementation. Results demonstrated that at a fermentation time of 6 h, temperature of 30 °C, and dry yeast dosage of 2‰, the highest ethanol production was achieved, which accounted for 6.2% of the total COD of pre-fermentation effluent of a mixture of waste-activated sludge and food waste. The methane yield of the pre-fermented waste averaged 161.3 mL/g VS/d, which was 18.7% higher than that of the control group without the yeast inoculation (135.8 mL/g VS/d). With supplementing biochar of 0.5 and 1 g/L, the average methane production was 27.8% and 36.4% higher than the control group, respectively. The volatile solid removal rate was over 10% higher than the control (58.2 ± 3.12%). Consistently, the electrochemical properties of sludge with biochar were significantly improved. A pilot-scale experiment further showed that the methane production with the yeast pre-fermentation and biochar supplementation reached 227 mL/g VS/d, 54.3% higher than that without yeast pre-fermentation and biochar. This study provided a feasible method to combine yeast pre-fermentation and biochar supplementation under optimal conditions, which effectively increased methane production during anaerobic digestion of organic waste.

Genetically proxied antidiabetic drugs targets and stroke risk.

BACKGROUND: Previous studies have assessed the association between antidiabetic drugs and stroke risk, but the results are inconsistent. Mendelian randomization (MR) was used to assess effects of antidiabetic drugs on stroke risk. METHODS: We selected blood glucose-lowering variants in genes encoding antidiabetic drugs targets from genome-wide association studies (GWAS). A two-sample MR and Colocalization analyses were applied to examine associations between antidiabetic drugs and the risk of stroke. For antidiabetic agents that had effect on stroke risk, an independent blood glucose GWAS summary data was used for further verification. RESULTS: Genetic proxies for sulfonylureas targets were associated with reduced risk of any stroke (OR=0.062, 95% CI 0.013-0.295, P=4.65×10－4) and any ischemic stroke (OR=0.055, 95% CI 0.010-0.289, P=6.25×10－4), but not with intracranial hemorrhage. Colocalization supported shared casual variants for blood glucose with any stroke and any ischemic stroke within the encoding genes for sulfonylureas targets (KCNJ11 and ABCC8) (posterior probability>0.7). Furthermore, genetic variants in the targets of insulin/insulin analogues, glucagon-like peptide-1 analogues, thiazolidinediones, and metformin were not associated with the risk of any stroke, any ischemic stroke and intracranial hemorrhage. The association was consistent in the analysis of sulfonylureas with stroke risk using an independent blood glucose GWAS summary data. CONCLUSIONS: Our findings showed that genetic proxies for sulfonylureas targets by lowering blood glucose were associated with a lower risk of any stroke and any ischemic stroke. The study might be of great significance to guide the selection of glucose-lowering drugs in individuals at high risk of stroke.

Repetitive nerve stimulation on survival in amyotrophic lateral sclerosis.

Objective: No previous studies investigated the association between decrement of low-frequency repetitive nerve stimulation (LF-RNS) and amyotrophic lateral sclerosis (ALS) survival. We aim to study the relationship between decrement and survival in ALS. Methods: Sporadic ALS patients diagnosed at the Department of Neurology, the First Medical Center, Chinese PLA General Hospital from January 2018 to December 2019 were enrolled in this study. Experienced neurologists followed up the participants regularly every 6 months until January 2022. A decremental response of 10% or greater at least in one muscle was considered positive. According to the decrement, the participants were divided into LF-RNS (+) and LF-RNS (-) groups. Results: One hundred and eighty-one sporadic ALS patients were recruited in our study, including 100 males and 81 females. Among them, 10 cases (5.5%) were lost to follow-up, 99 cases (54.7%) died, and 72 patients (39.8%) were still alive at the last follow-up. The median survival time of all ALS patients in this study was 42.0 months. There was no significant difference of median survival in LF-RNS(+) group and LF-RNS(-) group (p = 0.159, Kaplan-Meier method). In multivariate Cox regression analysis, age of onset, diagnostic delay, and ALS Functional Rating Scale-Revised (ALSFRS-R) score were associated with ALS survival, but the decrement was not correlated with ALS survival (p = 0.238). Conclusion: The decrement in accessory and ulnar nerves was not associated with the survival of ALS. The decrement of LF-RNS could not be an electrophysiological marker to predict ALS survival.

Embedding Hierarchical Pores by Mechanochemistry in Carbonates with Superior Chemoselective Catalysis and Stability.

Hierarchical porosity of carbonates can facilitate their performance in massive applications as compared to their corresponding bulk samples. Traditional solution-based precipitation is typically utilized to fabricate porous carbonates. However, this tactic is generally employed under humid conditions, which demand soluble metal precursors, solvents, and extended dry periods. A salt-assisted mechanochemistry is exploited in contemporary work to settle the shortcomings. Enlighted by solid-state technology, this approach eliminates the utilization of solvents, and the process of ball milling can create pores in 5 min. A range of highly porous carbonates and their derivatives are acquired, with several materials surpassing recording surface areas (e.g., H-CaCO3: 108 m2/g, SrCO3: 125 m2/g, BaCO3: 172 m2/g, Pd/H-CaCO3 catalyst: 101 m2/g). The results display that Pd/H-CaCO3 shows superior catalytic efficiency in the synthesis of aniline (turnover frequency [TON] = 1.33 × 104/h-1, yield ≥ 99%, and recycle stability: 11 cycles) and dye degradation. Combining mechanochemistry and salt-assisted tactic provides a facile and efficient pathway for processing porous materials.

Evaluating the causal association between microRNAs and amyotrophic lateral sclerosis.

BACKGROUND: Currently, miRNAs are involved in the development of amyotrophic lateral sclerosis (ALS), and identifying circulating miRNAs that are causally associated with ALS risk as biomarkers is imperative. METHODS: We performed a two-sample Mendelian randomization study to evaluate the causal relationship between miRNAs and ALS. Our analysis was conducted using summary statistics from miRNA expression quantitative loci (eQTL) data of the Framingham Heart Study and ALS genome-wide association studies data. Another independent miRNA data was used to further validate. RESULTS: We identified eight unique miRNAs that were causally associated with ALS risk. Using expression data of miRNAs from an independent study, we validated three high-confidence miRNAs, namely hsa-miR-27b-3p, hsa-miR-139-5p, and hsa-miR-152-3p, which might have a potential causal effect on ALS risk. CONCLUSION: We suggested that higher levels of hsa-miR-27b-3p and hsa-miR-139-5p had protective effects on ALS, whereas higher levels of hsa-miR-152-3p might act as a risk factor for ALS. The analytical framework presented in this study helps to understand the role of miRNAs in the development of ALS and to identify the biomarkers for ALS risk.

Hypertension, antihypertensive drugs, and age at onset of Huntington's disease.

BACKGROUND: Associations between blood pressure (BP) with age at onset of Huntington's disease (HD) have reported inconsistent findings. We used Mendelian randomization (MR) to assess effects of BP and lowering systolic BP (SBP) via the genes encoding targets of antihypertensive drugs on age at onset of HD. METHODS: Genetic variants from genome-wide association studies(GWAS) of BP traits and BP-lowering variants in genes encoding antihypertensive drugs targets were extracted. Summary statistics for age at onset of HD were retrieved from the GWAS meta-analysis of HD residual age at onset from the GEM-HD Consortium included 9064 HD patients of European ancestry (4417 males and 4,647 females). MR estimates were calculated using the inverse variance weighted method, supplemented by MR-Egger, weighted median, and MR-PRESSO methods. RESULTS: Genetically predicted SBP or diastolic BP increase was associated with a later age at onset of HD. However, after SBP/DBP was present as a covariate using multivariable MR method, no significant causal association was suggested. A 10-mm Hg reduction in SBP through variants in genes encoding targets of calcium channel blockers (CCB) was associated with an earlier age at onset of HD (ß=-0.220 years, 95% CI =-0.337 to -0.102, P = 2.42 × 10- 4). We did not find a causal association between angiotensin converting enzyme inhibitors and ß-blockers with the earlier HD onset. No heterogeneity and horizontal pleiotropy were identified. CONCLUSIONS: This MR analysis provided evidence that genetically determined SBP lowering through antihypertensive drugs might be associated with an earlier age at onset of HD. The results may have a potential impact on management of hypertension in the pre-motor-manifest HD population.

Angiotensin II receptor inhibition ameliorates liver fibrosis and enhances hepatocellular carcinoma infiltration by effector T cells.

Although viral hepatocellular carcinoma (HCC) is declining, nonviral HCC, which often is the end stage of nonalcoholic or alcoholic steatohepatitis (NASH, ASH), is on an upward trajectory. Immune checkpoint inhibitors (ICIs) that block the T cell inhibitory receptor PD-1 were approved for treatment of all HCC types. However, only a minority of HCC patients show a robust and sustained response to PD-1 blockade, calling for improved understanding of factors that negatively impact response rate and duration and the discovery of new adjuvant treatments that enhance ICI responsiveness. Using a mouse model of NASH-driven HCC, we identified peritumoral fibrosis as a potential obstacle to T cell-mediated tumor regression and postulated that antifibrotic medications may increase ICI responsiveness. We now show that the angiotensin II receptor inhibitor losartan, a commonly prescribed and safe antihypertensive drug, reduced liver and peritumoral fibrosis and substantially enhanced anti-PD-1-induced tumor regression. Although losartan did not potentiate T cell reinvigoration, it substantially enhanced HCC infiltration by effector CD8+ T cells compared to PD-1 blockade alone. The beneficial effects of losartan correlated with blunted TGF-ß receptor signaling, reduced collagen deposition, and depletion of immunosuppressive fibroblasts.

Fructose-1,6-bisphosphatase is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness.

Insulin inhibits gluconeogenesis and stimulates glucose conversion to glycogen and lipids. How these activities are coordinated to prevent hypoglycemia and hepatosteatosis is unclear. Fructose-1,6-bisphosphatase (FBP1) is rate controlling for gluconeogenesis. However, inborn human FBP1 deficiency does not cause hypoglycemia unless accompanied by fasting or starvation, which also trigger paradoxical hepatomegaly, hepatosteatosis, and hyperlipidemia. Hepatocyte FBP1-ablated mice exhibit identical fasting-conditional pathologies along with AKT hyperactivation, whose inhibition reversed hepatomegaly, hepatosteatosis, and hyperlipidemia but not hypoglycemia. Surprisingly, fasting-mediated AKT hyperactivation is insulin dependent. Independently of its catalytic activity, FBP1 prevents insulin hyperresponsiveness by forming a stable complex with AKT, PP2A-C, and aldolase B (ALDOB), which specifically accelerates AKT dephosphorylation. Enhanced by fasting and weakened by elevated insulin, FBP1:PP2A-C:ALDOB:AKT complex formation, which is disrupted by human FBP1 deficiency mutations or a C-terminal FBP1 truncation, prevents insulin-triggered liver pathologies and maintains lipid and glucose homeostasis. Conversely, an FBP1-derived complex disrupting peptide reverses diet-induced insulin resistance.

PD-1 blockade plus chemoradiotherapy as preoperative therapy for patients with BRPC/LAPC: A biomolecular exploratory, phase II trial.

This is a phase II study of PD-1 blockade plus chemoradiotherapy as preoperative therapy for patients with locally advanced or borderline resectable pancreatic cancer (LAPC or BRPC, respectively). Twenty-nine patients are enrolled in the study. The objective response rate (ORR) is 60%, and the R0 resection rate is 90% (9/10). The 12-month progression-free survival (PFS) rate and 12-month overall survival (OS) rate are 64% and 72%, respectively. Grade 3 or higher adverse events are anemia (8%), thrombocytopenia (8%), and jaundice (8%). Circulating tumor DNA analysis reveals that patients with a >50% decline in maximal somatic variant allelic frequency (maxVAF) between the first clinical evaluation and baseline have a longer survival outcome and a higher response rate and surgical rate than those who are not. PD-1 blockade plus chemoradiotherapy as preoperative therapy displays promising antitumor activity, and multiomics potential predictive biomarkers are identified and warrant further verification.