A case report of Stevens-Johnson syndrome caused by omeprazole.

RATIONALE: Stevens-Johnson syndrome (SJS) is a rare but severe skin-mucosal reaction with a high mortality rate. It is characterized by sudden, painful blistering lesions on the skin, often accompanied by high fever and systemic toxicity. Lesions typically appear on the dorsal surfaces of the hands, feet, forearms, legs, and soles of the feet. They can also affect the conjunctiva, oral mucosa, labial mucosa, and vaginal mucosa. Patients may experience complications such as pneumonia, severe comorbidities, and liver and renal failure. PATIENT CONCERNS: A 51-year-old female patient was admitted to the hospital due to "abdominal distention and skin yellowing for 20 days." After using omeprazole, she developed a rash all over her body, and her liver function further deteriorated, ultimately leading to chronic acute liver failure. DIAGNOSES: The diagnosis included fever, rash suspected to be drug-induced, chronic and acute liver failure, and decompensation of post-Hepatitis B cirrhosis. INTERVENTIONS: During hospitalization, suspected adverse drug reactions were discontinued, and symptomatic supportive treatment with methylprednisolone and fluid replacement was promptly provided. OUTCOMES: The patient's symptoms and follow-up showed that the rash disappeared and liver and kidney function improved significantly after treatment. LESSONS: We explored how chronic acute liver failure can cause immune system abnormalities and immune paralysis in patients, manifested as susceptibility to infection. This case report describes a drug-induced allergic reaction - SJS - in patients with chronic acute liver failure, as well as subsequent treatment, including hormone dosage and treatment duration. I hope this report will help enrich the relevant literature on drug-induced SJS combined with chronic and acute liver failure, laying the foundation for improving the survival rate of patients with the disease.

Lonidamine Increases the Cytotoxic Effect of 1-[(4-Amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosourea via Energy Inhibition, Disrupting Redox Homeostasis, and Downregulating MGMT Expression in Human Lung Cancer Cell Line.

Lung cancer ranks as the second most diagnosed cancer and the leading cause of cancer-related deaths worldwide. Novel chemotherapeutic strategies are crucial to efficiently target tumor cells while minimizing toxicity to normal cells. In this study, we proposed a combination strategy using energy blocker lonidamine (LND) and cytotoxic drug nimustine (ACNU, 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosourea) to enhance the killing of a human lung cancer cell line and investigated the potential chemo-sensitizing mechanism of LND. LND was found to remarkably increase the cytotoxicity of ACNU to A549 and H1299 cells without significantly affecting normal lung BEAS2B cells. The combination of LND and ACNU also produced significant effects on cell apoptosis, colony formation, cell migration, and invasion assays compared to single drug treatment. Mechanistically, LND decreased intracellular ATP levels by inhibiting glycolysis and inducing mitochondrial dysfunction. Furthermore, the combination of LND and ACNU could intensify cellular oxidative stress, decrease cellular GSH contents, and increase reactive oxygen species (ROS) production. Notably, LND alone dramatically downregulated the expression of DNA repair protein MGMT (O6-methylguanine-DNA methyltransferase), enhancing DNA interstrand cross-link formation induced by ACNU. Overall, LND represents a potential chemo-sensitizer to enhance ACNU therapy through energy inhibition, disrupting redox homeostasis and downregulating MGMT expression in human lung cancer cell line under preclinical and clinical background.

B7-H3-Targeted CAR-Vδ1T Cells Exhibit Potent Broad-Spectrum Activity Against Solid Tumors.

Vδ1T cells, a rare subset of γδT cells, hold promise for treating solid tumors. Unlike conventional T cells, they recognize tumor antigens independently of the MHC antigen-presentation pathway, making them a potential "off-the-shelf" cell therapy product. However, isolation and activation of Vδ1T cells is challenging, which has limited their clinical investigation. Here, we developed a large-scale clinical-grade manufacturing process for Vδ1T cells and validated the therapeutic potential of B7-H3-CAR-modified Vδ1T cells in treating solid tumors. Co-expression of interleukin-2 with the B7-H3-CAR led to durable anti-tumor activity of Vδ1T cells in vitro and in vivo. In multiple subcutaneous and orthotopic mouse xenograft tumor models, a single intravenous administration of the CAR-Vδ1T cells resulted in complete tumor regression. These modified cells demonstrated significant in vivo expansion and robust homing ability to tumors, akin to natural tissue-resident immune cells. Additionally, the B7-H3-CAR-Vδ1T cells exhibited a favorable safety profile. In conclusion, B7-H3-CAR-modified Vδ1T cells represent a promising strategy for treating solid tumors.

A Phase 1a/1b Dose Escalation/Expansion Study of the Anti-PD-1 Monoclonal Antibody Nofazinlimab in Chinese Patients with Solid Tumors or Lymphoma.

BACKGROUND: Immune checkpoint blockade with anti-programmed cell death 1 (PD-1) antibodies has demonstrated efficacy in multiple tumor types. Nofazinlimab is a humanized rat antibody targeting PD-1. A first-in-human study of nofazinlimab conducted in Australia found no dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) was not reached in the range of 1-10 mg/kg. OBJECTIVE: We evaluated nofazinlimab for multiple advanced malignancies in Chinese patients. PATIENTS AND METHODS: This was a phase 1a/1b, open-label, multicenter, dose-escalation/expansion trial. In phase 1a, patients received an abbreviated dose escalation of nofazinlimab at 60 mg and 200 mg every 3 weeks (Q3W) to determine DLTs and the recommended phase 2 dose (RP2D). In phase 1b, patients received the RP2D (monotherapy/combination) in six arms by tumor type; DLTs were evaluated for nofazinlimab plus lenvatinib in the unresectable hepatocellular carcinoma (uHCC) arm. Safety (continuously monitored in patients who received nofazinlimab) and efficacy (patients with measurable baseline disease) were assessed. RESULTS: Overall, 107 patients were eligible and received nofazinlimab. In phase 1a, no DLTs were observed; the RP2D was 200mg Q3W. In phase 1b, no DLTs were observed with nofazinlimab plus lenvatinib. The safety profile was consistent with that observed in the first-in-human study (NCT03475251). In phase 1b, 21/88 (23.9%) patients achieved confirmed objective responses, 26 (29.5%) had stable disease, and 9/20 (45.0%) patients with uHCC achieved confirmed objective responses to nofazinlimab plus lenvatinib. CONCLUSIONS: Nofazinlimab was well tolerated in Chinese patients. Preliminary efficacy was encouraging, particularly for nofazinlimab plus lenvatinib in uHCC, which is being studied in an ongoing phase 3 trial. CLINICAL TRIAL REGISTRATION: NCT03809767; registered 18 January 2019.

Mapping of dynamic quantitative trait loci for plant height in a RIL population of foxtail millet (Setaria italica L.).

Plant height (PH) is a crucial trait for strengthening lodging resistance and boosting yield in foxtail millet. To identify quantitative trait loci (QTL) and candidate genes associated with PH, we first developed a genetic map using a recombinant inbred line (RIL) population derived from a cross between Aininghuang and Jingu 21. Then, PH phenotyping data and four variations of best linear unbiased prediction (BLUP) were collected from nine environments and three development stages. Next, QTL mapping was conducted using both unconditional and conditional QTL methods. Subsequently, candidate genes were predicted via transcriptome analysis of parental samples at three developmental stages. The results revealed that the genetic map, based on re-sequencing, consisted of 4,360 bin markers spanning 1,016.06 cM with an average genetic distance of 0.23 cM. A total of 19 unconditional QTL, accounting for 5.23%-35.36% of the phenotypic variation explained (PVE), which included 7 major and 4 stable QTL, were identified. Meanwhile, 13 conditional QTL, explaining 5.88%-40.35% of PVE, including 5 major and 3 stable QTL, were discovered. Furthermore, four consistent and stable QTL were identified. Finally, eight candidate genes were predicted through RNA-seq and weighted gene co-expression network analysis (WGCNA). Those findings provide a crucial foundation for understanding the genetic mechanisms underlying PH development and facilitate molecular marker-assisted breeding of ideal plant types in foxtail millet.

Erdafitinib in Asian patients with advanced solid tumors: an open-label, single-arm, phase IIa trial.

BACKGROUND: FGFR genomic aberrations occur in approximately 5-10% of human cancers. Erdafitinib has previously demonstrated efficacy and safety in FGFR-altered advanced solid tumors, such as gliomas, thoracic, gastrointestinal, gynecological, and other rare cancers. However, its efficacy and safety in Asian patients remain largely unknown. We conducted a multicenter, open-label, single-arm phase IIa study of erdafitinib to evaluate its efficacy in Asian patients with FGFR-altered advanced cholangiocarcinoma, non-small cell lung cancer (NSCLC), and esophageal cancer. METHODS: Patients with pathologically/cytologically confirmed, advanced, or refractory tumors who met molecular and study eligibility criteria received oral erdafitinib 8 mg once daily with an option for pharmacodynamically guided up-titration to 9 mg on a 28-day cycle, except for four NSCLC patients who received erdafitinib 10 mg (7 days on/7 days off) as they were recruited before the protocol amendment. The primary endpoint was investigator-assessed objective response rate per RECIST v1.1. Secondary endpoints included progression-free survival, duration of response, disease control rate, overall survival, safety, and pharmacokinetics. RESULTS: Thirty-five patients (cholangiocarcinoma: 22; NSCLC: 12; esophageal cancer: 1) were enrolled. At data cutoff (November 19, 2021), the objective response rate for patients with cholangiocarcinoma was 40.9% (95% CI, 20.7-63.6); the median progression-free survival was 5.6 months (95% CI, 3.6-12.7) and median overall survival was 40.2 months (95% CI, 12.4-not estimable). No patient with RET/FGFR-altered NSCLC achieved objective response and the disease control rate was 25.0% (95% CI, 5.5-57.2%), with three patients with stable disease. The single patient with esophageal cancer achieved partial response. All patients experienced treatment-emergent adverse events, and grade ≥ 3 treatment-emergent adverse events were reported in 22 (62.9%) patients. Hyperphosphatemia was the most frequently reported treatment-emergent adverse event (all-grade, 85.7%). CONCLUSIONS: Erdafitinib demonstrated efficacy in a population of Asian patients in selected advanced solid tumors, particularly in those with advanced FGFR-altered cholangiocarcinoma. Treatment was tolerable with no new safety signals. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov (NCT02699606); study registration (first posted): 04/03/2016.

Causal effects of endometriosis stages and locations on menstruation, ovulation, reproductive function, and delivery modes: a two-sample Mendelian randomization study.

Background: Endometriosis is a chronic inflammatory disease of women during their reproductive years. The relationship between the severity and location of endometriosis and menstruation, ovulation, reproductive function, and mode of delivery remains unclear. Methods: We explored the association between the various phenotypes of endometriosis and menstruation, ovulation, reproductive function, and mode of delivery, using two-sample Mendelian randomization (MR) and summary data on endometriosis stages and locations from the FinnGen consortium and women's menstruation, ovulation, reproductive function, and mode of delivery from OpenGWAS and ReproGen. Inverse-variance weighting was used for the primary MR analysis. In addition, a series of sensitivity analyses, confounding analyses, co-localization analyses, and multivariate MR analyses were performed. Results: MR analysis showed a negative effect of moderate to severe endometriosis on age at last live birth (OR = 0.973, 95% CI: 0.960-0.986) and normal delivery (OR = 0.999, 95% CI: 0.998-1.000; values for endpoint were excluded), ovarian endometriosis on age at last live birth (OR = 0.976, 95% CI: 0.965-0.988) and normal delivery (OR = 0.999, 95% CI: 0.998-1.000; values for endpoint were excluded), and fallopian tubal endometriosis on excessive irregular menstruation (OR = 0.966, 95% CI: 0.942-0.990). Bidirectional MR analysis showed that age at menarche had a negative causal effect on intestinal endometriosis (OR = 0.417, 95% CI: 0.216-0.804). All MR analyses were confirmed by sensitivity analyses, and only the genetic effects of moderate to severe endometriosis on normal delivery and age at last live birth were supported by co-localization evidence. Conclusion: Our findings deepen the understanding of the relationship between various types of endometriosis and menstruation, ovulation, reproductive function, and mode of delivery and clarify the important role of moderate to severe endometriosis.

Alternating electric fields transform the intricate network of tumour vasculature into orderly parallel capillaries and enhance the anti-angiogenesis effect of bevacizumab.

The search for effective strategies to target tumour angiogenesis remains a critical goal of cancer research. We present a pioneering approach using alternating electric fields to inhibit tumour angiogenesis and enhance the therapeutic efficacy of bevacizumab. Chicken chorioallantoic membrane, cell viability and in vitro endothelial tube formation assays revealed that electric fields with a frequency of 1000 kHz and an electric intensity of 0.6 V/cm inhibited the growth of vascular endothelial cells and suppressed tumour-induced angiogenesis. In an animal U87MG glioma model, 1000 kHz electric fields inhibited tumour angiogenesis and suppressed tumour growth. As demonstrated by 3D vessel analysis, tumour vasculature in the control group was a stout, interwoven network. However, electric fields transformed it into slim, parallel capillaries that were strictly perpendicular to the electric field direction. This architectural transformation was accompanied by apoptosis of vascular endothelial cells and a notable reduction in tumour vessel number. Additionally, we found that the anti-angiogenesis and tumour-suppression effects of electric fields synergised with bevacizumab. The anti-angiogenic mechanisms of electric fields include disrupting spindle formation during endothelial cell division and downregulating environmental angiogenesis-related cytokines, such as interleukin-6, CXCL-1, 2, 3, 5 and 8, and matrix metalloproteinases. In summary, our findings demonstrate the potential of alternating electric fields (AEFs) as a therapeutic modality to impede angiogenesis and restrain cancer growth.

Variability in interseismic strain accumulation rate and style along the Altyn Tagh Fault.

Major strike-slip faults that develop between strong and weaker regions are thought to focus along narrow shear zones at the rheological boundary. Here we present the InSAR-derived velocity field spanning almost the entire length of one such fault, the 1600 km-long Altyn Tagh Fault (ATF), and analyse the strain distribution. We find that localisation of strain is actually variable, in contrast to other major strike-slip faults that show little variation, with strain concentrated at the fault for some sections and distributed over broad (>100 km) shear zones for others. Slip rate along the ATF is also variable, decreasing along the fault from 11.6 ± 1.6 mm/yr in the west to 7.2 ± 1.4 mm/yr in the central portion, before increasing again to 11.7  ± 0.9 mm/yr over the eastern portion. We show that the variable shear zone width may be linked to geological variability and the influence of heat flow, and the results imply that sub-parallel faults play an important role in the overall deformation field. This demonstrates the significance of accurately characterising strain rates over a broad region when assessing seismic hazard.

The biological applications of near-infrared optical nanomaterials in atherosclerosis.

PURPOSE OF REVIEW: Atherosclerosis, a highly pathogenic and lethal disease, is difficult to locate accurately via conventional imaging because of its scattered and deep lesions. However, second near-infrared (NIR-II) nanomaterials show great application potential in the tracing of atherosclerotic plaques due to their excellent penetration and angiographic capabilities. RECENT FINDINGS: With the development of nanotechnology, among many nanomaterials available for the visual diagnosis and treatment of cardiovascular diseases, optical nanomaterials provide strong support for various biomedical applications because of their advantages, such as noninvasive, nondestructive and molecular component imaging. Among optical nanomaterials of different wavelengths, NIR-II-range (900 ~ 1700 nm) nanomaterials have been gradually applied in the visual diagnosis and treatment of atherosclerosis and other vascular diseases because of their deep biological tissue penetration and limited background interference. This review explored in detail the prospects and challenges of the biological imaging and clinical application of NIR-II nanomaterials in treating atherosclerosis.

Endoplasmic Reticulum Membrane Protein Complex Regulates Cancer Stem Cells and is Associated with Sorafenib Resistance in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, underscoring the need for novel therapeutic targets. This study aimed to elucidate the role of endoplasmic reticulum membrane protein complex subunit 1 (EMC1) in HCC progression and its therapeutic potential. Methods: Publicly available sequencing data and biopsy specimens were analyzed to assess EMC's clinical value and functions in HCC. In vitro experiments validated EMC functions, and multiplex immunofluorescence analysis examined EMC-associated sorafenib resistance mechanisms. EMC1 expression was knocked down in HCC cell lines, followed by cell viability, wound healing, and transwell migration assays. Tumor growth and response to sorafenib treatment were evaluated in mouse models. Metabolomic analysis assessed changes in the TCA cycle. Results: EMC genes were aberrantly expressed in HCC, and high EMC1 expression correlated with poorer survival rates. EMC1 disruption enhanced HCC cells' sensitivity to sorafenib, reducing cell viability, increasing apoptosis, and decreasing tumor size and weight. EMC1 maintained cancer cell stemness and promoted M2 macrophage infiltration. Metabolomic analysis revealed significant changes in the TCA cycle, indicating EMC1's role in HCC metabolic reprogramming. Importantly, EMC1 is highly associated with sorafenib resistance, potentially linked to CTNNB1 mutation or activation. Conclusion: EMC1 plays a critical role in regulating the sorafenib resistance in HCC. Targeting EMC1 may improve HCC treatment efficacy.

Recurrent Hypoglycemia in a 67-Year-Old Woman with CD5- Positive Diffuse Large B-Cell Lymphoma.

Hypoglycemia is a rare complication of diffuse large B-cell lymphoma. We are presenting a case of 67-year-old woman presented to her primary care physician with fatigue and hyperhidrosis. Laboratory evaluation revealed a glucose level of 1.9 mmol/L. Computed tomographic scan of the abdomen and subsequent positron emission tomographic scan revealed extensive lymphadenopathy. The patient was then diagnosed with CD5-positive-diffuse large B-cell lymphoma and developed recurrent hypoglycemia despite continuous infusion of glucose. Following immunochemotherapy, hypoglycemia was resolved. Several explanations have been postulated but the exact pathophysiology is not well understood. Further investigation is warranted to more clearly define the pathophysiology of persistent hypoglycemia in patients with diffuse large B-cell lymphoma.

Implications of PD-L1 expression on the immune microenvironment in HER2-positive gastric cancer.

In the KEYNOTE-811 study, anti-HER2 and immunotherapy treatments resulted in longer survival in HER2-positive gastric cancer patients with CPS ≥ 1, whereas CPS < 1 patients lacked notable benefits. We studied this in a real-world cohort of 106 HER2-positive, CPS < 1 patients and found no survival differences between those treated with anti-HER2 therapy alone or with added immunotherapy. Thus, we investigate the tumor microenvironment variations in 160 HER2-positive patients, CPS ≥ 1 cases exhibited elevated spatial effective scores of immune cells, including CD4, CD8 subtypes, and NK cells, compared to CPS < 1. Furthermore, through single-cell sequencing in eight HER2-positive individuals, gene expressions revealed regulation of T-cell co-stimulation in CPS ≥ 1 and IL-1 binding in CPS < 1 cases. Notably, we discovered a CPS < 1 subtype marked by CXCR4+M2 macrophages, associated with poor prognosis, whose proportion and expression were reduced when benefiting from anti-HER2 therapy. These findings suggest CPS ≥ 1 patients, due to their immune microenvironment composition, may respond better to anti-PD-1/PD-L1 therapy.

Persistence of Lugol-unstaining is associated with an increased risk of progression to malignancy in the esophagus.

BACKGROUND AND AIMS: To investigate the persistence of Lugol-unstained lesions (LULs) in the esophagus detected by chromoendoscopy and explore its association with progression to malignancy. METHODS: We enrolled 647 participants from a population-based screening trial who had biopsied LULs at the baseline chromoendoscopy and underwent a chromoendoscopy reexamination after a median of 4.39 years. Cases of persistent LUL were defined as those in whom a visible LUL was observed during reexamination at the documented location (±2cm) where a LUL was detected at baseline chromoendoscopy. Logistic regression was applied to explore risk factors for the persistence of LULs. The primary outcome was clinical-stage esophageal squamous cell carcinoma (ESCC) identified over 6.78 years of follow-up and the secondary outcome was reexamination-detected severe dysplasia and above lesions (SDA). The cumulative incidence was calculated to assess the progression risk associated with the persistence of LULs. RESULTS: The proportion of participants with persistent LULs was 81.92%. Dysplasia (adjusted OR=6.16, 95%CI: 2.70 to 17.80), large LULs (adjusted OR=1.90, 95%CI: 1.18 to 3.15), and irregularly shaped LULs (adjusted OR=1.63, 95%CI: 1.03 to 2.56) at baseline were associated with an increased risk of LUL persistence. Eleven clinical-stage ESCC cases and 31 SDAs detected during reexamination were identified, all of which originated from patients with persistent LULs (Pclinical-stageESCC =0.136, Preexamination-detected SDA =0.015). CONCLUSION: The persistence of LULs is associated with progression to malignancy in the esophagus, even in individuals without dysplastic lesions. Based on this, a more efficient post-screening surveillance strategy could be established.

Predicting gastric cancer response to anti-HER2 therapy or anti-HER2 combined immunotherapy based on multi-modal data.

The sole use of single modality data often fails to capture the complex heterogeneity among patients, including the variability in resistance to anti-HER2 therapy and outcomes of combined treatment regimens, for the treatment of HER2-positive gastric cancer (GC). This modality deficit has not been fully considered in many studies. Furthermore, the application of artificial intelligence in predicting the treatment response, particularly in complex diseases such as GC, is still in its infancy. Therefore, this study aimed to use a comprehensive analytic approach to accurately predict treatment responses to anti-HER2 therapy or anti-HER2 combined immunotherapy in patients with HER2-positive GC. We collected multi-modal data, comprising radiology, pathology, and clinical information from a cohort of 429 patients: 310 treated with anti-HER2 therapy and 119 treated with a combination of anti-HER2 and anti-PD-1/PD-L1 inhibitors immunotherapy. We introduced a deep learning model, called the Multi-Modal model (MuMo), that integrates these data to make precise treatment response predictions. MuMo achieved an area under the curve score of 0.821 for anti-HER2 therapy and 0.914 for combined immunotherapy. Moreover, patients classified as low-risk by MuMo exhibited significantly prolonged progression-free survival and overall survival (log-rank test, P < 0.05). These findings not only highlight the significance of multi-modal data analysis in enhancing treatment evaluation and personalized medicine for HER2-positive gastric cancer, but also the potential and clinical value of our model.

Epigenetic identification of LTBP4 as a putative tumor suppressor in breast cancer.

Aim: To explore the LTBP4's expression, prognostic significance and molecular mechanism of action in breast cancer (BC).Methods: On the basis of omics datasets and experiments, we conducted a synthetical analysis of LTBP4 in BC.Results & conclusion: LTBP4 was downregulated in BC with high promoter methylation and low genetic alteration. DNA methylation was negatively associated with LTBP4 mRNA expression. Higher LTBP4 associated with better survival. LTBP4 was enrichment in extracellular matrix receptor interactions, cell adhesion molecules, cell cycle and MAPK pathway. LTBP4 expression and methylation were positively and negatively associated with tumor infiltrating immune cells, respectively. In conclusion, LTBP4 is a putative tumor suppressor in BC, which expression is regulated by DNA methylation and relates with prognosis.

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Recent developments in immunotherapy for gastrointestinal tract cancers.

The past few decades have witnessed the rise of immunotherapy for Gastrointestinal (GI) tract cancers. The role of immune checkpoint inhibitors (ICIs), particularly programmed death protein 1 (PD-1) and PD ligand-1 antibodies, has become increasingly pivotal in the treatment of advanced and perioperative GI tract cancers. Currently, anti-PD-1 plus chemotherapy is considered as first-line regimen for unselected advanced gastric/gastroesophageal junction adenocarcinoma (G/GEJC), mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC), and advanced esophageal cancer (EC). In addition, the encouraging performance of claudin18.2-redirected chimeric antigen receptor T-cell (CAR-T) therapy in later-line GI tract cancers brings new hope for cell therapy in solid tumour treatment. Nevertheless, immunotherapy for GI tumour remains yet precise, and researchers are dedicated to further maximising and optimising the efficacy. This review summarises the important research, latest progress, and future directions of immunotherapy for GI tract cancers including EC, G/GEJC, and CRC.

Construction of Highly Accurate Machine Learning Potential Energy Surfaces for Excited-State Dynamics Simulations Based on Low-Level Data Sets.

Machine learning is capable of effectively predicting the potential energies of molecules in the presence of high-quality data sets. Its application in the construction of ground- and excited-state potential energy surfaces is attractive to accelerate nonadiabatic molecular dynamics simulations of photochemical reactions. Because of the huge computational cost of excited-state electronic structure calculations, the construction of a high-quality data set becomes a bottleneck. In the present work, we first built two data sets. One was obtained from surface hopping dynamics simulations at the semiempirical OM2/MRCI level. Another was extracted from the dynamics trajectories at the CASSCF level, which was reported previously. The ground- and excited-state potential energy surfaces of ethylene-bridged azobenzene at the CASSCF computational level were constructed based on the former low-level data set. Although non-neural network machine learning methods can achieve good or modest performance during the training process, only neural network models provide reliable predictions on the latter external test data set. The BPNN and SchNet combined with the Δ-ML scheme and the force term in the loss functions are recommended for dynamics simulations. Then, we performed excited-state dynamics simulations of the photoisomerization of ethylene-bridged azobenzene on machine learning potential energy surfaces. Compared with the lifetimes of the first excited state (S1) estimated at different computational levels, our results on the E isomer are in good agreement with the high-level estimation. However, the overestimation of the Z isomer is unimproved. It suggests that smaller errors during the training process do not necessarily translate to more accurate predictions on high-level potential energies or better performance on nonadiabatic dynamics simulations, at least in the present case.

Clinical Efficacy of Taxol Plus Platinum (TP) Chemotherapy Combined with Delayed Administration of PD-1 Inhibitors in Patients with Locally Advanced, Recurrent or Metastatic Esophageal Squamous Cell Carcinoma: A Retrospective Study.

Purpose: Immune checkpoint inhibitors (ICIs) combined with chemotherapy have become the first-line standard treatment for locally advanced or metastatic esophageal squamous cell carcinoma (ESCC). The evidence also demonstrates improved synergistic effects of chemotherapy when combined with delayed administration of ICIs. In this study, we conducted a retrospective investigation into the treatment efficacy of taxol plus platinum (TP) chemotherapy combined with delayed administration of PD-1 inhibitors for ESCC patients. Patients and Methods: Clinical data of ESCC patients who received PD-1 inhibitors 3-5 days after TP chemotherapy as first-line treatment was retrospectively reviewed between January 2019 and April 2023. Clinical outcomes and treatment safety were analyzed. The potential roles of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and pan-immune-inflammation value (PIV) were investigated. Results: A total of 34 locally advanced, recurrent or metastatic ESCC patients received PD-1 inhibitors 3-5 days following TP chemotherapy were included. The objective response rate (ORR) and disease control rate (DCR) were 85.3% and 97.1% respectively. The median progression-free survival (PFS) and overall survival (OS) were 13.2 and 19.1 month respectively. Seven patients received radical surgery, 1 patient achieved pathologic complete response (pCR) and 3 patients achieved major pathologic response (MPR). Among the 27 patients without surgery, the median PFS and OS were 9.7 and 19.1 month respectively. A more favorable prognosis was correlated with NLR less than 3 at the 3rd and 4th cycle of immunochemotherapy. No significant correlations between other parameters (PLR, MLR and PIV) and prognosis were observed. A total of 22 patients developed grade 3-4 toxicity events. Conclusion: The optimized sequence of PD-1 inhibitors administered 3-5 days after TP chemotherapy as the first-line treatment of ESCC demonstrated favorable treatment efficacy. Pretreatment NLR of less than 3 at the 3rd and 4th cycle of immunochemotherapy is associated with a better prognosis.

Tislelizumab in previously treated, locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors.

Objective: The open-label, phase II RATIONALE-209 study evaluated tislelizumab (anti-programmed cell death protein 1 antibody) as a tissue-agnostic monotherapy for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) tumors. Methods: Adults with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled. Patients received tislelizumab 200 mg intravenously every 3 weeks. Objective response rate (ORR; primary endpoint), duration of response (DoR), and progression-free survival (PFS) were assessed by independent review committee (Response Evaluation Criteria in Solid Tumors v1.1). Results: Eighty patients were enrolled and treated; 75 (93.8%) patients had measurable disease at baseline. Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease (n=79; 98.8%). At primary analysis (data cutoff July 8, 2021; median follow-up 15.2 months), overall ORR [46.7%; 95% confidence interval (95% CI), 35.1-58.6; one-sided P<0.0001] and ORR across tumor-specific subgroups [colorectal (n=46): 39.1% (95% CI, 25.1-54.6); gastric/gastroesophageal junction (n=9): 55.6% (95% CI, 21.2-86.3); others (n=20): 60.0% (95% CI, 36.1-80.9)] were significantly greater with tislelizumab vs. a prespecified historical control ORR of 10%; five (6.7%) patients had complete responses. Median DoR, PFS, and overall survival were not reached with long-term follow-up (data cutoff December 5, 2022; median follow-up 28.9 months). Tislelizumab was well tolerated with no unexpected safety signals. Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 53.8% of patients; 7.5% of patients discontinued treatment due to TRAEs. Conclusions: Tislelizumab demonstrated a significant ORR improvement in patients with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.