Mutation status of the KMT2 family associated with immune checkpoint inhibitors (ICIs) therapy and implicating diverse tumor microenvironments.

Mounting evidence suggests a strong association between tumor immunity and epigenetic regulation. The histone-lysine N-methyltransferase 2 (KMT2) family plays a crucial role in the methylation of histone H3 at lysine 4. By influencing chromatin structure and DNA accessibility, this modification serves as a key regulator of tumor progression and immune tolerance across various tumors. These findings highlight the potential significance of the KMT2 family in determining response to immune checkpoint inhibitor (ICI) therapy, which warrants further exploration. In this study, we integrated four ICI-treated cohorts (n = 2069) across 10 cancer types and The Cancer Genome Atlas pan-cancer cohort and conducted a comprehensive clinical and bioinformatic analysis. Our study indicated that patients with KMT2 family gene mutations benefited more from ICI therapy in terms of overall survival (P < 0.001, hazard ratio [HR] = 0.733 [95% confidence interval (CI): 0.632-0.850]), progression-free survival (P = 0.002, HR = 0.669 [95% CI: 0.518-0.864]), durable clinical benefit (P < 0.001, 54.1% vs. 32.6%), and objective response rate (P < 0.001, 40.6% vs. 22.0%). Through a comprehensive analysis of the tumor microenvironment across different KMT2 mutation statuses, we observed that tumors harboring the KMT2 mutation exhibited enhanced immunogenicity, increased infiltration of immune cells, and higher levels of immune cell cytotoxicity, suggesting a propensity towards a "hot tumor" phenotype. Therefore, our study indicates a potential association between KMT2 mutations and a more favorable response to ICI therapy and implicates different tumor microenvironments associated with ICI therapy response.

Radiographic and α-fetoprotein response predict pathologic complete response to immunotherapy plus a TKI in hepatocellular carcinoma: a multicenter study.

BACKGROUND: Pathologic complete response (pCR) following preoperative systemic therapy is associated with improved outcomes after subsequent liver transplant/resection in hepatocellular carcinoma (HCC). However, the relationship between radiographic and histopathological response remains unclear. METHODS: We retrospectively examined patients with initially unresectable HCC who received tyrosine kinase inhibitor (TKI) plus anti-programmed death 1 (PD-1) therapy before undergoing liver resection between March 2019 and September 2021 across 7 hospitals in China. Radiographic response was evaluated using mRECIST. A pCR was defined as no viable tumor cells in resected samples. RESULTS: We included 35 eligible patients, of whom 15 (42.9%) achieved pCR after systemic therapy. After a median follow-up of 13.2 months, tumors recurred in 8 non-pCR and 1 pCR patient. Before resection, there were 6 complete responses, 24 partial responses, 4 stable disease cases, and 1 progressive disease case, per mRECIST. Predicting pCR by radiographic response yielded an area under the receiver operating characteristic curve (AUC) of 0.727 (95% CI: 0.558-0.902), with an optimal cutoff value of 80% reduction in the enhanced area in MRI (called major radiographic response), which had a 66.7% sensitivity, 85.0% specificity, and a 77.1% diagnostic accuracy. When radiographic response was combined with α-fetoprotein response, the AUC was 0.926 (95% CI: 0.785-0.999); the optimal cutoff value was 0.446, which had a 91.7% sensitivity, 84.6%, specificity, and an 88.0% diagnostic accuracy. CONCLUSIONS: In patients with unresectable HCC receiving combined TKI/anti-PD 1 therapy, major radiographic response alone or combined with α-fetoprotein response may predict pCR.

Clinical response to adding pyrotinib to pembrolizumab and lenvatinib for HER2-positive advanced intrahepatic cholangiocarcinoma: a case report.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly lethal hepatobiliary cancer, and very few patients can undergo surgery. The prognosis of advanced ICC is poor, especially in patients who progress after first-line chemotherapy, with a median overall survival of less than 10 months. CASE PRESENTATION: A 64-year-old male was diagnosed with advanced intrahepatic cholangiocarcinoma with ERBB2 (HER2) 3 + amplification determined by tissue-based testing and confirmed by next-generation sequencing. The patient was treated with pyrotinib added to pembrolizumab and lenvatinib after progressing with pyrotinib and tegafur and responded very well with regression of the tumor on imaging as well as normalization of tumor marker levels without serious adverse events. PET-CT after 6 months of treatment showed a partial response. The progression-free survival with second-line treatment was 17 months. For the third line of therapy, lenvatinib and pembrolizumab were used in combination with bevacizumab. Currently, he has had stable disease for approximately 6 months during third-line treatment. CONCLUSION: Adding pyrotinib to pembrolizumab and lenvatinib may represent a promising strategy for advanced ICC patients who have high levels of HER2.

Novel cellular therapies for hepatobiliary malignancies.

BACKGROUND: The mortalities of hepatobiliary malignancies are high. With the failure of conventional chemotherapy and unsatisfactory outcome of molecular targeted drugs, immune-based therapy has become a new focus of research in hepatobiliary cancers treatment. DATA SOURCES: We performed a PubMed search with relevant articles published up to May 2022 and the following keywords: cellular immunotherapy, hepatobiliary cancer, antigen receptor T cell therapy, and receptor-engineered T cell. Information of clinical trials was obtained from https://clinicaltrials.gov/. RESULTS: Cell therapies for hepatobiliary malignancies are at early stage of development. The current review showed that cellular therapies are safe and feasible in patients. These findings provide an important platform for future lager scale clinical trials on immunotherapy in patients with hepatobiliary malignancies. CONCLUSIONS: With the continuous advances of cellular immunotherapy, the combination of cellular immunotherapy with surgery, chemotherapy and radiotherapy will be new therapeutic strategies for patients with hepatobiliary cancer.

Establishment of validated models for non-invasive prediction of rectal temperature of sows using infrared thermography and chemometrics.

Rectal temperature is an important physiological indicator used to characterize the reproductive and health status of sows. Infrared thermography, a surface temperature measurement technology, was investigated in this study to explore its feasibility in non-invasive detection of rectal temperature in sows. A total of 124 records of rectal temperature and surface temperature in various body regions of 99 Landrace × Yorkshire crossbred sows were collected. These surface temperatures together with ambient temperature, ambient humidity, and wind speed in pig pens were correlated with the real rectal temperature of sows to establish rectal temperature prediction models by introducing chemometrics algorithms. Two types of models, i.e., full feature models and selected feature models, were established by applying the partial least squares regression (PLSR) method. The optimal model was attained when 7 important features were selected by LARS-Lasso, where correlation coefficients and root mean squared errors of calibration were 0.80 and 0.30 °C, respectively. Particularly, the validity and stability of established simplified models were further evaluated by applying the model to an independent prediction set, where correlation coefficients and root mean squared errors for prediction were 0.80 and 0.35 °C, respectively. The validation of established models is scarce in previous similar studies. Above all, this study demonstrated that introduction of chemometrics methodologies would lead to more reliable and accurate model for predicting sow rectal temperature, thus the potential for ensuring animal welfare in a broader view if extended to more applications.

Circulating Tumor DNA in Cancer Management.

Molecular techniques can be very useful in detecting a patient's tumor to guide treatment decisions is increasingly been applied in the care and management of cancer patients. Circulating tumor DNA (ctDNA) containing mutations can be identified in the plasma of cancer patients during the course of the disease. As a non-invasive "liquid biopsies",ctDNA is a potential surrogate for the entire tumor genome. The use of ctDNA might help to determine the disease prognosis,monitor disease progression,monitor the molecular resistance and monitor the tumor heterogeneity. Future developments will need to provide clinical standards to validate the ctDNA as a clinical biomarker and improve the reproducibility and accuracy,in order to be better exploited for personalized medicine.

Postconflict Conciliation within One-Male Breeding Units in Sichuan Snub-Nosed Monkeys in the Qinling Mountains, China.

This study analyzed conflict and postconflict (PC) conciliation between males and females within one-male breeding units in Sichuan snub-nosed monkeys (Rhinopithecus roxellana) in the Qinling Mountains, China. The PC matched-control and time rule methods were used to collect and analyze data recorded from September 2013 to June 2014. The conciliatory tendency among individuals following conflict was 82.07%, and affiliation occurred within a few minutes after the conflict, which was not significantly different between mating and nonmating seasons. The PC conciliation scenarios were different from those reported from captivity. Lumbar hold and grooming were the most common expressions in reconciliation. In addition, bystander affiliation was uniquely found, which may be associated with the more terrestrial locomotion of R. roxellana, compared with other colobines.

Thermal ethane activation by bare [V2O5]⁺ and [Nb2O5]⁺ cluster cations: on the origin of their different reactivities.

The gas-phase reactivity of [V2O5](+) and [Nb2O5](+) towards ethane has been investigated by means of mass spectrometry and density functional theory (DFT) calculations. The two metal oxides give rise to the formation of quite different reaction products; for example, the direct room-temperature conversions C2H6→C2H5OH or C2H6→CH3CHO are brought about solely by [V2O5](+). In distinct contrast, for the couple [Nb2O5](+)/C2H6, one observes only single and double hydrogen-atom abstraction from the hydrocarbon. DFT calculations reveal that different modes of attack in the initial phase of C-H bond activation together with quite different bond-dissociation energies of the M-O bonds cause the rather varying reactivities of [V2O5](+) and [Nb2O5](+) towards ethane. The gas-phase generation of acetaldehyde from ethane by bare [V2O5](+) may provide mechanistic insight in the related vanadium-catalyzed large-scale process.

Highly regioselective hydride transfer, oxidative dehydrogenation, and hydrogen-atom abstraction in the thermal gas-phase chemistry of [Zn(OH)](+)/C3H8.

The thermal reactions of [Zn(OH)](+) with C3H8 have been studied by means of gas-phase experiments and computational investigation. Two types of C-H bond activation are observed in the experiment, and pertinent mechanistic features include inter alia: (i) the metal center of [Zn(OH)](+) serves as active site in the hydride transfer to generate [i-C3H7](+) as major product, (ii) generally, a high regioselectivity is accompanied by remarkable chemoselectivity: for example, the activation of a methyl C-H bond results mainly in the formation of water and [Zn(C3,H7)](+). According to computational work, this ionic product corresponds to [HZn(CH3CH=CH2)](+). Attack of the zinc center at a secondary C-H bond leads preferentially to hydride transfer, thus giving rise to the generation of [i-C3H7](+); (iii) upon oxidative dehydrogenation (ODH), liberation of CH3CH2=CH2 occurs to produce [HZn(H2O)](+). Both, ODH as well as H2O loss proceed through the same intermediate which is characterized by the fact that a methylene hydrogen atom from the substrate is transferred to the zinc and one hydrogen atom from the methyl group to the OH group of [Zn(OH)](+). The combined experimental/computational gas-phase study of C-H bond activation by zinc hydroxide provides mechanistic insight into related zinc-catalyzed large-scale processes and identifies the crucial role that the Lewis-acid character of zinc plays.

Development and validation of web-based nomograms for predicting survival status in patients with intrahepatic cholangiocarcinoma depending on the surgical status: a SEER database analysis.

This study aimed to develop and validate prognostic nomograms that can estimate the probability of 1-, 3- and 5-year overall survival (OS) as well as cancer-specific survival (CSS) for Intrahepatic cholangiocarcinoma (ICCA) patients. Clinical data of 1446 patients diagnosed with ICCA between 2010 and 2017 from the Surveillance, Epidemiology, and End Results (SEER) database were analyzed. In both the OS and the CSS group, the training cohort and validation cohort were divided into a 7:3 ratio. Age, sex, AJCC T stage, AJCC N stage, AJCC M stage, surgical status, and tumor grade were selected as independent prognostic risk factors to build the nomograms. To compare the efficacy of predicting 1-, 3-, and 5-year OS and CSS rates of the nomogram with the 8th edition of the American Joint Committee on Cancer (AJCC) staging system, we evaluated the Harrell's index of concordance (C-index), area under the receiver operating characteristic curve (AUC) and decision curve analysis (DCA) in both cohorts. The results showed the nomogram for 1-, 3-, and 5-year OS and CSS prediction performed better than the AJCC staging system. In the subgroup analysis for patients could not receive surgery as the primary treatment. We developed two nomograms for predicting the 1-, and 2-year OS and CSS rates following the same analysis procedure. Results indicate that the performance of both nomograms, which contained sex, AJCC T stage, AJCC M stage, chemotherapy, and tumor grade and prognostic factors, was also superior to the AJCC staging system. Meanwhile, four dynamic network-based nomograms were published. The survival analysis showed the survival rate of patients classified as high-risk based on the nomogram score was significantly lower compared to those categorized as low-risk (P < 0.0001). Finally, accurate and convenient nomograms were established to assist clinicians in making more personalized prognosis predictions for ICCA patients.

Comprehensive molecular analysis identifies RET alterations association with response of ICIs in multi-immunotherapy cohorts.

BACKGROUND: The RET gene, which is frequently mutated across many types of cancer, has been proven to be critically involved in tumorigenesis and tumour development; however, its prediction of the therapeutic efficacy of immune checkpoint inhibitor (ICI) therapy remains to be elucidated. The present research aims to investigate the association between RET mutations and the efficiency of ICI therapy. METHOD: We analysed the role of RET mutations in predicting the prognosis of patients receiving ICIs therapy in the discovery cohort and validated it in the validation cohort. Then, multi-omics data from TCGA pan-cancer cohort was employed to propose the association between RET mutations and tumour inflamed anti-tumour immune response and tumour antigenicity. RESULTS: Our study revealed that among 606 cases and across five types of cancer, RET mutation was associated with better clinical outcomes for ICIs therapy, including elevated response rate, longer progression-free survival PFS, and longer overall survival OS. Multivariate analysis showed that RET mutation could independently predict the prognosis of patients treated with ICIs, after adjusting cancer types. The predictive value of RET status for the OS of patients treated with ICIs immunotherapy was further validated in the validation cohort (n = 1,409). Subgroup analysis suggested that only the monotherapy group showed significant differences in OS(P < 0.05) and PFS(P < 0.05) between RET-wildtype tumours and RET-mutant tumours. Multi-omics data analysis revealed potential anti-tumour immunity mechanisms of RET mutations, suggesting that RET-mutant tumours have enhanced immunogenicity, higher expression of immune checkpoints and chemokines, and higher immune cell infiltration than those observed in RET-wildtype tumours; thus, potentially indicating a more favourable response to immunotherapy. CONCLUSIONS: RET mutation may be a predictive biomarker of enhanced response to ICIs therapy. Extensive investigation of the underlying molecular mechanisms and prospective studies are needed in the future.

Worldwide research trends on tumor burden and immunotherapy: a bibliometric analysis.

Various immunotherapy has been greatly applied to comprehensive treatment of malignant cancer under different degrees of tumor burden. Scientific researchers have gained considerable progress in the relationship between immunotherapy and tumor burden in recent years. This review aimed to explore the prospect and developing trends in the field of tumor burden and immunotherapy from a bibliometric perspective. Articles about tumor burden and immunotherapy were collected from the Web of Science Core Collection (WoSCC) (retrieved on 3 January 2023). The R package 'Bibliometrix' analyzed the primary bibliometric features and created a three-filed plot to display the relationship between institutions, countries, and keywords. VOSviewer was used for co-authorship analysis, co-occurrence analysis, and their visualization. And CiteSpace calculated the citation burst references and keywords. A total of 1030 publications were retrieved from 35 years of scientific researches. The United States (US) and China published the most articles. The most productive journals were Cancer Immunology Immunotherapy and Journal for ImmunoTherapy of Cancer . The top one institution of the highest output was University of Texas MD Anderson Cancer Center. The hot keywords of strong citation burst strength in recent years were 'nivolumab', 'tumor microenvironment', and 'immune checkpoint inhibitor'. The most popular tumor type is melanoma. This bibliometric analysis mapped a basic knowledge structure. The field of tumor burden and immunotherapy is entering a rapid growing stage and keeping it value for future research.

Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study.

Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

Fiber Bragg grating-based plane strain monitoring of aerostat envelope structures.

A theoretical analysis of fiber Bragg grating (FBG)-based plane strain monitoring of aerostat envelope structures is presented. Plane strain analysis of FBG-based aerostat envelope structures is much more complex than the case along the axis of the optical fiber because the effect of transverse stress on the FBG should be taken into consideration. To achieve accurate strain measurement of the aerostat envelope, a theoretical model is set up by using two perpendicular fibers in the monitoring. An analytical formula that evaluates the relationship between the strain measured by FBG sensors and the real one in the aerostat envelope is established. On the other hand, the real strain of aerostat envelope strain is affected by two unknown parameters, axial transfer rate K(L) and the radial transfer rate K(R). An equation is derived to calculate the axial transfer rate K(L). Then, the finite element method results show that K(R) is a very small value, but it cannot be ignored in accurate measurement. This paper would lay a theoretical groundwork for the research and design of FBG sensors in the structural health monitoring of aerostat envelope structures.

[Correlative study between length of first metatarsal and transfer metatarsalgia after osteotomy of first metatarsal].

OBJECTIVE: To evaluate the correlation between the length of first metatarsal, hallux valgus angle (HVA), intermetatarsal 1-2 angle (IMA1-2), plantar appearance, sesamoid position and postoperative 2-5 transfer metatarsalgia. METHODS: Retrospective analysis was performed for the clinical data of 375 cases (626 feet) undergoing osteotomy of first metatarsal with mini-incision. All cases were examined radiographically via weight-bearing and lateral views. HVA, IMA1-2 and the length of first metatarsal were measured preoperatively and postoperatively. Forefoot plantar pressure was measured during walking by Foot scan system preoperatively and postoperatively. RESULTS: After a mean follow-up period of 12-30 (18.5 ± 6.8) months, all patients had satisfactory bone healing without late healing or disunion. There were superficial wound infection (n = 1, 1 foot) and suture reaction (n = 1, 1 foot). HVA was 7.18° ± 4.55° postoperatively and corrected by 30.54°; IMA1-2 5.07° ± 1.70° and corrected by 12.33°. The number of shorting of first metatarsal during 0-2 mm was 424 feet, there was 1 case of transfer metatarsalgia at rays 4; the number during 2-4 mm was 186 feet, there were 5 cases of transfer metatarsalgia at rays 2. The center of pressure shifted laterally; the number during 2-4 mm was 16 feet, there were 4 cases of transfer metatarsalgia at rays 2 and 3. The center of pressure shifted evidently medially; the shorting of first metatarsal was 4.8 ± 0.46 mm. A negative correlation was found between length of metatarsal and transfer metatarsalgia at rays 2 and 3. No correlation existed between transfer metatarsalgia at rays 2 and 5, HVA and IMA1-2. A positive correlation existed between HVA decrease and patient satisfaction with their postoperative foot alignment. There was no correlation between lengthening of metatarsal and IMA1-2 decrease. CONCLUSION: Length preservation of first metatarsal seems to prevent the postoperative transfer metatarsalgia on second and third rays. The shorting of first metatarsal should be no more than 2 mm.