Populus euphratica CPK21 Interacts with NF-YC3 to Enhance Cadmium Tolerance in Arabidopsis.

The toxic metal cadmium (Cd) poses a serious threat to plant growth and human health. Populus euphratica calcium-dependent protein kinase 21 (CPK21) has previously been shown to attenuate Cd toxicity by reducing Cd accumulation, enhancing antioxidant defense and improving water balance in transgenic Arabidopsis. Here, we confirmed a protein-protein interaction between PeCPK21 and Arabidopsis nuclear transcription factor YC3 (AtNF-YC3) by yeast two-hybrid and bimolecular fluorescence complementation assays. AtNF-YC3 was induced by Cd and strongly expressed in PeCPK21-overexpressed plants. Overexpression of AtNF-YC3 in Arabidopsis reduced the Cd inhibition of root length, fresh weight and membrane stability under Cd stress conditions (100 µM, 7 d), suggesting that AtNF-YC3 appears to contribute to the improvement of Cd stress tolerance. AtNF-YC3 improved Cd tolerance by limiting Cd uptake and accumulation, activating antioxidant enzymes and reducing hydrogen peroxide (H2O2) production under Cd stress. We conclude that PeCPK21 interacts with AtNF-YC3 to limit Cd accumulation and enhance the reactive oxygen species (ROS) scavenging system and thereby positively regulate plant adaptation to Cd environments. This study highlights the interaction between PeCPK21 and AtNF-YC3 under Cd stress conditions, which can be utilized to improve Cd tolerance in higher plants.

Tendon Decellularized Matrix Modified Fibrous Scaffolds with Porous and Crimped Microstructure for Tendon Regeneration.

Current engineered synthetic scaffolds fail to functionally repair and regenerate ruptured native tendon tissues, partly because they cannot satisfy both the unique biological and biomechanical properties of these tissues. Ideal scaffolds for tendon repair and regeneration need to provide porous topographic structures and biological cues necessary for the efficient infiltration and tenogenic differentiation of embedded stem cells. To obtain crimped and porous scaffolds, highly aligned poly(l-lactide) fibers were prepared by electrospinning followed by postprocessing. Through a mild and controlled hydrogen gas foaming technique, we successfully transformed the crimped fibrous mats into three-dimensional porous scaffolds without sacrificing the crimped microstructure. Porcine derived decellularized tendon matrix was then grafted onto this porous scaffold through fiber surface modification and carbodiimide chemistry. These biofunctionalized, crimped, and porous scaffolds supported the proliferation, migration, and tenogenic induction of tendon derived stem/progenitor cells, while enabling adhesion to native tendons. Together, our data suggest that these biofunctionalized scaffolds can be exploited as promising engineered scaffolds for the treatment of acute tendon rupture.

Genome-Wide Identification, Evolution, and Expression Analysis of the DIR Gene Family in Schima superba.

Schima superba, commonly known as the Chinese guger tree, is highly adaptable and tolerant of poor soil conditions. It is one of the primary species forming the evergreen broad-leaved forests in southern China. Dirigent proteins (DIRs) play crucial roles in the synthesis of plant lignin and lignans, secondary metabolism, and response to adversity stress. However, research on the DIR gene family in S. superba is currently limited. This study identified 24 SsDIR genes, categorizing them into three subfamilies. These genes are unevenly distributed across 13 chromosomes, with 83% being intronless. Collinearity analysis indicated that tandem duplication played a more significant role in the expansion of the gene family compared to segmental duplication. Additionally, we analyzed the expression patterns of SsDIRs in different tissues of S. superba. The SsDIR genes exhibited distinct expression patterns across various tissues, with most being specifically expressed in the roots. Further screening identified SsDIR genes that may regulate drought stress, with many showing differential expression under drought stress conditions. In the promoter regions of SsDIRs, various cis-regulatory elements involved in developmental regulation, hormone response, and stress response were identified, which may be closely related to their diverse regulatory functions. This study will contribute to the further functional identification of SsDIR genes, providing insights into the biosynthetic pathways of lignin and lignans and the mechanisms of plant stress resistance.

Early detection of pancreatic cancer in patients with recurrent pancreatitis: A case report.

BACKGROUND: Pancreatic cancer presents a challenge with its low early diagnosis and treatment rates, leading to high metastasis and mortality rates. The median survival time for advanced pancreatic cancer is a mere 3 months. However, there's hope: small pancreatic cancers diagnosed at an early stage (T1) or those less than or equal to 1 cm in diameter boast an impressive 5-year survival rate of nearly 100%. This underscores the critical importance of early pancreatic cancer detection for significantly improving prognosis. CASE SUMMARY: Pancreatic cancer, a malignant tumor of the digestive tract, poses challenges in both diagnosis and treatment due to its occult and atypical clinical symptoms. Clinically, patients with recurrent pancreatitis should be vigilant, as it may be indicative of pancreatic cancer, particularly in middle-aged and elderly patients. Here, we presented the case of a patient who experienced recurrent acute pancreatitis within a span of 2 months. During the initial episode of pancreatitis, routine imaging failed to identify the cause of pancreatic cancer. However, upon recurrence of acute pancreatitis, endoscopic ultrasonography (EUS) revealed a space-occupying lesion approximately 1 cm in size in the pancreatic body. Subsequent EUS coupled with fine-needle aspiration examination demonstrated atypical pancreatic gland epithelium. Ultimately, the patient underwent surgery and was diagnosed with an intraductal papillary mucinous tumor of the pancreas (severe epithelial dysplasia, focal cancer). CONCLUSION: We recommend EUS for patients with recurrent pancreatitis of unknown etiology to exclude early pancreatic cancer.

Investigation of the Driving Force of Replacing Adsorbed Hydrocarbons by CO2 in Organic Matter from an Energy Perspective.

Carbon dioxide (CO2) has been widely used to enhance the recovery of adsorbed hydrocarbons from the organic matter (OM) in shale formations. To reveal the driving force of replacing adsorbed hydrocarbons from OM by CO2, we performed molecular dynamics (MD) simulations of the replacement process and calculated the interaction forces between CO2 and hydrocarbons. In addition, based on the umbrella sampling method, steered MD simulations were performed, and the free energy profiles of hydrocarbons were obtained using the weighted histogram analysis method. Results show that the condition of the hydrocarbon replacement by CO2 requires the hydrocarbon to have sufficient kinetic energy or to have a sufficiently large attractive force exerted to ensure that the hydrocarbon escapes the potential well of the OM. The attractive forces exerted on hydrocarbon molecules by CO2 can significantly decrease the energy barrier associated with hydrocarbon movement away from the OM surface. Furthermore, both CO2 and supercritical CO2 can effectively displace adsorbed hydrocarbon gas (methane) on the OM, while supercritical CO2 is required to enhance the recovery of adsorbed hydrocarbon oil (n-dodecane). The results obtained in this study provide guidance for enhancing the recovery of adsorbed hydrocarbons by CO2 in shale formations.

Immune checkpoint inhibitor-associated new-onset hypophysitis: a retrospective analysis using the FAERS.

BACKGROUND: Our study aimed to investigate the prevalence and demographic characteristics of immune checkpoint inhibitor-associated hypophysitis (ICI-hypophysitis) using data from the FAERS, and the risk factors of prognosis were explored. METHODS: In this retrospective study, all cases of newly-diagnosed hypophysitis associated with FDA approved ICIs from 1st January 2007 to 31st December 2022 were accumulated using FAERS. Demographic data including age, sex, body weight, the prognosis of cases, and other co-occurred endocrinopathies induced by ICIs were analyzed and compared between different subgroups of immunotherapy. RESULTS: The reporting frequency of ICI-hypophysitis was 1.46% (2343/160089). Patients on the combination therapy had higher risk of hypophysitis reporting, followed by anti-CTLA-4 agent compared with other monotherapies (p < 0.001). Male subjects displayed higher reporting risk of ICI-hypophysitis (p = 0.015). Patients on anti-PD-1 therapy or the combination therapy showed higher occurrence rate of type 1 diabetes (anti-PD-1 vs. anti-PD-L1 vs. anti-CTLA-4 vs. combination therapy, 4.2% vs. 0.7% vs. 0.3% vs. 8.4%, p < 0.001). The occurrence rate of new-onset thyroid diseases in patients receiving combination therapy was higher than anti-PD-1 monotherapy (12.3% vs. 8.4%, p = 0.010). Elder age, lung cancer, and renal cancer emerged to be positively associated with severe clinical outcomes [>65 years, OR 1.042, 95%CI (1.022-1.063), p < 0.001; lung cancer, OR 1.400, 95%CI (1.019-1.923), p = 0.038; renal cancer, OR 1.667, 95%CI (1.153-2.412), p = 0.007]. Anti-CTLA-4 monotherapy was discovered to be a protective factor of severe outcomes [OR 0.433, 95%CI (0.335-0.558), p < 0.001]. Female sex and co-occurrence of ICI-related diabetes exhibited lower risk of death [female, OR 0.571, 95%CI (0.361-0.903), p = 0.017; diabetes, OR 0.090, 95%CI (0.016-0.524), p = 0.007]. CONCLUSIONS: ICI-induced hypophysitis is male-predominant irAE, most commonly seen in patients on anti-CTLA-4 mono- or combination therapy. Awareness among clinicians is critical when patients with elder age, lung or renal cancer develop hypophysitis, which indicates poor clinical outcomes. Female sex, anti-CTLA-4 monotherapy and co-occurrence of ICI-related diabetes are protective risk factors for poor prognosis.

New options for endoscopic treatment of gastric varices.

BACKGROUND: Gastric venous bleeding is one of the most common adverse events in liver cirrhosis. The therapeutic effect of isolated gastric varices is relatively clear. However, there is no appropriate clinical and endoscopic treatment for extensive variceal bleeding in the gastric fundus and body. METHODS: In this patient with non-isolated gastric varices, we decided to perform endoscopic multi-point ligation of the obvious varices in the gastric fundus and body. RESULTS: In this patient, endoscopic treatment of gastric varices with bleeding after surgery achieved a significant therapeutic effect. Reexamination of gastroscopy at 3 months after operation showed that multiple scars were formed in the gastric fundus and fundus, and no obvious varices were found. CONCLUSIONS: For patients with non-isolated gastric varices, endoscopic multi-point ligation is a safe and effective treatment option for the varices with obvious gastric fundus and body.

Sulfate-reducing consortium HQ23 stabilizes metal(loid)s and activates biological N-fixation in mixed heavy metal-contaminated soil.

Sulfate-reducing bacteria (SRB) are used in the remediation of mine pollution; however, the mechanism of stabilizing multiple heavy metal(loid)s by the SRB consortium under low oxygen conditions needs further study. Indigenous microflora were extracted from non-ferrous metal-contaminated soil co-inoculated with enriched SRB consortium and assembled as the HQ23 consortium. The presence of Desulfovibrio (SRB) in HQ23 was confirmed by 16S rRNA sequencing and qPCR. The effects of culture media, dissolved oxygen (DO), SO42¯, and pH on the HQ23 growth rate, and the SO42¯-reducing activity were examined. Data indicates that the HQ23 sustained SRB function under low DO conditions (3.67 ± 0.1 mg/L), but the SRB activity was inhibited at high DO content (5.75 ± 0.39 mg/L). The HQ23 can grow from pH 5 to pH 9 and can decrease mobile or bioavailable Cr, Cu, and Zn concentrations in contaminated soil samples. FTIR revealed that Cu and Cr adsorbed to similar binding sites on bacteria, likely decreasing bacterial Cu toxicity. Increased abundances of DSV (marker for Desulfovibrio) and nifH (N-fixation) genes were observed, as well as an accumulation of nitrate-N content in soils suggesting that HQ23 stimulates the biological N-fixation in soils. This study strongly supports the future application of SRB for the bioremediation of heavy metal-polluted sites.

Neurovascular coupling dysfunction associated with cognitive impairment in presbycusis.

The neuropathological mechanism underlying presbycusis remains unclear. This study aimed to illustrate the mechanism of neurovascular coupling associated with cognitive impairment in patients with presbycusis. We assessed the coupling of cerebral blood perfusion with spontaneous neuronal activity by calculating the correlation coefficients between cerebral blood flow and blood oxygen level-dependent-derived quantitative maps (amplitude of low-frequency fluctuation, fractional amplitude of low-frequency fluctuation, regional homogeneity, degree centrality). Four neurovascular coupling metrics (cerebral blood flow-amplitude of low-frequency fluctuation, cerebral blood flow-fractional amplitude of low-frequency fluctuation, cerebral blood flow-regional homogeneity and cerebral blood flow-degree centrality) were compared at the global and regional levels between the presbycusis group and the healthy control group, and the intrinsic association between the altered neurovascular coupling metrics and the neuropsychological scale was further analysed in the presbycusis group. At the global level, neurovascular coupling was significantly lower in the presbycusis group than in the control group and partially related to cognitive level. At the regional level, neurovascular biomarkers were significantly elevated in three brain regions and significantly decreased in one brain region, all of which involved the Papez circuit. Regional neurovascular coupling provides more information than global neurovascular coupling, and neurovascular coupling dysfunction within the Papez circuit has been shown to reveal the causes of poor cognitive and emotional responses in age-related hearing loss patients.

Efficacy and Safety of Sintilimab Combined with Pemetrexed and Platinum Chemotherapy in Non-Small Cell Lung Cancer Patients.

Objective: This study aimed to evaluate the clinical efficacy and safety of siltuximab in combination with pemetrexed and platinum-based chemotherapeutic agents for treating non-small cell lung cancer (NSCLC) through a randomized trial. Methods: Ninety-two NSCLC patients admitted to our hospital between July 2020 and July 2022 were randomly assigned to receive either pemetrexed + platinum drugs (observation group) or sintilimab plus pemetrexed + platinum drugs (experimental group) in a 1:1 ratio. Outcome measures included clinical efficacy, safety, serum tumor marker levels (CA125, CEA, CA199), immune function (CD4+, CD8+, CD4+/CD8+), cell growth factors (VEGF, bFGF, MMP-9), and survival quality indices (KPS, FACT-L scale). Results: In the observation group, the objective remission rate (ORR) was 36.96%, and the disease control rate (DCR) was 76.09%. In the experimental group, the ORR was 63.04%, and the DCR was 91.30%. Sintilimab enhanced the clinical efficacy of pemetrexed + platinum drugs, as indicated by improved ORR and DCR in the observation group (P < .05). The incidence of toxic side effects was 39.13% in the observation group and 43.48% in the experimental group, showing no significant difference (P > .05). Sintilimab + pemetrexed + platinum drugs demonstrated marked anti-tumor efficacy, reducing serum CA125, CEA, and CA199 concentrations compared to the regimen without sintilimab (P < .05). Patients with sintilimab exhibited enhanced immune function, with significantly higher CD4+ and CD4+/CD8+ levels and lower CD8+ levels (P < .05). Sintilimab + pemetrexed + platinum drugs resulted in lower levels of VEGF, bFGF, and MMP-9 compared to pemetrexed + platinum drugs (P < .05), suggesting better cell growth. Sintilimab + pemetrexed + platinum drugs enriched the survival quality of patients, indicated by higher KPS and FACT-L levels (P < .05). Additionally, the demographic characteristics of patients, including age, gender distribution, and disease stage, were comparable between the two groups. Conclusion: The combination of sintilimab with pemetrexed + platinum-based chemotherapeutic agents shows therapeutic benefits in NSCLC. Improved ORR and DCR in the experimental group underscore clinical relevance. While promising, caution is needed due to the modest sample size and potential biases. A nuanced understanding of limitations is crucial for future research and application. This study prompts further research in NSCLC, advocating for larger cohorts and long-term follow-ups to explore sustained efficacy and potential biomarkers, guiding improvements in patient care.

LncRNA MEG3 regulates ferroptosis of lens epithelial cells via PTBP1/GPX4 axis to participate in age-related cataract.

Age-related cataract (ARC) is regarded as the principal cause of vision impairment among the aged. The regulatory role of long noncoding RNAs (LncRNAs) in ARC remains unclear. The lncRNA maternally expressed gene 3 (MEG3) has been reported to promote ARC progression, and the underlying mechanism was further investigated in this study. Lens epithelium samples were collected to verify the expression of MEG3. Lens epithelial cells (LECs) were treated with H2O2 to mimic microenvironment of ARC in vitro. Cell viability, reactive oxygen species, and ferroptosis were evaluated during the in viro experiments. In the present work, lncRNA MEG3 was highly expressed in ARC group, compared with normal group. MEG3 was induced, cell viability and glutathione peroxidase 4 (GPX4) level were inhibited, and ferroptosis was promoted in H2O2 treated LECs. LncRNA MEG3 silence reversed the effects of H2O2 on viability and ferroptosis in LECs. Thereafter, lncRNA MEG3 was found to bind to PTBP1 for GPX4 degradation. Silencing of GPX4 reversed the regulation of lncRNA MEG3 inhibition in H2O2-treated LECs. To sum up, lncRNA MEG3 exhibited high expression in ARC. In H2O2-induced LECs, inhibition of lncRNA MEG3 accelerated cell viability and repressed ferroptosis by interaction with PTBP1 for GPX4 messenger RNA decay. Targeting lncRNA MEG3 may be a novel treatment of ARC.

Simplified single-session EUS-guided transhepatic antegrade stone removal for management of choledocholithiasis in patients with surgically altered anatomy.

Background: Endoscopic ultrasound (EUS)-guided transhepatic antegrade stone removal (TASR) has been reserved for choledocholithiasis after failed endoscopic retrograde cholangiopancreatography (ERCP) in recent years. The aim of this study was to evaluate the techniques, feasibility, and safety of simplified single-session EUS-TASR for choledocholithiasis in patients with surgically altered anatomy (SAA). Methods: A retrospective database of patients with SAA and choledocholithiasis from the Second Hospital of Hebei Medical University (Shijiazhuang, China) between August 2020 and February 2023 was performed. They all underwent single-session EUS-TASR after ERCP failure. Basic characteristics of the patients and details of the procedures were collected. The success rates and adverse events were evaluated and discussed. Results: During the study period, 13 patients underwent simplified single-session EUS-TASR as a rescue procedure (8 males, median age, 64.0 [IQR, 48.5-69.5] years). SAA consisted of four Whipple procedures, one Billroth II gastrectomy, four gastrectomy with Roux-en-Y anastomoses, and four hepaticojejunostomy with Roux-en-Y anastomoses. The technical success rate was 100% and successful bile duct stone removal was achieved in 12 of the patients (92.3%). Adverse events occurred in two patients (15.4%), while one turned to laparoscopic surgery and the other was managed conservatively. Conclusions: Simplified single-session EUS-TASR as a rescue procedure after ERCP failure appeared to be effective and safe in the management of choledocholithiasis in patients with SAA. But further evaluation of this technique is still needed, preferably through prospective multicenter trials.

Combination of static and dynamic neural imaging features to distinguish sensorineural hearing loss: a machine learning study.

Purpose: Sensorineural hearing loss (SNHL) is the most common form of sensory deprivation and is often unrecognized by patients, inducing not only auditory but also nonauditory symptoms. Data-driven classifier modeling with the combination of neural static and dynamic imaging features could be effectively used to classify SNHL individuals and healthy controls (HCs). Methods: We conducted hearing evaluation, neurological scale tests and resting-state MRI on 110 SNHL patients and 106 HCs. A total of 1,267 static and dynamic imaging characteristics were extracted from MRI data, and three methods of feature selection were computed, including the Spearman rank correlation test, least absolute shrinkage and selection operator (LASSO) and t test as well as LASSO. Linear, polynomial, radial basis functional kernel (RBF) and sigmoid support vector machine (SVM) models were chosen as the classifiers with fivefold cross-validation. The receiver operating characteristic curve, area under the curve (AUC), sensitivity, specificity and accuracy were calculated for each model. Results: SNHL subjects had higher hearing thresholds in each frequency, as well as worse performance in cognitive and emotional evaluations, than HCs. After comparison, the selected brain regions using LASSO based on static and dynamic features were consistent with the between-group analysis, including auditory and nonauditory areas. The subsequent AUCs of the four SVM models (linear, polynomial, RBF and sigmoid) were as follows: 0.8075, 0.7340, 0.8462 and 0.8562. The RBF and sigmoid SVM had relatively higher accuracy, sensitivity and specificity. Conclusion: Our research raised attention to static and dynamic alterations underlying hearing deprivation. Machine learning-based models may provide several useful biomarkers for the classification and diagnosis of SNHL.

Metabolomics efficiently discriminates monozygotic twins in peripheral blood.

Monozygotic (MZ) twins cannot be distinguished using conventional forensic STR typing because they present identical STR genotypings. However, MZ twins do not always live in the same environment and often have different dietary and other lifestyle habits. Metabolic profiles are deyermined by individual characteristics and are also influenced by the environment in which they live. Therefore, they are potential markers capable of identifying MZ twins. Moreover, the production of proteins varies from organism to organism and is influenced by both the physiological state of the body and the external environment. Hence, we used metabolomics and proteomics to identify metabolites and proteins in peripheral blood to discriminate MZ twins. We identified 1749 known metabolites and 622 proteins in proteomic analysis. The metabolic profiles of four pairs of MZ twins revealed minor differences in intra-MZ twins and major differences in inter-MZ twins. Each pair of MZ twins exhibited distinct characteristics, and four metabolites-methyl picolinate, acesulfame, paraxanthine, and phenylbenzimidazole sulfonic acid-were observed in all four MZ twin pairs. These four differential exogenous metabolites conincidently show that the different external environments and life styles can be well distinguished by metabolites, considering that twins do not all have the same eating habits and living environments. Moreover, MZ twins showed different protein profiles in serum but not in whole blood. Thus, our results indicate that differential metabolites provide potential biomarkers for the personal identification of MZ twins in forensic medicine.

Choline suppresses hepatocellular carcinoma progression by attenuating AMPK/mTOR-mediated autophagy via choline transporter SLC5A7 activation.

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated death. Emerging evidence suggests that autophagy plays a critical role in HCC tumorigenesis, metastasis, and prognosis. Choline is an essential nutrient related to prolonged survival and reduced risk of HCC. However, it remains unclear whether this phenomenon is mediated by autophagy. Methods: Two HCC cell lines (HUH-7 and Hep3B) were used in the present study. Cell growth was evaluated by cell counting kit 8 (CCK-8), colony formation, and in vivo mouse xenografts assays. Cell motility was calculated by wound healing and transwell assays. Autophagosomes were measured by transmission electron microscope (TEM), and autophagy flux was detected by mRFP-GFP-labeled LC3 protein. The mRNA level of genes was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels were detected by Western blotting (WB). Results: We found that choline inhibited the proliferation, migration, and invasion of HCC cells by downregulating autophagy in vitro and in vivo. Upregulated expression of the solute carrier family 5 member 7 (SLC5A7), a specific choline transporter, correlated with better HCC prognosis. We further discovered that choline could promote SLC5A7 expression, upregulate cytoplasm p53 expression to impair the AMPK/mTOR pathway, and attenuate autophagy. Finally, we found that choline acted synergistically with sorafenib to attenuate HCC development in vitro and in vivo. Conclusions: Our findings provide novel insights into choline-mediated autophagy in HCC, providing the foothold for its future application in HCC treatment.

Dexmedetomidine improves the circulatory dysfunction of the glymphatic system induced by sevoflurane through the PI3K/AKT/ΔFosB/AQP4 pathway in young mice.

Multiple sevoflurane exposures may damage the developing brain. The neuroprotective function of dexmedetomidine has been widely confirmed in animal experiments and human studies. However, the effect of dexmedetomidine on the glymphatic system has not been clearly studied. We hypothesized that dexmedetomidine could alleviate sevoflurane-induced circulatory dysfunction of the glymphatic system in young mice. Six-day-old C57BL/6 mice were exposed to 3% sevoflurane for 2 h daily, continuously for 3 days. Intraperitoneal injection of either normal saline or dexmedetomidine was administered before every anaesthesia. Meanwhile the circulatory function of glymphatic system was detected by tracer injection at P8 and P32. On P30-P32, behavior tests including open field test, novel object recognition test, and Y-maze test were conducted. Primary astrocyte cultures were established and treated with the PI3K activator 740Y-P, dexmedetomidine, and small interfering RNA (siRNA) to silence ΔFosB. We propose for the first time that multiple exposure to sevoflurane induces circulatory dysfunction of the glymphatic system in young mice. Dexmedetomidine improves the circulatory capacity of the glymphatic system in young mice following repeated exposure to sevoflurane through the PI3K/AKT/ΔFosB/AQP4 signaling pathway, and enhances their long-term learning and working memory abilities.

Neoadjuvant SHR-1701 with or without chemotherapy in unresectable stage III non-small-cell lung cancer: A proof-of-concept, phase 2 trial.

We conducted a proof-of-concept, phase 2 trial to assess neoadjuvant SHR-1701 with or without chemotherapy, followed by surgery or radiotherapy, and then consolidation SHR-1701 in unresectable stage III non-small-cell lung cancer (NSCLC). In the primary cohort of patients receiving neoadjuvant combination therapy (n = 97), both primary endpoints were met, with a post-induction objective response rate of 58% (95% confidence interval [CI] 47-68) and an 18-month event-free survival (EFS) rate of 56.6% (95% CI 45.2-66.5). Overall, 27 (25%) patients underwent surgery; all achieved R0 resection. Among them, 12 (44%) major pathological responses and seven (26%) pathological complete responses were recorded. The 18-month EFS rate was 74.1% (95% CI 53.2-86.7) in surgical patients and 57.3% (43.0-69.3) in radiotherapy-treated patients. Neoadjuvant SHR-1701 with chemotherapy, followed by surgery or radiotherapy, showed promising efficacy with a tolerable safety profile in unresectable stage III NSCLC. Surgical conversion was feasible in a notable proportion of patients and associated with better survival outcomes.

Hetrombopag for the management of chemotherapy-induced thrombocytopenia in patients with advanced solid tumors: a multicenter, randomized, double-blind, placebo-controlled, phase II study.

Background: Chemotherapy-induced thrombocytopenia (CIT) increases the risk of bleeding, necessitates chemotherapy dose reductions and delays, and negatively impacts prognosis. Objectives: This study aimed to evaluate the efficacy and safety of hetrombopag for the management of CIT in patients with advanced solid tumors. Design: A multicenter, randomized, double-blind, placebo-controlled, phase II study. Methods: Patients with advanced solid tumors who experienced a chemotherapy delay of ⩾7 days due to thrombocytopenia (platelet count <75 × 109/L) were randomly assigned (1:1) to receive oral hetrombopag at an initial dose of 7.5 mg once daily or a matching placebo. The primary endpoint was the proportion of treatment responders, defined as patients resuming chemotherapy within 14 days (platelet count ⩾100 × 109/L) and not requiring a chemotherapy dose reduction of ⩾15% or a delay of ⩾4 days or rescue therapy for two consecutive cycles. Results: Between 9 October 2021 and 5 May 2022, 60 patients were randomized, with 59 receiving ⩾1 dose of assigned treatment (hetrombopag/placebo arm, n = 28/31). The proportion of treatment responders was significantly higher in the hetrombopag arm than in the placebo arm [60.7% (17/28) versus 12.9% (4/31); difference of proportion: 47.6% (95% confidence interval (CI): 26.0-69.3); odds ratio = 10.44 (95% CI: 2.82-38.65); p value (nominal) based on the Cochran-Mantel-Haenszel: <0.001)]. During the double-blind treatment period, grade 3 or higher adverse events (AEs) occurred in 35.7% (10/28) of patients with hetrombopag and 38.7% (12/31) of patients on placebo. The most common grade 3 or higher AEs were decreased neutrophil count [35.7% (10/28) versus 35.5% (11/31)] and decreased white blood cell count [17.9% (5/28) versus 19.4% (6/31)]. Serious AEs were reported in 3.6% (1/28) of patients with hetrombopag and 9.7% (3/31) of patients with placebo. Conclusion: Hetrombopag is an effective and well-tolerated alternative for managing CIT in patients with solid tumors. Trial registration: ClinicalTrials.gov identifier: NCT03976882.