Efficacy and safety of transarterial chemoembolization combined with targeted therapy and immunotherapy versus with targeted monotherapy in unresectable hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: The application of transarterial chemoembolization (TACE) in combination with targeted therapy and immunotherapy (TACE-T-I) for unresectable hepatocellular carcinoma (HCC) has gained increasing attention. However, there are variations in the efficacy and safety outcomes between TACE-T-I versus TACE combined with targeted drugs (TACE-T). This study aims to systematically evaluate the efficacy and safety of TACE-T-I versus TACE-T in unresectable HCC. METHODS: PubMed, Embase, Cochrane Library, and Web of Science databases were searched from inception to August 21, 2023, for comparative studies on TACE-T-I versus TACE-T for unresectable HCC. Outcome measures included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and the incidence of treatment-related adverse events (TRAEs). OS was the primary outcome of this study. Weighted mean difference (WMD) or hazard ratio (HR) was used as the pooled statistic for OS and PFS. Relative risk (RR) was employed as the pooled statistic for ORR, DCR and the incidence of TRAEs. And 95% confidence intervals (CIs) were calculated for all effect measures. Data analysis was conducted using Stata 14.0 software. RESULTS: The meta-analysis included 14 studies with 2144 patients. The pooled results showed that compared with patients in the TACE-T group, patients in the TACE-T-I group had higher ORR (RR = 1.61; 95%CI: 1.38-1.89) and DCR (RR = 1.17; 95%CI: 1.09-1.26). Patients in the TACE-T-I group experienced prolonged PFS (WMD = 3.08; 95%CI: 2.63-3.53) and OS (WMD = 5.76; 95%CI: 4.68-6.84). And the risk of disease progression (HR = 0.45; 95%CI: 0.37-0.55) and death (HR = 0.43; 95%CI: 0.38-0.49) was lower in the TACE-T-I group. Common TRAEs included fever, pain, abdominal pain, nausea, vomiting, elevated ALT, elevated AST, hypertension, hand-foot syndrome, proteinuria, and diarrhea. The incidence and severity of TRAEs in the TACE-T-I group were similar to those in the TACE-T group, with no significant differences (P > .05). CONCLUSION: Current evidence suggests that, on the basis of TACE combined with targeted therapy, the addition of immunotherapy provides better clinical efficacy and survival benefits for unresectable HCC patients, with good tolerability.

A competing risk nomogram to predict cancer-specific mortality of patients with late-onset colorectal cancer.

OBJECTIVE: This study aimed to compare the clinical characteristics and survival differences between early-onset colorectal cancer (EOCRC) patients and late-onset colorectal cancer (LOCRC) patients, identify the risk factors for cancer-specific mortality (CSM) in LOCRC patients and construct a mortality risk assessment nomogram. METHODS: CRC patients diagnosed pathologically between 2010 and 2019 in the SEER database were included and divided into the early-onset group and the late-onset group, and the late-onset group was divided into the training and validation sets. The Fine-Gray competing risk model was applied to analyze the prognostic factors of LOCRC patients and establish a competing risk nomogram for CSM. RESULTS: There are differences in the distribution of multiple clinical features between the early-onset group and the late-onset group. Age, tumor size, histological type, pathological grading, T stage, N stage, M stage, SEER stage, primary tumor surgery, metastatic lesion surgery, radiotherapy, chemotherapy, neural invasion, and carcinoembryonic antigen (CEA) were independent influencing factors of the CSM rate in LOCRC patients. The C-index of the prognosis model outweighed 0.8, and the calibration curves fitted the reference line well. CONCLUSION: The CSM competing risk nomogram for LOCRC patients in this study had acceptable predictive performance that could be applied to the clinic.

DNA repair genes are associated with tumor tissue differentiation and immune environment in lung adenocarcinoma: a bioinformatics analysis based on big data.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common type of lung cancer. DNA repair genes (DRGs) is important in lung cancer. The relationship between the immune environment and the expression levels of DRGs in LUAD remains unclear. The purpose of this study is to assess the relationship between DRGs and the immune environment and clinical characteristics of LUAD. METHODS: Data of 169 LUAD cases were obtained from cbioportal. The RNA-seq data came from the The Cancer Genome Atlas (TCGA) database. We collected DRGs from the Reactom database (KW0037, Reactom.org). The 302 genes expressed in each sample were analyzed by hierarchical clustering and grouped using the Gene Cluster 3.0 program. The Java Treeview program was used to generate heat maps of cluster indications and tumor staging patterns. GraphPad Prism 8 was used to draw survival curves and compare overall survival (OS). For single genes, an OS difference analysis between low and high expression populations was performed in GraphPad Prism 8. RESULTS: Matrix clustering showed no difference in the prognosis of the two clusters. The comparison of subgroups showed that Subcluster 1 (SC1) had the best prognosis, and Subcluster 2 (SC2) had the worst. There was a significant difference in tumor grades between Cluster 1 and Cluster 2 (P=0.01). There were significant differences in smoking status, histological grade and adenocarcinoma subtype among subgroups. In Subcluster 3 (SC3), the proportion of poorly differentiated cases was highest. Immunological index analysis showed that there were significant differences between Cluster 1 and Cluster 2 in interferon, macrophages, monocytes, neutrophils, natural killer (NK) cells, and T cells. Tumor purity, interferon, macrophages, monocytes, neutrophils, NK cells, T cells, translation, and proliferation all showed significant differences between subgroups. In SC2, the proliferation index increased (0.082 vs. 0.070); the protein translation index decreased (0.134 vs. 0.137); and the interferon level increased (0.099 vs. 0.097). In SC3, the proliferation index decreased (0.076 vs. 0.071); the protein translation index decreased (0.140 vs. 0.136); and the level of neutrophils increased (0.083 vs. 0.086). CONCLUSIONS: The differences of DRGs in LUAD are related to tissue differentiation and immune indicators but not to prognosis.

Adjuvant EGFR-TKIs for Patients With Resected EGFR-Mutant Non-Small Cell Lung Cancer: A Meta-Analysis of 1,283 Patients.

BACKGROUND: Cisplatin-based chemotherapy was previously considered as the standard adjuvant therapy for improved overall survival (OS) in patients with non-small cell lung cancer (NSCLC) after surgery. However, the benefit was limited due to high risks of recurrence and adverse events. In the present study, the efficacy of adjuvant epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for EGFR-mutant patients after surgery was investigated using the latest updated data. METHODS: This meta-analysis included a comprehensive range of relevant studies identified from database searches. Disease-free survival (DFS) and OS with hazard ratios (HRs) were calculated using random-effect or fixed-effect models. Subgroup analysis was also performed. RESULTS: A total of seven randomized clinical trials were included in the meta-analysis and involved 1,283 NSCLC patients harboring EGFR mutations. In resected EGFR-mutant NSCLC patients, adjuvant EGFR-TKIs were significantly better than chemotherapy in terms of DFS (HR: 0.41; 95%CI: 0.24-0.70, P = 0.001), without showing any benefit in OS (HR: 0.72; 95%CI: 0.37-1.41, P = 0.336). No significant difference in DFS was observed between patients with EGFR exon 19 deletion and those with L858R mutation. Resected EGFR-mutant NSCLC patients treated with osimertinib experienced improved DFS and a lower risk of brain recurrence than those treated with gefitinib or erlotinib. Adjuvant EGFR-TKIs reduced the risk of bone and lung relapse, without decreasing the risk of local recurrence and liver relapse. CONCLUSION: This meta-analysis shows that adjuvant EGFR-TKI therapy could significantly prolong DFS in patients with resected EGFR-mutant NSCLC. Treatment with osimertinib showed improved DFS with a lower risk of brain recurrence than treatment with gefitinib or erlotinib for resected disease.

Construction of a Prognostic Immune Signature for Squamous-Cell Lung Cancer to Predict Survival.

Background: Limited treatment strategies are available for squamous-cell lung cancer (SQLC) patients. Few studies have addressed whether immune-related genes (IRGs) or the tumor immune microenvironment can predict the prognosis for SQLC patients. Our study aimed to construct a signature predict prognosis for SQLC patients based on IRGs. Methods: We constructed and validated a signature from SQLC patients in The Cancer Genome Atlas (TCGA) using bioinformatics analysis. The underlying mechanisms of the signature were also explored with immune cells and mutation profiles. Results: A total of 464 eligible SQLC patients from TCGA dataset were enrolled and were randomly divided into the training cohort (n = 232) and the testing cohort (n = 232). Eight differentially expressed IRGs were identified and applied to construct the immune signature in the training cohort. The signature showed a significant difference in overall survival (OS) between low-risk and high-risk cohorts (P < 0.001), with an area under the curve of 0.76. The predictive capability was verified with the testing and total cohorts. Multivariate analysis revealed that the 8-IRG signature served as an independent prognostic factor for OS in SQLC patients. Naive B cells, resting memory CD4 T cells, follicular helper T cells, and M2 macrophages were found to significantly associate with OS. There was no statistical difference in terms of tumor mutational burden between the high-risk and low-risk cohorts. Conclusion: Our study constructed and validated an 8-IRG signature prognostic model that predicts clinical outcomes for SQLC patients. However, this signature model needs further validation with a larger number of patients.

The efficacy of PD-1/PD-L1 inhibitors in advanced squamous-cell lung cancer: a meta-analysis of 3112 patients.

Aim: We performed a meta-analysis to explore the efficacy of immunotherapy for patients with squamous non-small-cell lung cancer (NSCLC). Materials & methods: Randomized clinical trials comparing immunotherapy with chemotherapy for advanced NSCLC patients were included. Results: A total of 11 trials (3112 patients) were included. PD-1/PD-L1 inhibitors demonstrated significant superiority to chemotherapy in overall survival (OS) (hazard ratio [HR]: 0.74; p < 0.001) and progression-free survival (PFS) (HR: 0.66; p < 0.001) for squamous NSCLC. The OS and PFS benefits of PD-1/PD-L1 inhibitors for squamous NSCLC were similar in subgroup analyses of line settings, PD-L1 expression and different study methodologies. No advantage in OS was found in advanced squamous NSCLC patients treated with atezolizumab (HR: 0.87; p = 0.087). Conclusion: PD-1/PD-L1 inhibitors significantly improved OS and PFS in advanced squamous NSCLC patients when compared with chemotherapy.

Glioma coexisting with angiographically occult cerebrovascular malformation: A case report.

Angiographically occult cerebrovascular malformation (AOVM) is a type of complex cerebrovascular malformation that is not visible on digital subtraction angiography (DSA). Vascular malformation coexisting with glioma is clinically rare, and glioma coexisting with AOVM is even more rare. To the best of our knowledge, the present study is the first to report glioma coexisting with AOVM in the literature. The present study reports a rare case of glioma coexisting with AOVM in a 30-year-old male patient. Computed tomography (CT) scan revealed calcification, hemorrhage and edema in the right frontal lobe. CT angiography revealed a vascular malformation in the right frontal lobe, which was not observed on DSA. Finally, glioma coexisting with AOVM was confirmed by 2.0T magnetic resonance imaging and postoperative pathological examination. The present patient had a positive outcome and no neurological dysfunctions during the 6-month follow-up subsequent to surgery.

Treatment of a giant arteriovenous malformation associated with intracranial aneurysm rupture during pregnancy: A case report.

Arteriovenous malformations (AVMs) associated with aneurysm have rarely been reported in the literature. The present study reports the case of a 21-year-old pregnant female patient who presented with a subarachnoid hemorrhage and an intracranial hematoma located in the anterior end of the corpus callosum. Furthermore, an anterior cerebral aneurysm and an AVM were identified by digital subtraction angiography and magnetic resonance angiography. The aneurysm was clipped and the AVM was successfully removed by microsurgery. The diagnosis of AVM associated with an aneurysm was confirmed via intraoperative and postoperative pathological examinations. By performing a review of the current literature, issues and surgical considerations associated with AVM associated with aneurysm were analyzed.

Ultra-early microsurgical treatment within 24 h of SAH improves prognosis of poor-grade aneurysm combined with intracerebral hematoma.

Spontaneous subarachnoid hemorrhage (SAH) is the most common cerebrovascular disease. The conventional treatment for SAH is usually associated with high mortality. The present study aims to assess the prognosis of microsurgical treatment for patients with poor-grade aneurysm (Hunt and Hess grades IV-V) associated with intracerebral hematoma. A total of 18 consecutive patients who were diagnosed with poor-grade aneurysm accompanied with intracerebral hematoma were retrospectively recruited. All patients underwent microsurgical treatment between April 2010 and June 2013 at The 101st Hospital of Chinese People's Liberation Army (Wuxi, China). Among them, 15 cases underwent microsurgery within 24 h of SAH, and 3 cases underwent microsurgery 24 h following SAH. All 18 cases were examined by computed tomography angiography (CTA). The outcome was assessed during a follow-up time of 6-36 months. According to the Glasgow Outcome Scale, 4 patients experienced a good recovery, 6 were dissatisfied with the outcome, 4 were in vegetative state and 4 succumbed to disease. Poor outcome occurred in patients with an aneurysm diameter >10 mm, exhibited >50 ml volume of intracerebral hematoma or presented cerebral hernia prior to the surgical operation. The outcome of ultra-early surgery (within 24 h of SAH) was improved, compared with that of surgery following 24 h of SAH (P=0.005). Among 7 patients who accepted extraventricular drainage, good outcomes were achieved in 4 of them, whereas dissatisfaction and mortality occurred in 2 and 1 patients, respectively. Therefore, ultra-early microsurgery (within 24 h of SAH) combined with extraventricular drainage may improve the prognosis of patients with poor-grade aneurysm.

[Correlation analysis of efficacy of yiqi chutan recipe in treating NSCLC and P4HB expression].

OBJECTIVE: To study the predicting effect of proly 4-hydroxylase beta polypeptide (P4HB) in treating non-small cell lung cancer (NSCLC) patients by Yiqi Chutan Recipe (YCR). METHODS: Totally 46 stage III and IV NSCLC patients were treated by YCR for 4 therapeutic courses. Effect was assessed by RECIST of solid tumor. P4HB expression was detected in the lung cancer tissue by immunohistochemical assay. Factors affecting disease control rates (DCR) of YCR were analyzed by Logistic regression analysis. The correlation between P4HB expression and the effect of YCR was analyzed. RESULTS: The DCR of advanced NSCLC treated by YCR was 36.96% (17/46 cases). P4HB was high expressed in advanced lung cancer tissue (6/15 cases). Gender, initial treatment, and retreatment are independent factors for affecting DCR of treating lung cancer by YCR. CONCLUSION: P4HB might be taken as a factor for predicting the effect of YCR in treating NSCLC.

Expression of prolyl 4-hydroxylase beta-polypeptide in non-small cell lung cancer treated with Chinese medicines.

OBJECTIVES: To investigate the role of prolyl 4-hydroxylase beta polypeptide (P4HB) expressed in lung carcinoma and the intervention effect of Yiqi Chutan Formula (, YQCTF). METHODS: Lung carcinoma model was established by subcutaneously inoculating LEWIS lung carcinoma cells in C57BL/6J mice. The differential expression of P4HB protein between the YQCTF (3.0 g/kg, gavage, once daily, 21 days) group and the control group was acquired by a 2 fluorescence difference gel electrophoresis (2D-DIGE), verified by Western blotting and identified by matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF/TOF-MS). The expression of P4HB and P4HB mRNA in cultured A549 cells from cisplatin (DDP) 1.5 µg/mL group and 15% serum combined with DDP 1.5 µg/mL group were detected by cellular immunohistochemistry and reverse transcription-polymerase chain reaction, respectively. RESULTS: The proteomics research discovered that one-third of differential proteins including P4HB were decreased in the YQCTF group (P<0.01). Clinical pathology and tissue microarray studies showed that P4HB expression in lung cancer tissue was stronger than adjacent tissues and normal lung epithelial (P<0.01). In the YQCTF and DDP combined groups, the expression of P4HB and P4HB mRNA in A549 cell were decreased significantly (P<0.01). CONCLUSION: YQCTF could inhibit the LEWIS lung carcinoma's growth, decrease the expression of P4HB in LEWIS lung carcinoma and A549 cells. YQCTF might take effect through regulating P4HB in endoplasmic reticulum to inhibit the incidence and growth process of lung carcinoma.

LIN28 is involved in glioma carcinogenesis and predicts outcomes of glioblastoma multiforme patients.

LIN28, an evolutionarily conversed RNA binding protein which can bind to the terminal loops of let-7 family microRNA precursors and block their processing to maturation, is highly expressed in several subsets of tumors that carry poor prognoses, such as ovarian carcinoma, hepatocellular carcinoma, colon carcinoma and germ cell carcinoma. However, there has been no study on the expression of LIN28 in glioma tissues or their importance as a prognostic predictor of glioma patients. This study aimed to examine the expression of LIN28 in glioma and correlate the results to patient outcome. We found that LIN28 expression was significantly higher in the group of patients with a poor prognosis compared to patients with a good prognosis by gene microarray. Log-rank analysis showed patients with higher LIN28 expression level in tumor had a shorter progression-free survival and overall survival times compared to those with lower LIN28 expression level. Similar results were also obtained from the tissue microarray analysis. Univariate and multivariate analyses showed high LIN28 expression was an independent prognostic factor for a shorter progression-free survival and overall survival in GBM patients. Furthermore in vitro experiments showed that down-regulation of LIN28 in U251 and U373 cells caused cell cycle arrest in the G1 phase, delayed cell proliferation, increased apoptosis, and resulted in fewer colonies compared to controls. Summarily, our data provides a potential target for cancer therapy as an approach to overcome the poor options currently available for GBM patients.

MicroRNA-326 functions as a tumor suppressor in glioma by targeting the Nin one binding protein (NOB1).

Malignant glioma is the most common type of primary brain tumor in adults, characterized by rapid tumor growth and infiltration of tumor cells throughout the brain. Alterations in the activity of the 26S proteasome have been associated with malignant glioma cells, although the specific defects have not been identified. Recently, microRNA-326 (miR-326) was shown to play an important role in glioblastoma and breast cancer, but the underlying molecular mechanisms remain unclear. In the present study, the human Nin one binding protein (NOB1) was identified as a direct target of miR-326 and a potential oncogene in human glioma. Similar to NOB1 silencing by shRNA, overexpression of miR-326 in human glioma cell lines (A172 and U373) caused cell cycle arrest at the G1 phase, delayed cell proliferation and enhanced apoptosis. MiR-326 inhibited colony formation in soft agar and decreased growth of a xenograft tumor model, suggesting that miR-326 and NOB1 are required for tumorigenesis in vitro and in vivo. Furthermore, these processes were shown to involve the MAPK pathway. NOB1 overexpression in human glioma samples was detected by Affymetrix array analysis, and NOB1 mRNA and protein levels were shown to be increased in high-grade glioma compared to low-grade glioma and normal brain tissue. Furthermore, high levels of NOB1 were associated with unfavorable prognosis of glioma patients. Taken together, these results indicate that miR-326 and NOB1 may play an important role in the development of glioma.

HMGN5: a potential oncogene in gliomas.

Gliomas are the most common primary brain tumors in the central nervous system and a leading cause of tumor-related death. High-mobility group nucleosome binding domain 5 (HMGN5/NSBP1), which is highly expressed in breast cancer and in hormone-induced mouse uterine adenocarcinoma, acts as a potential oncogene in gliomas. In this study, the role of HMGN5 in the proliferation of human glioma cells was investigated by lentivirus-mediated RNA interference (RNAi). The decrease in HMGN5 expression in human glioma U251 and U87 cells caused cell cycle arrest in the G1 phase and a delay in cell proliferation, as well as resulting in more apoptosis and an inhibition of clonogenic growth in soft agar in U251 cells; these results suggest that HMGN5 is required for tumorigenesis in vitro. Furthermore, HMGN5 was highly expressed in both high-grade and low-grade glioma tissue samples compared with normal brain tissues. Collectively, our data suggest that HMGN5 may play a critical role in the development of gliomas.

[Effects of yiqi chutan recipe on tumor growth, survival time and expressions of PRDX-1 and PRDX-6 in Lewis lung carcinoma model mice with pi-deficiency syndrome].

OBJECTIVE: To investigate the effects of Yiqi Chutan Recipe (YCR, a Chinese herbal prescription for invigorating qi and removing phlegm) on the growth and metastasis of tumor, survival time, and the expressions of peroxiredoxin (PRDX-1 and PRDX-6) in tumor tissue of C57BL/6J mice bearing Lewis lung carcinoma. METHODS: Lewis lung carcinoma cells were transplanted to 90 C57BL/6J mice receiving preconditioning for inducing Pi-deficiency syndrome and divided into three groups treated respectively with saline, high dose YCR (3.0 g/kg) and low dose YCR (1.0 g/kg) once a day via gastric infusion. Besides, a group of 30 healthy mice simply received tumor cell transplantation was set up for controls. Ten mice selected from each group were sacrificed 21 days later, the size, weight and lung metastasis foci of tumor in mice were measured, and expressions of PRDX-1 and PRDX-6 in tumor tissue were detected using immunohistochemical method. The survival time of the remained 20 mice in each groups was observed. RESULTS: Tumor size, weight and the numbers of lung metastatic foci were (1.14 +/- 0.30) cm3, (0.83 +/- 0.26) g, (6.20 +/- 2.53) foci in the high dose YCR treated group, which were significantly lower than those in the control group [(2.83 +/- 0.35) cm3, (2.08 +/- 0.28) g, and (8.60 +/- 1.84) foci] respectively, also lower than those in the saline treated group [(2.29 +/- 0.49) cm3, (1.67 +/- 0.33) g and (8.70 +/- 2.00) foci]. The median survival time in the three groups, in above order, were 29.00 +/- 0.89 days, 22.00 +/- 0.75 days and 21.00 +/- 0.53 days; the average survival time in them 29.60 +/- 0.53 days, 22.90 +/- 0.50 days and 20.95 +/- 0.44 days; the PRDX-1 expression were 0.15 +/- 0.03, 0.52 +/- 0.07 and 0.61 +/- 0.09; and the PRDX-6 expression were 0.12 +/- 0.02, 0.43 +/- 0.06 and 0.56 +/- 0.07, all showed significant difference in comparing the indices in the high dose treated group with those in the control group and in the saline treated group (P < 0.05 or P < 0.01). The tumor growth inhibition rate was 50.30% in the high dose YCR group with life prolongation rate of 41.29%, all better than those in the low dose YCR treated group (P < 0.05). CONCLUSIONS: YCR can remarkably inhibit the growth and metastasis of Lewis lung carcinoma in mice with Pi-asthenia syndrome, prolong their survival period, and its mechanism is possibly related to the reduction of over expressed PRDX-1 and PRDX-6.

Carboxyl terminus of Hsp70-interacting protein (CHIP) contributes to human glioma oncogenesis.

Malignant glioma is the most common adult primary brain tumor, and the mechanism of its oncogenesis is poorly understood. Growing evidence has shown that E3 ubiquitin ligases can promote tumorgenesis of glioma. CHIP is an E3 ubiquitin ligase that can induce ubiquitylation and degradation of many tumor-related proteins, and it has been reported to act as an upstream regulator in breast cancer; however, its role in human gliomas has not been evaluated yet. In this study, the expression of CHIP in glioma tissues was studied using immunohistochemistry. CHIP expression in glioma cells was studied by real-time RT-PCR, western blot and double immunofluorescence staining. The role of CHIP in glioma oncogenesis was investigated by lentivirus-mediated RNA interference (RNAi) and overexpression in vitro and in vivo. We showed CHIP expression in glioma samples was related to tumor grades, with stronger staining in high-grade gliomas than in low-grade gliomas. Knocking down of CHIP suppressed proliferation, colony formation of U251 and U87 glioma cells, while overexpression of CHIP resulted in enhanced proliferation and colony formation in vitro. In a nude mouse xenograft model, intratumoral injection of CHIP RNAi lentivirus significantly delayed tumor growth. In contrast, overexpression of CHIP resulted in enhanced tumor growth in vivo. After CHIP RNAi, both survivin mRNA and protein were decreased, while CHIP overexpression induced increased mRNA and protein levels of survivin. This is the first study demonstrating CHIP contributes to oncogenesis of glioma.

[Integrative medical strategy for treatment of senile lung cancer].

Senile lung cancer has its own characteristics, thus its treatment is also particular. Viewing from the therapeutic angle of integrative medicine, the current status of research and application of various clinical treatment strategies and measures for senile lung cancer were preliminarily reviewed in this paper in items of surgical operation, chemotherapy, radiotherapy, molecular target drugs therapy and Chinese medical therapy.