Biomedical subjects

Han Liang

Publications and source records attributed to Han Liang.

At least 19 recordsLinked to original sources

PubMed2026

Intramuscular patient-derived xenografts achieve high engraftment rates in gastric cancer: implications for pharmacodynamic testing and genomic biomarker discovery.

BACKGROUND: Gastric cancer (GC) exhibits marked inter-patient heterogeneity, limiting empirical chemotherapy efficacy. Patient-derived xenograft (PDX) models preserve the molecular features of parental tumors and can serve as pharmacodynamic surrogates, but conventional subcutaneous PDX suffers from low engraftment rates. This study evaluated an optimized intramuscular PDX platform for individualized drug testing in GC and applied whole exome sequencing (WES) for biomarker identification (Clinical trial registry: ChiCTR-OOC-17012731). MATERIALS AND METHODS: Ninety-eight treatment-naive GC patients were enrolled between April 2018 and December 2020. Fresh tumor tissues were engrafted into NCG mice by intramuscular transplantation. Drug efficacy was evaluated using tumor cell necrosis rate and Ki-67 expression. WES was performed on 32 engrafted tumorgrafts to characterize driver mutations in fast- and slow-growing subgroups. RESULTS: An engraftment rate of 71.7% (43/60) was achieved, substantially exceeding rates reported in prior studies. Clinical characteristics were independent of engraftment success and outgrowth time (all p > 0.05). Fast- and slow-growing tumorgrafts diverged in frequently altered genes: KMT2C, APOB, CDK12 and MSH2 predominated in fast-growing grafts, whereas TP53, CHD3 and TET2 were enriched in slow-growing grafts. Slow-growing tumorgrafts correlated with longer progression-free survival (p = 0.02). PDX-guided treatment was associated with improved prognosis. CONCLUSIONS: Intramuscular transplantation into NCG mice yields high engraftment rates for GC PDX. PDX-guided chemotherapy selection is associated with favorable outcomes. Driver mutation divergence between fast- and slow-growing tumorgrafts provides candidate prognostic biomarkers.

Animals↗

PubMed2024

Induced degradation of lineage-specific oncoproteins drives the therapeutic vulnerability of small cell lung cancer to PARP inhibitors.

Although BRCA1/2 mutations are not commonly found in small cell lung cancer (SCLC), a substantial fraction of SCLC shows clinically relevant response to PARP inhibitors (PARPis). However, the underlying mechanism(s) of PARPi sensitivity in SCLC is poorly understood. We performed quantitative proteomic analyses and identified proteomic changes that signify PARPi responses in SCLC cells. We found that the vulnerability of SCLC to PARPi could be explained by the degradation of lineage-specific oncoproteins (e.g., ASCL1). PARPi-induced activation of the E3 ligase HUWE1 mediated the ubiquitin-proteasome system (UPS)-dependent ASCL1 degradation. Although PARPi induced a general DNA damage response in SCLC cells, this signal generated a cell-specific response in ASCL1 degradation, leading to the identification of HUWE1 expression as a predictive biomarker for PARPi. Combining PARPi with agents targeting these pathways markedly improved therapeutic response in SCLC. The degradation of lineage-specific oncoproteins therefore represents a previously unidentified mechanism for PARPi efficacy in SCLC.

Humans↗

PubMed2006

SWAKK: a web server for detecting positive selection in proteins using a sliding window substitution rate analysis.

We present a bioinformatic web server (SWAKK) for detecting amino acid sites or regions of a protein under positive selection. It estimates the ratio of non-synonymous to synonymous substitution rates (K(A)/K(S)) between a pair of protein-coding DNA sequences, by sliding a 3D window, or sphere, across one reference structure. The program displays the results on the 3D protein structure. In addition, for comparison or when a reference structure is unavailable, the server can also perform a sliding window analysis on the primary sequence. The SWAKK web server is available at http://oxytricha.princeton.edu/SWAKK/.

Amino Acid Substitution↗

PubMed2006

Prognostic factors of young patients with colon cancer after surgery.

AIM: To investigate the prognostic factors of 96 young patients with colon cancer within a cancer center by univariate and multivariate analysis. METHODS: A total of 723 patients with colon cancer were treated surgically during a period of 10 years. Ninety six of them were 40 years old or younger.R0, R1 and R2 operations were performed in 69 (71.9%), 4(4.1%) and 23 patients(24%), respectively. Left hemicolectomy was performed in 43 patients, right hemicolectomy in 37 patients, transverse colon resection in 9 patients and low anterior resection in 7 patients. Cox multivariate regression analysis was performed to identify predictors of survival. RESULTS: The operation mortality was 0%, 54 patients died within 111 mo after operation due to occurrence or metastases of the tumor. Liver,lung and bone metastases occurred in 3, 1 and 5 patients, respectively. The mean survival time for all patients was 77.9 +/- 5.01 mo and the overall 3-,5- and 10- year survival rates were 66.68%, 58.14% and 46.54%, respectively. In the univariate survival analysis,patient age,type of operation, radical resection, blood transfusion, histological type, diameter of tumor,depth of tumor invasion, lymphatic invasion, distant metastases, liver metastases and TNM stage were found to be predictors of survival in young patients with colon cancer. In the Cox-regression analysis,blood transfusion and lymphatic invasion were determined as independent prognostic factors of survival. CONCLUSIONS: Age, type of operation, radical resection, blood transfusion, histological type, diameter of tumor,depth of tumor invasion, lymphatic invasion, distant metastasis and TNM stage are the predictors of survival in young patients with colon cancer after surgery.

Adult↗

PubMed2005

A genome-wide study of dual coding regions in human alternatively spliced genes.

Alternative splicing is a major mechanism for gene product regulation in many multicellular organisms. By using different exon combinations, some coding regions can encode amino acids in multiple reading frames in different transcripts. Here we performed a systematic search through a set of high-quality human transcripts and show that approximately 7% of alternatively spliced genes contain dual (multiple) coding regions. By using a conservative criterion, we found that in these regions most secondary reading frames evolved recently in mammals, and a significant proportion of them may be specific to primates. Based on the presence of in-frame stop codons in orthologous sequences in other animals, we further classified ancestral and derived reading frames in these regions. Our results indicated that ancestral reading frames are usually under stronger selection than are derived reading frames. Ancestral reading frames mainly influence the coding properties of these dual coding regions. Compared with coding regions of the whole genome, ancestral reading frames largely maintain similar nucleotide composition at each codon position and amino acid usage, while derived reading frames are significantly different. Our results also indicated that prior to acquisition of a new reading frame, the suppression of in-frame stop codons in the ancestral state is mainly achieved by one-step transition substitutions at the first or second codon position. Finally, the selective forces imposed on these dual coding regions will also be discussed.

Alternative Splicing↗

PubMed2005

The evolutionary origin of a complex scrambled gene.

Some species of ciliates undergo massive DNA elimination and genome rearrangement to construct gene-sized "chromosomes" in their somatic nucleus. An example is the extensively scrambled DNA polymerase alpha gene that is broken into 48 pieces and distributed over two unlinked loci in Stylonychia. To understand the emergence of this complex phenomenon during evolution, we examined DNA polymerase alpha genes in several earlier diverging species, representing evolutionary intermediates. Mapping these data onto an evolutionary tree suggests that this gene became extensively fragmented and scrambled over evolutionary time through a series of steps, each leading to greater complexity. Our results also suggest a possible mechanism for intron loss by deletion of intron sequences as DNA during development of the somatic nucleus.

Animals↗

PubMed2005

Conservation of tandem stop codons in yeasts.

BACKGROUND: It has been long thought that the stop codon in a gene is followed by another stop codon that acts as a backup if the real one is read through by a near-cognate tRNA. The existence of such 'tandem stop codons', however, remains elusive. RESULTS: Here we show that a statistical excess of stop codons has evolved at the third codon downstream of the real stop codon UAA in yeasts. Comparative analysis indicates that stop codons at this location are considerably more conserved than sense codons, suggesting that these tandem stop codons are maintained by selection. We evaluated the influence of expression levels of genes and other biological factors on the distribution of tandem stop codons. Our results suggest that expression level is an important factor influencing the presence of tandem stop codons. CONCLUSIONS: Our study demonstrates the existence of tandem stop codons, which represent one of many meaningful genomic features that are driven by relatively weak selective forces.

Base Sequence↗

PubMed2005

Decoding the decoding region: analysis of eukaryotic release factor (eRF1) stop codon-binding residues.

Peptide synthesis in eukaryotes terminates when eukaryotic release factor 1 (eRF1) binds to an mRNA stop codon and occupies the ribosomal A site. Domain 1 of the eRF1 protein has been implicated in stop codon recognition in a number of experimental studies. In order to further pinpoint the residues of this protein involved in stop codon recognition, we sequenced and compared eRF1 genes from a variety of ciliated protozoan species. We then performed a series of computational analyses to evaluate the conservation, accessibility, and structural environment of each amino acid located in domain 1. With this new dataset and methodology, we were able to identify eight specific amino acid sites important for stop codon recognition and also to propose a set of cooperative paired substitutions that may underlie stop codon reassignment. Our results are more consistent with current experimental data than previously described models.

Amino Acid Sequence↗

PubMed2005

Are stop codons recognized by base triplets in the large ribosomal RNA subunit?

The precise mechanism of stop codon recognition in translation termination is still unclear. A previously published study by Ivanov and colleagues proposed a new model for stop codon recognition in which 3-nucleotide Ter-anticodons within the loops of hairpin helices 69 (domain IV) and 89 (domain V) in large ribosomal subunit (LSU) rRNA recognize stop codons to terminate protein translation in eubacteria and certain organelles. We evaluated this model by extensive bioinformatic analysis of stop codons and their putative corresponding Ter-anticodons across a much wider range of species, and found many cases for which it cannot explain the stop codon usage without requiring the involvement of one or more of the eight possible noncomplementary base pairs. Involvement of such base pairs may not be structurally or thermodynamically damaging to the model. However, if, according to the model, Ter-anticodon interaction with stop codons occurs within the ribosomal A-site, the structural stringency which that site imposes on sense codon.tRNA anticodon interaction should also extend to stop codon.Ter-anticodon interactions. Moreover, with Ter-tRNA in place of an aminoacyl-tRNA, for each of the various Ter-anticodons there is a sense codon that can interact with it preferentially by complementary and wobble base-pairing. Both these considerations considerably weaken the arguments put forth previously.

Base Pairing↗

PubMed2005

Molecular mimicry: quantitative methods to study structural similarity between protein and RNA.

With rapidly increasing availability of three-dimensional structures, one major challenge for the post-genome era is to infer the functions of biological molecules based on their structural similarity. While quantitative studies of structural similarity between the same type of biological molecules (e.g., protein vs. protein) have been carried out intensively, the comparable study of structural similarity between different types of biological molecules (e.g., protein vs. RNA) remains unexplored. Here we have developed a new bioinformatics approach to quantitatively study the structural similarity between two different types of biopolymers--proteins and RNA--based on the spatial distribution of conserved elements. We applied it to two previously proposed tRNA-protein mimicry pairs whose functional relatedness between two molecules has been recently determined experimentally. Our method detected the biologically meaningful signals, which are consistent with experimental evidence.

Conserved Sequence↗

PubMed2005

[Pharmacokinetic study of intraperitoneal chemotherapy with mitomycin C bound to activated carbon particles].

OBJECTIVE: To analyze the pharmacokinetics of intraperitoneal chemotherapy with mitomycin C (MMC) bound to activated carbon particles. METHODS: A nude mouse model with transplanted human gastric cancer was established. The mice were given MMC by i.v. or intraperitoneal (i.p.) injections, or given i.p. MMC bound to activated carbon particles (MMC-CH). Pharmacokinetic assays were carried out at different time points (0.5, 1, 2, 3, 6, 12 and 24 h) in 7 mice per each time point, to compare the MMC concentrations revealed by the above mentioned methods. RESULTS: The MMC concentration in peritoneal exudate, omentum and lymph nodes of MMC-CH group was significantly higher than that of MMC solution i.p. group and MMC i.v. group (P < 0.001). On the other hand, the MMC level in serum was significantly lower than that in two control groups (P < 0.001). High MMC level was maintained longer than 24 hours in the MMC-CH group. Intraperitoneal chemotherapy with MMC solution resulted in a low MMC concentration in serum, peritoneal exudates and lymph nodes, and only a transient high level of MMC in the omentum. After i.v. administration, a significantly higher level of MMC concentration occurred in the serum, but only a shortly increased concentration of MMC in the omentum, and lower concentration in peritoneal exudate and lymph nodes as compared with those in the other two groups (P < 0.001). CONCLUSION: High concentration of MMC in peritoneal exudate, omentum and lymph nodes maintained longer than 24 hours and a significantly lower MMC serum concentration can be achieved by administration of intraperitoneal administration of MMC bound to activated carbon particles.

Animals↗

PubMed2005

[Determinants of long-term survival in 38 patients with carcinoma of ampulla of Vater treated by local resection].

OBJECTIVE: To investigate determinants of long-term survival for carcinoma of ampulla of Vater treated by local resection. METHODS: The clinical and pathological data of 38 such patients treated by local resection from 1983 to 2003 were retrospectively analyzed. According to UICC staging system, there were T1 30, T2 7 and T3 1. Lymph nodes were involved in 4 during operation which was present in primary lesions larger than 2 cm across. All patients were treated by local resection. At first, external palpation was carried out to ascertain accessibility. Then with the duodenum opened, direct exploration was carried out. On deciding for resection, the common bile duct was probe explored which guided the circumferential ring resection 1 cm, away from the tumor, including all layers of duodenum, ampula and partial bile and terminal pancreatic ducts and the posterial wall of duodenum was completed in steps. Meticulous care was taken not to suture the pancreatic duct and endotheliation was ensured at the mouth of common bile duct and duodenum. The basal tissue was frozen sectioned to ensure negative stumps. The gall bladder of 6 patients was also resected. SPSS 10.0 software was used in data processing, log-rank test used in univariate analysis and Cox equation for multivariate analysis and Kaplan-Meirer method for the survival rates. RESULTS: Thirty-eight patients received local resection giving an operative mortality of 0% and morbidity of 13.2%. The 1-, 5- and 10-year survival rate was 83.5%, 51.4%, and 38.9%, respectively, with a median survival of 3.35 years. Up to now, 13 patients have survived for more than five years and 2 patients beyond ten years. The tumour size, tumour grading, lymph node status and UICC stage were significant prognostic factors in univariate analysis. However, only lymph node status was a statistically independent predictor of prognosis in multivariate analysis. CONCLUSION: Local excision is safe giving low morbidity and good survival in carefully selected cases. Preferably it is indicated only in high risk patients with a pT1 and well differentiated ampullary cancer smaller than 1 cm in diameter.

Adenocarcinoma↗

PubMed2004

[Change in E-cadherin, alpha-, beta- and gamma-catenin expression after hyperthermia of a human colon carcinoma cell line in vitro].

OBJECTIVE: To investigate changes in E-cadherin, alpha-, beta-, and gamma-catenin expression after hyperthermia of a human colon cancer cell line in vitro. METHODS: E-cadherin and alpha-, beta-, and gamma-catenin expression on a human colon carcinoma cell line HT29 at 7 successive times after hyperthermia at 43 degrees C for 60 min were investigated in vitro by RT-PCR and immunochemistry. RESULTS: In vitro studies revealed that E-cadherin expression had increased significantly on HT29 cells at 24 hours after hyperthermia at 43 degrees C for 60 min. In a time-course analysis, the expression of E-cadherin had major increase at 24 to 72 hours after hyperthermia compared with an unheated control cell. gamma-catenin expression had increased significantly at 8 to 72 hours. After hyperthermia at 43 degrees C for 60 min, beta-catenin expression had decreased gradually at 4 hours to 72 hours. alpha-catenin expression kept unchanged after hyperthermia. CONCLUSION: Hyperthermia at 43C for 60 min upregulated E-cadherin and gamma-catenin expressions but downregulated beta-catenin expression on colon carcinoma cells in vitro. alpha-catenin expression was not regulated by hyperthermia.

Adenocarcinoma↗

PubMed2004

Management of nonfunctioning islet cell tumors.

AIM: To more clearly define the clinical and pathological characteristics and appropriate diagnosis and treatment of nonfunctioning (NFICTs) islet cell tumors, and to review our institutional experience over the last 30 years. METHODS: The records of 43 patients confirmed to have nonfunctioning islet cell tumors of pancreas were retrospectively reviewed. Survival was estimated by the Kaplan-Meier methods and potential risk factors for survival were compared with the log-rank tests. RESULTS: The mean age was 31.63 years (range, 8 to 67 years). There were 7 men and 36 women. Twenty-eight patients had a confirmed diagnosis of nonfunctioning islet cell carcinoma (NFICC) and benign islet cell tumors were found in 15 patients. The most common symptoms in patients with NFICTs were abdominal pain (55.8%), nausea and/or vomiting (32.6%), fatigue (25.6%) and abdominal mass (23.3%). Preoperative ultrasonic and computed tomography localized the tumors in all patients. Forty-three NFICTs were distributed throughout the pancreas, with 21 located to the right of the superior mesenteric vessels, 10 in the body of the pancreas, 6 in the tail of the pancreas, and multiple tumors were found in one patient. Thirty-nine of 43 patients (91%) underwent surgical resection. Surgical treatment was curative in 30 patients (70%) and palliative in 9(21%). The resectability and curative resection rate in patients with NFICC of pancreas were 89% and 61%, respectively. The overall cumulative 5- and 10-year survival rates for patients with NFICC were 58.05% and 29.03%, respectively. Radical operation and diameter of cancer small than 10 cm were positive prognostic factors in females younger than 30 years old. Multivariate Cox regression analysis indicated that radical operation was the only independent prognostic factor, P=0.007. CONCLUSION: Nonfunctioning islet cell tumors of pancreas are found mainly in young women. The long-term results for patients undergone surgery, especially curative resection are good.

Adolescent↗

PubMed2004

[Analysis of prognostic factors of rectal cancer in the elderly].

BACKGROUND & OBJECTIVE: The relation between patient age and outcomes from colorectal cancer surgery is complex. It is generally believed that age should not be a determinant in consideration of prognosis for colorectal cancer patient. But there were few studies on the prognostic factors of rectal cancer in the elderly. We therefore performed a retrospective analysis of clinicopathologic characteristics of rectal cancer in 343 old patients with rectal cancer by univariate and multivariate analysis. METHODS: A total of 343 patients (older than 60 years) with rectal cancer were treated surgically during a period of 10 years. R0, R1, and R2 operations were carried out in 261 patients (76.09%), 29 patients (8.45%), and 53 patients (15.45%), respectively. Low anterior resection was performed in 116 patients; 169 patients underwent Miles operation; 58 patients underwent the other operations. RESULTS: The operation mortality was 0.87%; 149 patients died of occurrence or metastases of the tumor within 108 months postoperatively. Liver, lung, and bone metastases were occurred in 17, 18, and 1 patients, respectively. The mean survival time for all patients was 72.12+/-2.60 months and the overall 3-, 5-, and 10-year survival rates were 69.62%, 55.73%, and 34.23%, respectively. Univariate analysis showed that the predictors of survival were type of operations, radical resection, histological type, diameter of the tumors, depth of tumor invasion, lymphatic invasion, distance metastases, liver and lung metastases. Multivariate analysis showed that only radical resection, lymphatic invasion, liver and lung metastases were independent factors. CONCLUSION: The follow prognostic factors can influence the survival of rectal cancer in the elderly: type of operations, nature of operation, histological type, diameter of the tumors, depth of tumor invasion, lymphatic invasion, distance metastases, liver and lung metastases. The independent factors were nature of operation, lymphatic invasion, liver and lung metastases.

Aged↗

PubMed2004

[Malignant fibrous histiocytoma of the retroperitoneum: an analysis of 31 cases].

OBJECTIVE: To investigate the diagnosis and treatment of malignant fibrous histiocytoma of the retroperitoneum (MFHR). METHODS: The clinicopathological features, treatment and prognosis of 31 patients with MFHR were retrospectively analyzed. RESULTS: The mean age of the patients was 52.7 +/- 14.1 years. Male:Female = 22:9. The primary symptoms were abdominal mass and pain. The average diameter of tumor was 15 cm. The histopathologic types of the tumor were inflammatory, storiform-pleomorphic, myxoid and giant cell in 16, 10, 4 and 1 cases. The overall survival rate of 1-, 3- and 5-year was 61.3% +/- 9.8%, 31.6% +/- 11.3% and 21.1% +/- 11.4% with a median survival time of 17.0 +/- 6.3 months. Complete resection of the tumor was the major prognostic factor. Postoperative radiotherapy of 20 - 45 Gy was able to prolong the median survival from 12.1 +/- 11.6 months of surgery alone to 26.4 +/- 22.0 months of surgery plus postoperative radiotherapy though without statistical significance (P = 0.051). Postoperative CHOP chemotherapy was not shown to be beneficial. CONCLUSION: Chemotherapy remains the important method of cure. The survival in patients with MFHR might be improved by complete resection combined with chemotherapy or/and radiotherapy.

Adult↗

PubMed2004

[Multivariate Cox analysis on prognostic factors after surgery for rectal carcinoma].

OBJECTIVE: To analyze a large cohort of patients with rectal cancer within a cancer center to determine the prognostic factors by univariate and multivariate analyses. METHODS: A total of 952 patients with rectal cancer were treated surgically during a period of 10 years. R0, R1 and R2 operations were carried out in 741 patients (77.8%), 75 patients (7.9%) and 136 patients (14.3%), respectively. There were more Miles operation (53.5%) than lower abdominal resection (LAR, 33.7%). RESULTS: The operation mortality was 0.3%, 418 patients were dead within 108 months postoperatively due to recurrence or metastases to liver, lung and bone in 53, 39 and 12 patients. The overall mean survival time for all patients was 73.52 +/- 1.70 months and the overall 3-, 5-and 10-year survival rates were 67.6%, 55.4% and 38.2%. The overall 3-, 5- and 10-year survival rates for patients treated by radical operation were 81.4%, 70.3%, 48.8%, respectively. Kaplan-Meier estimate showed that patient gender, age, radicality of resection, histological type, liver and pulmonary metastasis and TNM stage were the predictors of survival. Multivariate analysis showed statistically significant correlation with radicality of operation, histological type, depth of tumor invasion, lymphatic invasion, TNM stage, liver and pulmonary metastasis. CONCLUSION: For survival, statistically significant differences among prognostic factors in relation to radicality of resection, lymphatic invasion, TNM stage, depth of tumor invasion, histological type, liver and pulmonary metastasis are found.

Adenocarcinoma↗

PubMed2003

[Prospective randomized trial of prophylaxis of postoperative peritoneal carcinomatosis of advanced gastric cancer: intraperitoneal chemotherapy with mitomycin C bound to activated carbon particles].

OBJECTIVE: To evaluate the beneficial effect of intraperitoneally applied mitomycin bound to activated carbon particles (MMC-CH) in the prevention and treatment of intraabdominal recurrence after curative surgery for gastric cancer. METHODS: One hundred and twenty-four patients with radically resected gastric cancer infiltrating the serosal surface were randomly divided into group receiving 50 mg mitomycin bound to a solution of 375 mg carbon adsorbent intraperitoneally before closure of the abdominal wound (n = 62) and a control group (n = 62). The patients with MMC-CH and the control group were received systemic chemotherapy 3 months or 3 weeks after operation respectively. The postoperative recurrence-free survival was evaluated to analyze the benefits of this treatment. RESULTS: After observation for 8 months (range, 2 - 65). The 3-, 5-year postoperative recurrence-free survival rates were significantly higher in the MMC-CH group (70.16%, 44.51%) than in the control group (27.09%, 14.45%), P < 0.01. CONCLUSION: Adjuvant intraperitoneal chemotherapy of gastric cancer by mitomycin bound to activated carbon particles is effected by an increased postoperative recurrence-free survival rate.

Antibiotics, Antineoplastic↗