Development and external validation of a machine-learning based model to predict pre-sarcopenia in MASLD population: Results from NHANES 2017-2018.

INTRODUCTION AND OBJECTIVES: With rising prevalence of pre-sarcopenia in metabolic dysfunction-associated steatotic liver disease (MASLD), this study aimed to develop and validate machine learning-based model to identify pre-sarcopenia in MASLD population. MATERIALS AND METHODS: A total of 571 MASLD subjects were screened from the National Health and Nutrition Examination Survey 2017-2018. This cohort was randomly divided into training set and internal testing set with a ratio of 7:3. Sixty-six MASLD subjects were collected from our institution as external validation set. Four binary classifiers, including Random Forest (RF), support vector machine, and extreme gradient boosting and logistic regression, were fitted to identify pre-sarcopenia. The best-performing model was further validated in external validation set. Model performance was assessed in terms of discrimination and calibration. Shapley Additive explanations were used for model interpretability. RESULTS: The pre-sarcopenia rate was 17.51 % and 15.16 % in NHANES cohort and external validation set, respectively. RF outperformed other models with area under receiver operating characteristic curve (AUROC) of 0.819(95 %CI: 0.749, 0.889). When six top-ranking features were retained as per variable importance, including weight-adjusted waist, sex, race, creatinine, education and alkaline phosphatase, a final RF model reached an AUROC being 0.824(0.737, 0.910) and 0.732(95 %CI: 0.529, 0.936) in internal and external validation sets, respectively. The model robustness was proved in sensitivity analysis. The calibration curve and decision curve analysis confirmed a good calibration capacity and good clinical usage. CONCLUSIONS: This study proposed a user-friendly model using explainable machine learning algorithm to predict pre-sarcopenia in MASLD population. A web-based tool was provided to screening pre-sarcopenia in community and hospitalization settings.

Antibody-dependent cell-mediated cytotoxicity using T cells with NK-like phenotype in combination with avelumab, an anti-PD-L1 antibody.

Though the PD-L1 checkpoint inhibitor avelumab has shown efficacy in the treatment of some types of cancer, improved treatment strategies are desperately needed. We evaluated whether combined treatment with avelumab and adoptively transferred T-NK cells can provide enhanced anti-cancer effects for treating PD-L1-expressing tumours. Our results demonstrate that avelumab specifically targets tumour cells with high PD-L1 expression, and that cytolytic effects are mediated by T-NK effector cells cultured from patient peripheral blood monocytic cell populations. The effects were dependent on CD16 and the perforin/granzyme pathway, supporting a role for the T-NK subpopulation. In vivo assays verified the efficacy of T-NK cells in combination with avelumab in reducing tumour growth. Furthermore, T-NK + avelumab prolonged survival in a mouse orthotopic xenograft model. Collectively, our findings provide a basis for the combined use of adoptively transferred T-NK cells with avelumab as a novel strategy for cancer treatment.

All-pass phase shifting enabled by symmetric topological unidirectional guided resonances.

All-pass phase shifting (APS), which involves a wave propagating at a constant, unitary amplitude but with pure phase variation, is extremely desired in many optoelectronic applications. In this work, we propose a method of realizing APS by out-of-plane excitation of a topologically enabled unidirectional guided resonance (UGR), which resides in a photonic crystal slab with P or C2z symmetries. Briefly, the symmetries and unidirectional features reduce the number of ports to one that simultaneously adds or drops energy. As a result, the phase independently shifts by varying the frequency but the amplitude remains as unitary under plane wave excitation. Theory and simulations confirm our findings. A paradox that the background contribution deviates from Fabry-Perot resonance is clarified from a multi-resonances picture.

IL-15-induced lymphocytes as adjuvant cellular immunotherapy for gastric cancer.

Objectives To test the antitumor potential of lymphocytes transferred via adoptive cell therapy (ACT) in a mouse model of human gastric cancer (GC), and to evaluate the clinical efficacy and safety of combining lymphocytes as adjuvant therapy with first-line chemotherapy in patients with GC. Methods We constructed a human GC xenograft model in sublethally irradiated 6-8-week-old male NCG mice. MKN-45 cells (1 × 106 cells/mouse) were subcutaneously injected into mice's flanks. After tumors had become palpable, we randomized the mice into control, ACTIL-2, and ACTIL-15 groups. Human lymphocytes were then injected into mouse tail veins. In addition, 63 human patients with histologically or cytologically confirmed stage III-IV GC randomly received S-1 + oxaliplatin + ACTIL-15 (combination therapy group) or S-1 + oxaliplatin (chemotherapy group). Results In the mouse study, treatment with ACTIL-15 cells inhibited tumor growth on adoptive transfer, and mice that received ACTIL-15 cells had significantly longer survival rates (p < 0.05, ACTIL-15 vs. ACTIL-2). In the human study, the median survival rate of patients in the combination therapy group was 472 days (95% confidence interval [CI], 276-668 days), whereas that of patients in the chemotherapy group was 266 days (95% CI, 200-332 days; p < 0.05). Eleven percent (7/63) of patients had adverse reactions, but these reactions did not interfere with treatment. Conclusion Adoptive transfer of ACTIL-15 cells in a mouse model of GC and in patients with advanced GC treated with S1 + oxaliplatin improved survival rates in both, with an acceptable safety profile.

Synergistic effect of adoptive immunotherapy and docetaxel inhibits tumor growth in a mouse model.

Adoptive T cell transfer therapy (ACT) has emerged as a promising approach to cancer immunotherapy; however, the efficacy of ACT is limited by the T-cell suppressive activity of myeloid-derived suppressor cells (MDSCs), which accumulate in the tumor microenvironment after ACT. We sought to determine whether the efficacy of ACT could be enhanced by co-treatment with docetaxel, a taxane chemotherapy agent that has been shown previously to inhibit MDSC function. Using a mouse tumor model, we demonstrated that ACT and docetaxel synergistically inhibit the growth either of engrafted CT26 colon cancer or 4T1 mammary carcinoma cells. While ACT mediated an increase in the recruitment of MDSCs to the site of the tumor, docetaxel reversed this increase. Furthermore, ex vivo cultures of tumor-associated MDSCs suppressed the cytotoxic activity of tumor-specific T cells, and this suppressive activity was abolished by docetaxel treatment. These results suggest that docetaxel inhibits both the tumor recruitment and T cell suppressive activity of MDSCs. Inhibitors of iNOS and arginase partially inhibited ex vivo MDSC activity, and combined inhibition of iNOS and arginase had a similar effect as docetaxel, which supports the possibility that docetaxel may function by inhibiting ACT-associated activation of these pathways. Furthermore, docetaxel mediated inhibition of the T cell suppressive activity of MDSCs from human blood, which supports the potential clinical applicability of these findings. On the basis of these findings, docetaxel treatment may represent an effective therapeutic approach for reversing immunosuppression by MDSCs subsequent to ACT-based therapy.

Correlation between computed tomography-based body composition parameters and hepatic venous pressure gradient in patients with cirrhosis: a systematic review and meta-analysis.

PURPOSE: Computed tomography (CT)-based body composition parameters and the hepatic venous pressure gradient (HVPG) are key characteristics in patients with liver cirrhosis. The present study aims to explore the correlation between CT-based body composition parameters and HVPG, as well as the difference in HVPG between patients with and patients without sarcopenia. METHODS: A literature search for studies reporting the correlation between HVPG and CT-based body composition parameters published in English up to August 2023 in four databases, Embase, MEDLINE (via PubMed), Web of Science, and Cochrane Library, was conducted. The correlation coefficient between HVPG and CT-based body composition parameters was the primary outcome, and the difference in the HVPG value between the sarcopenia and non-sarcopenia groups was the secondary outcome. A meta-analysis was conducted using a random-effects models. The methodologic quality was assessed using the Quality Assessment of Diagnostic Studies instrument. RESULTS: A total of 652 articles were identified, of which nine studies (n = 1,569) met the eligibility criteria. Among them, seven studies reported the primary outcome via the muscle index, five via the skeletal muscle index (SMI), two via the psoas-muscle-related index (PRI), and three via two adipose tissue indexes. A total of five studies reported the secondary outcome: four via SMI and one via PRI. No evidence of a significant correlation was determined between the various body composition parameters and the HVPG value, either in the muscle index or the adipose tissue index. Higher HVPG values were observed in patients with sarcopenia than in patients without sarcopenia [pooled standardized mean difference (SMD): 0.628 (-0.350, 1.606), P < 0.001; I2 = 92.8%; P < 0.001] when an Asian sarcopenia definition was adopted. In contrast, when a Western cut-off value was applied, the HVPG value was higher in patients without sarcopenia than in patients with sarcopenia [pooled SMD: -0.201 (-0.366, -0.037), P = 0.016; I2 = 0.00%; P = 0.785]. CONCLUSION: No sufficient evidence regarding a correlation between the CT-based body composition and HVPG value was discovered. The difference in the HVPG value between the sarcopenia and non-sarcopenia groups was likely dependent on the sarcopenic cut-off value.

Ultralow-loss optical interconnect enabled by topological unidirectional guided resonance.

Grating couplers that interconnect photonic chips to off-chip components are crucial for various optoelectronics applications. Despite numerous efforts in past decades, the existing grating couplers are still far from optimal in energy efficiency and thus hinder photonic integration toward a larger scale. Here, we propose a strategy to achieve ultralow-loss grating couplers by using unidirectional guided resonances (UGRs), suppressing the useless downward radiation with no mirror on the bottom. By engineering the dispersion and apodizing the geometry of grating, we experimentally realize a grating coupler with a record-low loss of -0.34 dB and 1-dB bandwidth exceeding 30 nm at the telecom wavelength of 1550 nm and further demonstrate an optic via with a loss of only -0.94 dB. Given that UGRs ubiquitously exist in a variety of grating geometries, our work sheds light on a systematic method to achieve energy-efficient optical interconnect and paves the way to large-scale photonic integration.

Observation of hemostatic effectiveness and safety of ultrasound-CT guided 3D intracavitary and interstitial brachytherapy in the treatment of larger cervical cancer with bleeding: A retrospective study.

Cervical cancer is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer death in women. This study explored the effectiveness and safety of ultrasound-CT guided 3D intracavitary and interstitial brachytherapy (US-CT-3D-IGBT) in the treatment of larger cervical cancer with bleeding. A retrospective study was conducted on 31 patients with larger cervical squamous cell carcinoma (tumor short diameter >4 cm) with vaginal bleeding. US-CT-3D-IGBT was used to deliver a single high-dose prescription of high-risk clinical target volume (HR-CTV) 1000 to 1200 centigray (cGy) to the cervical tumor, followed by conventional intensity-modulated radiation therapy (IMRT) synchronous chemoradiotherapy (45-50 gray (Gy)/25-28 fraction(f)) with weekly cisplatin 25 mg/m2. After external radiotherapy, simple intracavitary brachytherapy (BT) combined with manual interstitial BT was administered at 30 Gy/5F or 28 Gy/4F. Within 24 hours after high-dose 3D-IGBT, bleeding stopped in 2 patients (6.4%), and bleeding was reduced in a total of 11 patients (35.4%) within 48 hours. A total of 29 patients achieved hemostasis within 72 hours, with an effective rate of 93.5%. The remaining 2 patients reached the clinical hemostasis requirement on the 4th and 5th day. All patients experienced a significant reduction in vaginal bleeding after the initial BT, with an average reduction of 66 mL (160-20 mL). US-CT-3D-IGBT is effective in rapidly controlling bleeding in patients with larger cervical cancer (tumor short diameter >4 cm), and the treatment is relatively safe and feasible.

Study on efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with regorafenib and PD-1 antibody versus continued TACE combined with regorafenib in patients with hepatocellular carcinoma after failed second-line treatment with regorafenib.

Background: At present, there is no standard for the posterior treatment of hepatocellular carcinoma (HCC). This study isTo evaluate and compare the safety and efficacy of transcatheter arterial chemoembolization (TACE) combined with regorafenib and anti-PD-1 antibody with continued TACE combined with regorafenib in patients with HCC after the failure of second-line treatment with regorafenib. Methods: We enrolled patients with advanced HCC who were treated with sorafenib and sequential regorafenib. All patients were treated with TACE and found to have tumor progression in 2021. After tumor progression, patients were treated with TACE combined with regorafenib and PD-1 antibody or with continued TACE combined with regorafenib according to the wishes of the patient. Efficacy was evaluated after 1 month of treatment. The objective response rate (ORR), disease-control rate (DCR), and safety were evaluated according to adverse reactions of patients. Results: Nine patients were treated with TACE combined with regorafenib and PD-1 antibody, and the 9 patients continued to receive TACE combined with regorafenib. There was no significant difference in baseline data between the 2 groups. In the PD-1 group five patients achieved a partial response (PR), three achieved stable disease (SD), and one patient had progressive disease (PD) after 1 month of treatment. The ORR was 55.6% and the DCR was 88.9%. In the continued TACE-regorafenib group, four patients achieved PR, one achieved SD, and four patients achieved PD after 1 month of treatment, while the ORR was 44.4% and the DCR was 55.6%. There was a significant difference in the DCR between the two groups (P=0.012), while adverse events were similar in both. Conclusions: TACE combined with regorafenib and PD-1 antibody had a higher DCR and was more effective than continued TACE combined with regorafenib in patients with HCC who failed second-line treatment with regorafenib. However, PD-1 antibody therapy might increase the risk of death by causing an uncontrollable immune response. Given the risk of an immune response, patients may choose to continue TACE combined with regorafenib, given the similar ORR of the two treatments.

Predictive value of hepatic venous pressure gradient and efficacy and significance of early PTVE for gastrointestinal bleeding after TACE for liver cancer.

Aims: To investigate the predictive value of hepatic venous pressure gradient (HVPG) and the efficacy and significance of early percutaneous transhepatic varices embolization (PTVE) for gastrointestinal bleeding after transcatheter arterial chemoembolization (TACE) for liver cancer. Methods and Materials: This retrospective study enrolled 60 patients diagnosed with stage B or stage C liver cancer, according to the Barcelona Clinic Liver Cancer (BCLC) staging system, between December 2019 and October 2021. TACE and HVPG measurement (>16 mmHg or >20 mmHg) were performed on all 60 patients, who were randomized into control and experimental (PTVE) groups. All patients were followed up for 12 months. Statistical Analysis Used: SPSS 20.0 software was used for data analysis. The two groups were compared with respect to the initial occurrence time of hemorrhage after TACE, recurrence time of hemorrhage, liver function, TACE frequency, TACE type, and tumor control. Results: The initial hemorrhage rates at one, three, six, and 12 months after TACE were 3.2%, 12.9%, 22.6%, and 48.4%, respectively, in the control group (n = 31) and 0%, 0%, 3.4%, and 10.3%, respectively, in the PTVE group (n = 29). Differences between the groups in terms of initial hemorrhage rate at six and 12 months postoperatively were significant (P < 0.05). The recurrence rates of hemorrhage at one, three, six, and 12 months after TACE were 11.1%, 22.2%, 22.2%, and 33.3%, respectively, in 27 patients in the control group. In eight patients in the PTVE group, the corresponding rates were 0%, 0%, 0%, and 25.0%. The differences between the groups in the recurrence rate of hemorrhage at the four time points were significant (P < 0.05). At six months postoperatively, liver function recovery and remission were noted in eight (25.8%) and 18 (66.7%) patients, respectively, in the control group; these events were noted in 10 (34.5%) and 19 patients (65.5%), respectively, in the PTVE group, and the difference between the groups was not significant (P > 0.05). In the control group, TACE was performed for a total of 94 times on 31 patients within 12 months, including conventional transcatheter arterial chemoembolization (C-TACE, 75.5%) and the drug-eluting bead TACE (DEB-TACE, 24.5%); the objective response rate (ORR) was 39.3%. In the PTVE group, TACE was performed for a total of 151 times on 29 patients within 12 months, with an average of 5.21 times on each patient, including the C-TACE (57.6%) and DEB-TACE (42.4%); the ORR was 60.1%. Differences in TACE frequency, proportion of C-TACE/DEB-TACE, and ORR were significant between the two groups (P < 0.05). Conclusion: HVPG can accurately evaluate gastrointestinal bleeding after TACE in patients with liver cancer. Early PTVE can significantly lower the risk of gastrointestinal bleeding and help TACE control tumor progression in patients with an HVPG >16 mmHg or >20 mmHg.

Study on safety and efficacy of regorafenib combined with transcatheter arterial chemoembolization in the treatment of advanced hepatocellular carcinoma after first-line targeted therapy.

Background: Targeted drug therapy and transcatheter arterial chemoembolization (TACE) is the most effective control method for middle and late-stage hepatocellular carcinoma (HCC). Regorafenib as the second-line treatment of patients with advanced HCC, combined with TACE treatment still achieved good results in clinic. However, there is no relevant research at present. However, there is no relevant research at present. This study was to investigate the efficacy and safety of regorafenib combined with TACE in the treatment of patients with advanced HCC after the failure of first-line targeted treatment. Methods: Fifty-nine patients with advanced HCC received second-line regorafenib treatment between October 2019 and September 2021 were enrolled in the study. Patients were treated with routine TACE. Oral administration of regorafenib was started 1 week after the operation for 3 weeks and then stopped for 1 week. Objective response rate (ORR), disease control rate (DCR), median progression-free survival (m-PFS), and safety were evaluated according to the modified Response Evaluation Criteria in Solid Tumors (m-RECIST). In our study, most of the analyses are descriptive. Results: One patient achieved complete response (CR), and 24 patients achieved partial response (PR). stable disease (SD) was observed in 14 patients, while progression disease (PD) was observed in 20 patients. The ORR was 42.3% (25/59), and the DCR was 66.1% (39/59). The longest follow-up was 23 months, and the shortest was 1 month. Disease progression was found in 45 patients during follow-up. Among these patients, the longest interval before the detection of disease progression was 16 months, and the shortest was 1 month. Among patients who had disease progression, the median PFS was 8 months. Adverse events (AEs) were observed in 59 patients. These included hand-foot reaction (n=50, 84.7%), weight decrease (n=18, 30.5%), hypertension (n=8, 13.6%), proteinuria (n=1, 1.7%), weakness (n=12, 20.3%), diarrhea (n=1, 1.7%), and hoarseness (n=9, 15.3%). No treatment-related death occurred. Conclusions: Regorafenib combined with TACE achieved a good ORR and DCR among patients with advanced HCC receiving second-line targeted therapy, with only 9 patients experiencing grade 3 or 4 adverse reactions. Therefore, regorafenib combined with TACE is effective and safe in the treatment of advanced HCC.

Prostaglandin E2 and PD-1 mediated inhibition of antitumor CTL responses in the human tumor microenvironment.

Accumulating evidence indicates that inflammation plays a critical role in cancer development; however, mechanisms of immunosuppression hinder productive anti-tumor immunity to limit immunopathology. Tumor-specific cytotoxic T lymphocyte (CTL) dysfunction or exhaustion by upregulating inhibitory receptors such as programmed cell death 1 (PD-1) in tumor-bearing hosts is one such mechanism. Identification and blockade of the pathways that induce CTL dysfunction has been shown to partially restore CTL function in tumor-bearing hosts. Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme for prostanoid biosynthesis, including prostaglandin E2 (PGE2), and plays a key role in both inflammation and cancer. The disruption of COX2/PGE2 signaling using COX2 inhibitors or PGE2 receptors EP2 and EP4 antagonists, combined with anti-PD-1 blockade was therapeutic in terms of improving eradication of tumors and augmenting the numbers of functional tumor-specific CTLs. Thus, COX2/PGE2 axis inhibition is a promising adjunct therapy to PD-1 blockade for immune-based therapies in cancer.

Targeting PD-1 and Tim-3 Pathways to Reverse CD8 T-Cell Exhaustion and Enhance Ex Vivo T-Cell Responses to Autologous Dendritic/Tumor Vaccines.

The paradoxical coexistence of spontaneous tumor antigen-specific immune response with progressive disease in cancer patients need to dissect the molecular pathways involved in tumor-induced T-cell dysfunction or exhaustion. Programmed cell death 1 (PD-1) has been identified as a marker of exhausted T cells in chronic disease states, and blockade of PD-1-PD-L1 interactions has been shown to partially restore T-cell function. We have found that T-cell immunoglobulin mucin (Tim) 3 is expressed on CD8+ tumor-infiltrating lymphocytes (TILs) isolated from patients with colorectal cancer. All T-cell immunoglobulin mucin 3 (Tim-3+) TILs coexpress PD-1, and Tim-3+ PD-1+ CD8+ TILs represent the predominant fraction of Tcells infiltrating tumors. Tim-3+PD-1+ CD8+ TILs exhibit the most severe exhausted phenotype as defined by failure to produce cytokines, such as interferon-γ, tumor necrosis factor-α, and interleukin-2. We further find that combined targeting of the Tim-3 and PD-1 pathways increased the frequencies of not only interferon-γ and tumor necrosis factor-α but also frequencies of proliferating tumor antigen-specific CD8+ T cells than targeting either pathway alone. A concomitant decrease in regulatory T cells and enhanced killing in a cytotoxicity assay was observed. Collectively, our findings support the use of Tim-3-Tim-3L blockade together with PD-1-PD-L1 blockade to reverse tumor-induced T-cell exhaustion/dysfunction in patients with colorectal cancer.

Room-temperature self-powered ethanol sensing of a Pd/ZnO nanoarray nanogenerator driven by human finger movement.

A flexible room-temperature self-powered active ethanol sensor has been realized from a Pd/ZnO nanoarray nanogenerator. Pd nanoparticles are uniformly loaded on the whole surface of the ZnO nanowire arrays by a simple hydrothermal method. The piezoelectric output of the Pd/ZnO nanowire arrays can act as both the power source of the device and the room-temperature ethanol sensing signal. Upon exposure to 800 ppm ethanol gas at room temperature, the piezoelectric output voltage decreased from 0.52 V (in air) to 0.25 V. Such a room-temperature self-powered ethanol sensing behavior can be attributed to the catalytic effect of Pd, the Schottky barrier at the Pd/ZnO interface, and the piezotronics effect of the ZnO nanowires. Moreover, this flexible device can be driven by tiny mechanic energy in the environment, such as human finger movement. The present results can stimulate a research trend on designing new material systems and device structures in self-powered ethanol sensing at room temperature.