Lung cancer is the leading cause of cancer death, with non-small cell lung cancer (NSCLC) accounting for approximately 85 % of all lung cancers and having a poor treatment and prognosis. Conventional clinical chemotherapy and immunotherapy are challenged by systemic toxicity and drug resistance, so researchers are increasingly focusing on antibody-drug conjugate (ADC), an innovative concept combining chemotherapy and targeted therapy, in which a drug selectively binds to antigens on the surface of a tumor cell via antibodies, which internalize the ADC, and then transfers the ADC to the lysosome via the endosomes to degrade the drug and kill the tumor cell. Despite the promising nature of ADCs, no ADC product for any indication including NSCLC has been approved for marketing by the FDA to date. In this review, we summarize the main advantages of ADCs and discuss in depth the design of the most desirable ADCs for NSCLC therapy. In addition to preclinical studies, we focus on the current state of clinical research on ADCs as interventions for the treatment of NSCLC by summarizing real-time clinical trial data from ClinicalTrials.gov, and reasonably speculate on the direction of the design of future generations of ADCs.

BACKGROUND: Globally, breast cancer, with diverse subtypes and prognoses, necessitates tailored therapies for enhanced survival rates. A key focus is glutamine metabolism, governed by select genes. This study explored genes associated with T cells and linked them to glutamine metabolism to construct a prognostic staging index for breast cancer patients for more precise medical treatment.
METHODS: Two frameworks, T-cell related genes (TRG) and glutamine metabolism (GM), stratified breast cancer patients. TRG analysis identified key genes via hdWGCNA and machine learning. T-cell communication and spatial transcriptomics emphasized TRG\'s clinical value. GM was defined using Cox analyses and the Lasso algorithm. Scores categorized patients as TRG_high+GM_high (HH), TRG_high+GM_low (HL), TRG_low+GM_high (LH), or TRG_low+GM_low (LL). Similarities between HL and LH birthed a \"Mixed\" class and the TRG_GM classifier. This classifier illuminated gene variations, immune profiles, mutations, and drug responses.
RESULTS: Utilizing a composite of two distinct criteria, we devised a typification index termed TRG_GM classifier, which exhibited robust prognostic potential for breast cancer patients. Our analysis elucidated distinct immunological attributes across the classifiers. Moreover, by scrutinizing the genetic variations across groups, we illuminated their unique genetic profiles. Insights into drug sensitivity further underscored avenues for tailored therapeutic interventions.
CONCLUSIONS: Utilizing TRG and GM, a robust TRG_GM classifier was developed, integrating clinical indicators to create an accurate predictive diagnostic map. Analysis of enrichment disparities, immune responses, and mutation patterns across different subtypes yields crucial subtype-specific characteristics essential for prognostic assessment, clinical decision-making, and personalized therapies. Further exploration is warranted into multiple fusions between metrics to uncover prognostic presentations across various dimensions.

Therapeutic vaccines containing aluminum adjuvants have been widely used in the treatment of tumors due to their powerful immune-enhancing effects. However, the neurotoxicity of aluminum adjuvants with different physicochemical properties has not been completely elucidated. In this study, a library of engineered aluminum oxyhydroxide (EAO) and aluminum hydroxyphosphate (EAHP) nanoparticles was synthesized to determine their neurotoxicity in vitro. It was demonstrated that the surface charge of EAHPs and size of EAOs did not affect the cytotoxicity in N9, bEnd.3, and HT22 cells; however, soluble aluminum ions trigger the cytotoxicity in three different cell lines. Moreover, soluble aluminum ions induce apoptosis in N9 cells, and further mechanistic studies demonstrated that this apoptosis was mediated by mitochondrial reactive oxygen species generation and mitochondrial membrane potential loss. This study identifies the safety profile of aluminum-containing salts adjuvants in the nervous system during therapeutic vaccine use, and provides novel design strategies for their safer applications. SIGNIFICANCE STATEMENT: In this study, it was demonstrated that engineered aluminum oxyhydroxide and aluminum hydroxyphosphate nanoparticles did not induce cytotoxicity in N9, bEnd.3, and HT22 cells. In comparation, soluble aluminum ions triggered significant cytotoxicity in three different cell lines, indicating that the form in which aluminum is presenting may play a crucial role in its safety. Moreover, apoptosis induced by soluble aluminum ions was dependent on mitochondrial damage. This study confirms the safety of engineered aluminum adjuvants in vaccine formulations.

PARP was an enzyme found in the nucleus of eukaryotic cells that played a crucial role in repairing damaged DNA. Recently, PARP inhibitors have demonstrated great potential in cancer treatment. Thus, the FDA has approved several small-molecule PARP inhibitors for cancer maintenance therapy. The combination of PARP inhibitors and radiotherapy relies on synthetic lethality, taking advantage of the flaws in DNA repair pathways to target cancer cells specifically. Studies conducted prior to clinical trials have suggested that the combination of PARP inhibitors and radiotherapy can enhance the sensitivity of cancer cells to radiation, intensify DNA damage, and trigger cell death. Combining radiotherapy with PARP inhibitors in clinical trials has enhanced the response rate and progression-free survival of diverse cancer patients. The theoretical foundation of PARP inhibitors combined with radiotherapy is explained in detail in this article, and the latest advances in preclinical and clinical research on these inhibitors for tumor radiotherapy are summarized. The problems in the current field are recognized in our research and potential therapeutic applications for tumors are suggested. Nevertheless, certain obstacles need to be tackled when implementing PARP inhibitors and radiotherapies in clinical settings. Factors to consider when using the combination therapy are the most suitable schedule and amount of medication, identifying advantageous candidates, and the probable adverse effects linked with the combination. The combination of radiotherapy and PARP inhibitors can greatly enhance the effectiveness of cancer treatment.

To investigate the value of drug exposure and host germline genetic factors in predicting apatinib (APA)-related toxicities.
METHODS: In this prospective study, plasma APA concentrations were quantified using liquid chromatography with tandem mass spectrometry, and 57 germline mutations were genotyped in 126 advanced solid tumor patients receiving 250 mg daily APA, a vascular endothelial growth factor receptor II inhibitor. The correlation between drug exposure, genetic factors, and the toxicity profile was analyzed.
RESULTS: Non-small cell lung cancer (NSCLC) was more prone to APA-related toxicities and plasma concentrations of APA, and its main metabolite M1-1 could be associated with high-grade adverse events (AEs) (P < 0.01; M1-1, P < 0.01) and high-grade antiangiogenetic toxicities (APA, P = 0.034; P < 0.05), including hypertension, proteinuria, and hand-foot syndrome, in the subgroup of NSCLC. Besides, CYP2C9 rs34532201 TT carriers tended to have higher levels of APA (P < 0.001) and M1-1 (P < 0.01), whereas CYP2C9 rs1936968 GG carriers were predisposed to higher levels of M1-1 (P < 0.01).
CONCLUSIONS: Plasma APA and M1-1 exposures were able to predict severe AEs in NSCLC patients. Dose optimization and drug exposure monitoring might need consideration in NSCLC patients with CYP2C9 rs34532201 TT and rs1936968 GG.
CONCLUSIONS: Apatinib is an anti-VEGFR2 inhibitor for the treatment of multiple cancers. Though substantial in response, apatinib-induced toxicity has been a critical issue that is worth clinical surveillance. Few data on the role of drug exposure and genetic factors in apatinib-induced toxicity are available. Our study demonstrated a distinct drug-exposure relationship in NSCLC but not other tumors and provided invaluable evidence of drug exposure levels and single nucleotide polymorphisms as predictive biomarkers in apatinib-induced severe toxicities.

With the application of bedaquiline (Bdq), the success rate of multidrug-resistant tuberculosis (MDR-TB) treatment has been significantly improved; however, the cardiac safety of the patients during treatment cannot be ignored. Hence, this study compared the effects of bedaquiline alone and bedaquiline combined with fluoroquinolones (FQs) and/or clofazimine (CFZ) on the QT interval. This single-center retrospective cohort study analyzed the clinical data of MDR-TB patients treated with bedaquiline for 24 weeks from January 2020 to May 2021 in Xi\'an Chest Hospital and compared the changes in QTcF between the two groups. Eighty-five patients were included in the study and grouped by types of anti-TB drugs affecting the QT interval they used. Group A included bedaquiline (n = 33), and group B included bedaquiline in combination with fluoroquinolones and/or clofazimine (n = 52). Out of patients with available corrected QT interval by Fridericia\'s formula (QTcF) data, 2.4% (2/85) experienced a postbaseline QTcF of ≥500 ms, and 24.7% (21/85) had at least one change of QTcF of ≥60 ms from baseline. In group A, 9.1% (3/33) had at least one ΔQTcF of >60 ms, as did 34.6% (18/52) of group B. Multivariate Cox regression analysis showed that the adjusted risk of QT prolongation was 4.82 times higher in group B (95% confidence interval [CI], 1.406 to 16.488). Bedaquiline combined with other anti-TB drugs affecting QT interval significantly increased the incidence of grade 3 or 4 QT prolongation; however, no serious ventricular arrhythmia and permanent drug withdrawal occurred. The use of bedaquiline combined with fluoroquinolone and/or clofazimine is an independent risk factor affecting QT interval. IMPORTANCE Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis. The emergence of MDR-TB is caused by an organism that is resistant to at least isoniazid and rifampin and is currently considered the major challenge for the global control of TB. Bedaquiline is the first new TB drug in 50 years with a unique mechanism of action, strong anti-M. tuberculosis activity. Yet unexplained excess deaths in the bedaquiline arms have been found in some phase II clinical trials; thus, the FDA has issued a \"boxed warning.\" However, the cardiac safety of the patients during treatment cannot be ignored. Accordingly, further investigations are needed to establish whether bedaquiline combined with clofazimine, fluoroquinolones, or anti-TB drugs affecting the QT interval in a long-course or short-course treatment increases the risk of QT prolongation.

OBJECTIVE: To investigate the predictive ability of clinical and chest computed tomography (CT) features to predict the severity of symptomatic immune checkpoint inhibitor-related pneumonitis (CIP).
METHODS: This study included 34 patients diagnosed with symptomatic CIP (grades 2-5) and divided into mild (grade 2) and severe CIP (grades 3-5) groups. The groups\' clinical and chest CT features were analyzed. Three manual scores (extent, image finding, and clinical symptom scores) were conducted to evaluate the diagnostic performance alone and in combination.
RESULTS: There were 20 cases of mild CIP and 14 cases of severe CIP. More severe CIP occurred within 3 months than after 3 months (11 vs. 3 cases, p = 0.038). Severe CIP was significantly associated with fever (p < 0.001) and the acute interstitial pneumonia/acute respiratory distress syndrome pattern (p = 0.001). The diagnostic performance of chest CT scores (extent score and image finding score) was better than that of clinical symptom score. The combination of the three scores demonstrated the best diagnostic value, with an area under the receiver operating characteristic curve of 0.948.
CONCLUSIONS: The clinical and chest CT features have important application value in assessing the disease severity of symptomatic CIP. We recommend the routine use of chest CT in a comprehensive clinical evaluation.

Tacrolimus (Tac) is a common immunosuppressant that used in organ transplantation. However, its therapeutic index is narrow, and it is prone to adverse side effects, along with an increased risk of toxicity, namely, cardio-, nephro-, hepato-, and neurotoxicity. Prior metabolomic investigations involving Tac-driven toxicity primarily focused on changes in individual organs. However, extensive research on multiple matrices is uncommon. Hence, in this research, the authors systemically evaluated Tac-mediated toxicity in major organs, namely, serum, brain, heart, liver, lung, kidney, and intestines, using gas chromatography-mass spectrometry (GC-MS). The authors also employed multivariate analyses, including orthogonal projections to the latent structure (OPLS) and t-test, to screen 8 serum metabolites, namely, D-proline, glycerol, D-fructose, D-glucitol, sulfurous acid, 1-monopalmitin (MG (16:0/0:0/0:0)), glycerol monostearate (MG (0:0/18:0/0:0)), and cholesterol. Metabolic changes within the brain involved alterations in the levels of butanamide, tartronic acid, aminomalonic acid, scyllo-inositol, dihydromorphine, myo-inositol, and 11-octadecenoic acid. Within the heart, the acetone and D-fructose metabolites were altered. In the liver, D-glucitol, L-sorbose, palmitic acid, myo-inositol, and uridine were altered. In the lung, L-lactic acid, L-5-oxoproline, L-threonine, phosphoric acid, phosphorylethanolamine, D-allose, and cholesterol were altered. Lastly, in the kidney, L-valine and D-glucose were altered. Our findings will provide a systematic evaluation of the metabolic alterations in target organs within a Tac-driven toxicity mouse model.

Emodin is the main pharmacodynamic components of rhubarb, with significant pharmacological effects and clinical efficacy.Emodin has a variety of therapy effects, such as anti-cancer, anti-fibrosis effects, and is widely used to treat encephalitis, diabetic cataract and organ fibrosis. Several studies have shown that emodin has a good treatment effect on organ fibrosis, but the mechanism is complex. Moreover, the evidence of some studies is conflicting and confusing. This paper reviewed the mechanism, pharmacokinetics and toxicology of emodin in fibrosis treatment, and briefly discussed relevant cutting-edge new formulations to improve the efficacy, the result can provide some reference for future study.

Breast cancer (BC) is the prevailing malignancy and major cause of cancer-related death in females. Doxorubicin is a part of BC neoadjuvant and adjuvant chemotherapy regimens. The administration of anthracycline derivates, such as doxorubicin, may cause several side effects, including hematological disfunction, gastrointestinal toxicity, hepatotoxicity, nephrotoxicity, and cardiotoxicity. Cardiotoxicity is a major adverse reaction to anthracyclines, and it may vary depending on individual differences in doxorubicin pharmacokinetics. Determination of specific polymorphisms of genes that can alter doxorubicin metabolism was shown to reduce the risk of adverse reactions and improve the safety and efficacy of doxorubicin. Genes which encode cytochrome P450 enzymes (CYP3A4 and CYP2D6), p-glycoproteins (ATP-binding cassette (ABC) family members such as Multi-Drug Resistance 1 (MDR1) protein), and other detoxifying enzymes were shown to control the metabolism and pharmacokinetics of doxorubicin. The effectiveness of doxorubicin is defined by the polymorphism of cytochrome p450 and p-glycoprotein-encoding genes. This study critically discusses the latest data about the role of gene polymorphisms in the regulation of doxorubicin\'s anti-BC effects. The correlation of genetic differences with the efficacy and safety of doxorubicin may provide insights for the development of personalized medical treatment for BC patients.