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Background Immune checkpoint inhibitors had a great effect in triple-negative breast cancer (TNBC); however, they benefited only a subset of patients, underscoring the need to co-target alternative pathways and select optimal patients. Herein, we investigated patient subpopulations more likely to benefit from immunotherapy and inform more effective combination regimens for TNBC patients. Methods We conducted exploratory analyses in the FUSCC cohort to characterize a novel patient selection method and actionable targets for TNBC immunotherapy. We investigated this in vivo and launched a phase 2 trial to assess the clinical value of such criteria and combination regimen. Furthermore, we collected clinicopathological and next-generation sequencing data to illustrate biomarkers for patient outcomes. Results CD8-positivity could identify an immunomodulatory subpopulation of TNBCs with higher possibilities to benefit from immunotherapy, and angiogenesis was an actionable target to facilitate checkpoint blockade. We conducted the phase II FUTURE-C-Plus trial to assess the feasibility of combining famitinib (an angiogenesis inhibitor), camrelizumab (a PD-1 monoclonal antibody) and chemotherapy in advanced immunomodulatory TNBC patients. Within 48 enrolled patients, the objective response rate was 81.3% (95% CI, 70.2–92.3), and the median progression-free survival was 13.6 months (95% CI, 8.4–18.8). No treatment-related deaths were reported. Patients with CD8- and/or PD-L1- positive tumors benefit more from this regimen. PKD1 somatic mutation indicates worse progression-free and overall survival. Conclusion This study confirms the efficacy and safety of the triplet regimen in immunomodulatory TNBC and reveals the potential of combining CD8, PD-L1 and somatic mutations to guide clinical decision-making and treatments. Trial registration ClinicalTrials.gov: NCT04129996 . Registered 11 October 2019.

Sirolimus, also known as rapamycin, is an mTOR receptor inhibitor that suppresses cell proliferation and angiogenesis, demonstrating efficacy against multiple types of vascular anomalies. However, sub-therapeutic concentrations (below effective levels) and supra-therapeutic concentrations (leading to adverse reactions) of sirolimus may both negatively impact patient treatment outcomes. This study aimed to establish optimal models to predict the risk of sirolimus exposure using machine learning, ensure that sirolimus blood concentrations remain within the therapeutic range, and thus enhance the efficacy and safety of sirolimus therapy for children with vascular anomalies. We retrospectively analyzed 134 sirolimus therapeutic drug monitoring (TDM) measurements from 49 patients. Data were randomly split into training (80%) and testing (20%) sets, with an additional temporal cohort for external validation. Six machine learning models were developed to predict sub-therapeutic and supra-therapeutic risks, and evaluated primarily by the area under the receiver operating characteristic curve (AUROC) and Brier score. The optimal model was interpreted using SHapley Additive exPlanations (SHAP) analysis. The sub-therapeutic risk model included body mass index (BMI), white blood cells (WBC), mean corpuscular hemoglobin (MCH), triglycerides (TG), and total bilirubin (TBIL); while the supra-therapeutic model comprised height, platelet count (PLT), alanine aminotransferase (ALT), high-density lipoprotein cholesterol (HDL), and total cholesterol (TC). The multilayer perceptron (MLP) and extreme gradient boosting (XGB) models showed optimal performance for sub-therapeutic (AUROC = 0.646, Brier = 0.190) and supra-therapeutic (AUROC = 0.825, Brier = 0.143) risk prediction, respectively, with consistent results in temporal validation (AUROC: 0.678, Brier = 0.190 and AUROC: 0.767, Brier = 0.190). This study is the first to use machine learning models to predict the risk of sub- or supra-therapeutic sirolimus concentrations in vascular anomalies children. By enabling personalized exposure risk prediction, the dosing accuracy of sirolimus for the treatment of children with vascular anomalies can be optimized, thereby enhancing effectiveness and safety.

Henagliflozin, a novel selective inhibitor of sodium–glucose cotransporter 2, is under development as a treatment for type 2 diabetes mellitus. To evaluate the tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of henagliflozin in healthy Chinese volunteers. Two clinical studies were conducted. One was a single ascending dose (SAD) study (2.5–200 mg) involving 80 healthy subjects, and the other was a multiple ascending dose (MAD) study (1.25–100 mg for 10 days) involving 48 healthy subjects. The tolerability, PK profiles of henagliflozin and its main metabolites, and the urinary glucose excretion over 24 h were characterized in these 2 studies. No serious adverse events were observed in the healthy subjects after single- and multiple-dose oral administration of henagliflozin, suggesting that this drug was well tolerated. Henagliflozin was rapidly absorbed, with a Tmax of 1.5–3 h, and then eliminated from plasma with a half-life of 11–15 h. It was not accumulated following once-daily oral administration. Plasma exposure of henagliflozin exhibited dose-proportional PK properties over the dose ranges of 2.5–200 mg (SAD) and 1.25–100 mg (MAD). The excretion of henagliflozin in urine was found to be very low, with 3.00%–5.13% of the dose. The glucuronide metabolites M5-1, M5-2 and M5-3 were the main metabolites detected in plasma samples, which accounted for up to 54.3%, 19.8%, and 27.5%, respectively, of the parent drug at steady state. Both the SAD and MAD studies demonstrated that the urinary glucose excretion over 24 h was dose-dependently increased and displayed saturation kinetics at >25 mg. No significant changes in the levels of serum glucose and urine electrolytes were found following a single or multiple doses of henagliflozin administration. Henagliflozin was well tolerated and showed predictable PK/PD profiles in these healthy subjects. Henagliflozin did not affect blood glucose level or urinary electrolyte excretion. It is best characterized for once-daily administration with a maximum dose of 25 mg. ChinaDrugTrials.org.cn identifiers: CTR20131986 and CTR20140132. •Henagliflozin was well tolerated in healthy subjects.•Henagliflozin was rapidly absorbed and exhibited dose-proportional PK profiles.•The UGE24h was dose-dependently increased to henagliflozin and saturated at > 25 mg.•Henagliflozin did not change blood glucose in healthy subjects.•Henagliflozin did not affect urinary electrolytes excretion in healthy subjects.

Background It is not a rare clinical scenario to have patients presenting with coexisting malignant tumor and tuberculosis. Whether it is feasible to conduct programmed death-(ligand) 1 [PD-(L)1] inhibitors to these patients, especially those with active tuberculosis treated with concurrent anti-tuberculosis, is still unknown. Methods This study enrolled patients with coexisting malignancy and tuberculosis and treated with anti-PD-(L)1 from Jan 2018 to July 2021 in 2 institutions. The progression-free survival (PFS), objective response rate (ORR), and safety of anti-PD-(L)1 therapy, as well as response to anti-tuberculosis treatment, were evaluated. Results A total of 98 patients were screened from this cohort study, with 45 (45.9%), 21 (21.4%), and 32 (32.7%) patients diagnosed with active, latent, and obsolete tuberculosis, respectively. The overall ORR was 36.0% for anti-PD-(L)1 therapy, with 34.2%, 35.5%, and 41.2% for each subgroup. Median PFS was 8.0 vs 6.0 vs 6.0 months ( P =0.685) for each subgroup at the time of this analysis. For patients with active tuberculosis treated with concurrent anti-tuberculosis, median duration of anti-tuberculosis therapy was 10.0 (95% CI, 8.01–11.99) months. There were 83.3% (20/24) and 93.3% (42/45) patients showing sputum conversion and radiographic response, respectively, after anti-tuberculosis therapy, and two patients experienced tuberculosis relapse. Notably, none of the patients in latent and only one patient in obsolete subgroups showed tuberculosis induction or relapse after anti-PD-(L)1 therapy. Treatment-related adverse events (TRAEs) occurred in 33 patients (73.3%) when treated with concurrent anti-PD-(L)1 and anti-tuberculosis. Grade 3 or higher TRAEs were hematotoxicity ( n = 5, 11.1%), and one patient suffered grade 3 pneumonitis leading to the discontinuation of immunotherapy. Conclusions This study demonstrated that patients with coexisting malignant tumor and tuberculosis benefited equally from anti-PD-(L)1 therapy, and anti-tuberculosis response was unimpaired for those with active tuberculosis. Notably, the combination of anti-PD-(L)1 and anti-tuberculosis therapy was well-tolerated without significant unexpected toxic effects.

Henagliflozin is a highly selective and effective sodium glucose co-transporter (SGLT)-2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate the effects of meal intake on the pharmacokinetic properties of henagliflozin, and to understand the excretion pathways of henagliflozin in humans. In this Phase I, randomized, open-label, single-dose, two-period crossover study, 12 healthy male Chinese volunteers were randomized to receive either henagliflozin 10 mg in the fasted condition followed by henagliflozin 10 mg in the fed condition, or the reverse schedule, with the two administrations separated by a washout period of at least 7 days. Samples of blood, urine, and feces were collected and analyzed for the investigation of the pharmacokinetic profile and excretion pathways in the fasted and fed conditions. Any adverse events that occurred throughout the study were recorded for tolerability assessment. After the administration of a single oral dose of henagliflozin, mean (SD) plasma AUC0–∞ and Cmax were 1200 (274) h · ng/mL and 179 (48.8) ng/mL, respectively, in the fasted state and were decreased to 971 (245) h · ng/mL and 115 (34.2) ng/mL in the fed state. The fed/fasted ratios (90% CIs) of the geometric mean values of Cmax, AUC0–t, and AUC0–∞ were 64% (54%–76%), 80% (76%–85%), and 80% (76%–85%), respectively. The median (range) Tmax was prolonged from 1.5 (1–3) hours in the fasted condition to 2 (1.5–6) hours in the fed condition. Mass-balance testing revealed that henagliflozin was eliminated primarily as the parent drug in feces and as glucuronide metabolites in urine. In the fasted state, the cumulative excretion percentages of the parent drug and its metabolites to dose in feces and urine were 40.6% and 33.9%, respectively. The values in the fed condition were changed to 50.4% and 25.5%, respectively. These findings suggest that postprandial administration decreases the absorption rate and the extent of henagliflozin exposure in humans, but has no effect on the metabolism or elimination of the drug. In the present study, the consumption of a high-fat meal prior to henagliflozin administration was associated with reductions in AUC0–∞ and Cmax of 19.4% and 36.4%, respectively. However, based on the analysis of the pharmacokinetic/pharmacodynamic findings on henagliflozin, this slight change may not have clinical significance. Mass balance of henagliflozin in humans was achieved with ∼75% of the administered dose recovered in excretions within 4 days after administration whether in the fasted or fed state. These findings suggest that henagliflozin tablets can be administered with or without food.

Background and Objective: Clopidogrel (CLOP) is commonly used in coronary artery disease (CAD) patients with or without diabetes (DM), but these patients often suffer CLOP resistance, especially those with diabetes. This study was aimed to develop a physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) model to describe the pharmacokinetics and pharmacodynamics of clopidogrel active metabolite (CLOP-AM) in CAD patients with or without DM. Methods: The PBPK-PD model was first established and validated in healthy subjects and then in CAD patients with or without DM. The influences of CYP2C19, CYP2C9, CYP3A4, carboxylesterase 1 (CES1), gastrointestinal transit rates ( K t,i ) and platelets response to CLOP-AM ( k irre ) on predicted pharmacokinetics and pharmacodynamics were investigated, followed with their individual and integrated effects on CLOP-AM pharmacokinetics due to changes in DM status. Results: Most predictions fell within 0.5–2.0 folds of observations, indicating successful predictions. Sensitivity analysis showed that contributions of interested factors to pharmacodynamics were CES1> k irre > K t,i > CYP2C19 > CYP3A4> CYP2C9. Mimicked analysis showed that the decreased exposure of CLOP-AM by DM was mainly attributed to increased CES1 activity, followed by decreased CYP2C19 activity. Conclusion: The pharmacokinetics and pharmacodynamics of CLOP-AM were successfully predicted using the developed PBPK-PD model. Clopidogrel resistance by DM was the integrated effects of altered K t,i , CYP2C19, CYP3A4, CES1 and k irre .

Some studies in the white population have shown that carriers of at least 1 loss-of-function allele in the gene that encodes the cytochrome P-450 2C19 isozyme (CYP2C19) have lower levels of the clopidogrel active metabolite (CAM) and a reduced antiplatelet effect of clopidogrel. However, data are limited regarding the association between CYP2C19 genetic variants and exposure to CAM and on the pharmacodynamic properties of CAM in the Chinese population. Data from the white population cannot be extrapolated to the Chinese population because of the marked interethnic differences in CYP2C19 variants. This study was aimed to investigate the influence of CYP2C19 genetic polymorphisms on the pharmacokinetic properties of CAM and the antiplatelet effect of clopidogrel in healthy Chinese volunteers, and to provide evidence for the role of a CYP2C19 genotyping test in predicting the antiplatelet effect of clopidogrel in the Chinese population. Twenty healthy subjects received a single 300-mg dose of clopidogrel and were assigned to 1 of 3 groups according to CYP2C19 genotype: CYP2C19 *1/*1 (normal metabolizers [NM]; n = 8), CYP2C19 *1/*2 or *3 (intermediate metabolizers [IM]; n = 10) and CYP2C19 *2/*2 or *3 and *3/*3 (poor metabolizers [PM]; n = 2). Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after administration. The plasma concentrations of clopidogrel and CAM were analyzed by LC-MS/MS, and adenosine diphosphate–induced platelet aggregation was measured by light-transmittance aggregometry. There were no significant differences in Cmax and AUC0–t of clopidogrel prodrug in the NM group compared with the IM and PM groups. The mean CAM Cmax value was significantly higher in the NM group than in IM and PM groups (45.39 [12.57] vs 29.15 [7.92] ng/mL [P = 0.003] and 19.55 [2.19] ng/mL [P = 0.004], respectively). The mean CAM AUC0–t value was significantly higher in the NM group than in the IM and PM groups (61.05 [21.63] vs 37.67 [11.01] ng · h/mL [P = 0.007] and 27.08 [2.72] ng · h/mL [P = 0.016]). The NM group exhibited a significantly higher percentage of inhibition of platelet aggregation than did the IM or PM group (P = 0.001). The correlations between the pharmacokinetic properties (Cmax, AUC0–t) of CAM and the pharmacodynamic data (maximal and inhibition of platelet aggregation) were significant (both, Pearson r > 0.5 and P < 0.01). In these healthy Chinese subjects, carriers of CYP2C19 loss-of-function allele(s) had significantly reduced exposure of CAM and decreased levels of inhibition of platelet aggregation with clopidogrel; these genotypes therefore might be a determinant for the formation of CAM and its antiplatelet effects. Study identifier: ChiCTR-OCH-14004382.

Some clinical studies have demonstrated that the proton pump inhibitor (PPI) could decrease clopidogrel platelet response and increase major adverse cardiovascular events (MACE) in white or black subjects. However, that remains to be determined in Chinese patients. In this study, we sought to determine whether there could be an increased risk for developing MACE after concomitant use of dual antiplatelet therapy (DAT) and a PPI in Chinese patients treated with percutaneous coronary intervention (PCI) and stenting. This study was a 5-year, single-center, retrospective cohort analysis of eligible patients (n = 6188) who received DAT and a PPI concomitantly (defined as PPI users) before discharge and/or 12-month follow-up after discharge as compared with those who received DAT alone (also defined as non-PPI users, n = 1465). The incidence of recurrent MACE, such as myocardial infarction (MI), definite stent thromboses (ST), or cardiovascular death, was compared between the PPI users and non-users. PPI users had a significantly higher incidence of the MACE than non-users (13.9% vs. 10.6%; adjusted HR: 1.33; 95% CI: 1.12 - 1.57, P = 0.007). Stratified analysis revealed that concurrent use of DAT and a PPI was associated with a significantly increased risk for developing ST compared with DAT alone (1% vs. 0.4%; adjusted HR: 2.66, 95% CI: 1.16 - 5.87, P = 0.012). However, there were no significant differences in the risk of MI, cardiovascular death and other adverse events, regardless of combination of clopidogrel and a PPI. The study further suggests that concomitant use of DAT and a PPI may be associated with an increased risk for developing MACE, in particular definite ST, in Chinese PCI patients after discharge as compared with use of DAT alone.

Purpose. Studies on genetic alterations of the heterogenous small cell lung cancer (SCLC) are rare. We carried out the present study to clarify the genomic alterations and TMB levels of Chinese SCLC patients by whole-exome sequencing. Materials and Methods. Whole-exome sequencing by next-generation sequencing technique was implemented on twenty SCLC samples. Significant somatic mutations and copy number variations were screened, followed by comparison with the data extracted from COSMIC. Besides, altered signaling pathways were examined in order to figure out actionable targets. Results. A total of 8,062 nonsynonymous mutations were defined. The number of mutations for each case ranged from 98 to 864. As for base substitutions, a total of 15,817 substitutions were detected with C > A conversion which was correlated to smoking occupying 25.57%. The TMB values ranged from 2.51/Mb to 22.1/Mb with a median value of 9.95/Mb. RB1 was the most frequently mutated gene altered in 18 (90%) cases, followed by TP53 altered in 17 (85%) cases. Other commonly changed genes were PTEN, and RBL1, with frequencies of 55% and 50%, respectively. SOX2 significantly amplified in 6 (30%) cases and MYCN amplified in 1 (5%) patient. Notch signaling pathway and PI3K/AKT/mTOR signaling pathway were universally and significantly changed. Major genomic alterations were in consistency with data from COSMIC, but frequencies of less common mutations were different. Conclusion. TP53 and RB1 inactivations were universally detected in SCLC. The Notch and PI3K/AKT/mTOR signaling pathways were both significantly altered, implying potential actionable targets.

We investigated an alkenone-based sea surface temperature (SST) and the hydrographic change records of the subarctic Northwestern (NW) Pacific from the last glacial to interglacial. The core we investigated is a piston core (LV 63-41-2, 52.56° N, 160.00° E; water depth 1924 m) retrieved from the southern offshore east coast of the Kamchatka Peninsula, which is a location of high sedimentation rate, with highly dynamic interactions with the cold/warm water masses of the Bering Sea/the NW Pacific. Based on our alkenone analysis with a previously well-established chronology of the core, we found high glacial C37:4 contents suggesting larger freshwater influences prior to the last deglacial in approximately 27–16 ka BP. The most significant features of what we found are alkenone indicative of “warming” intervals with minimum alkenone productions that occurred prior to the stadial Heinrich event 1 and the Younger Dryas. In contrast, for the interval corresponding to the Bølling–Allerød period, our alkenone analysis shows relatively “colder” but maximum alkenone productions. We conclude that this particular subarctic alkenone SST proxy record is mainly masked by non-thermal environmental influences, such as strong shifts of timing and duration of the sea ice retreat and/or salinity changes in surface water at this site, which could cause changes in water stratification that affect nutrient supplies of the upper ocean that modulate growth durations of phytoplankton/coccolithophore productions. Our studies suggest that this subarctic alkenone “SST” proxy record is indicative of the changes of seasonality that control the timing and duration of the blooming seasons of coccolithophores. The alkenone “SST” proxy is also dominantly driven by water stratification effects that, instead of SSTs, reflect most likely a combination of the following local to regional climate and ocean current patterns: (1) the amount of meltwater inputs from high mountain glaciers at Kamchatka; (2) less saline, nutrient-rich Alaskan Stream waters from the Cordilleran Ice Sheet in the Gulf of Alaska; (3) downwelling waters associated with the interactions between the southward Eastern Kamchatka Current and the spinning-up of the North Pacific Subarctic Gyre; and (4) the strength of the Kuroshio Current since the last glacial.