Oncofetal protein IGF2BPs in human cancer: functions, mechanisms and therapeutic potential.

N6-methyladenosine (m6A) is the most prevalent and well-characterized internal chemical modification in eukaryotic RNA, influencing gene expression and phenotypic changes by controlling RNA fate. Insulin-like growth factor-2 mRNA-binding proteins (IGF2BPs) preferentially function as m6A effector proteins, promoting stability and translation of m6A-modified RNAs. IGF2BPs, particularly IGF2BP1 and IGF2BP3, are widely recognized as oncofetal proteins predominantly expressed in cancer rather than normal tissues, playing a critical role in tumor initiation and progression. Consequently, IGF2BPs hold potential for clinical applications and serve as a good choice for targeted treatment strategies. In this review, we discuss the functions and mechanisms of IGF2BPs as m6A readers and explore the therapeutic potential of targeting IGF2BPs in human cancer.

Thoracolaparoscopic radical esophagectomy for esophageal cancer based on the mesoesophageal theory.

To explore the feasibility of mesangium or membrane anatomy theory in thoracolaparoscopic radical esophagectomy for esophageal cancer, 98 patients with esophageal cancer were enrolled including 45 patients in the mesoesophageal esophagectomy group and 53 patients in the non-mesoesophageal esophagectomy group. Thoracolaparoscopic radical esophagecotmy was technically successful in all patients. Compared the non-mesoesophageal group, the mesoesophageal group had significantly (P < 0.05) shorter surgical duration (211.9 ± 42.0 min vs. 282.0 ± 44.5 min), less blood loss during the procedure (68.9 ± 45.9 ml vs. 167.0 ± 91.4 ml), more harvested lymph nodes (25.9 ± 6.3 vs. 21.8 ± 7.3), shorter hospital stay after surgery (10.5 ± 2.5 d vs. 12.5 ± 4.2 d), shorter fasting time or quicker postoperative feeding time (7.3 ± 1.2 d vs. 9.5 ± 3.9 d), and quicker removal of the thoracic drainage tube after surgery (7.7 ± 2.0 d vs. 9.2 ± 4.1 d). The overall incidence of postoperative complications was 46.7% (21/45) in the mesoesophageal group, which was significantly (P = 0.02) fewer than that (69.8% or 37/53) of the non-mesoesophageal group (P = 0.020). During follow-up 20.6 ± 4.3 or 20.8 ± 3.4 months after esophagectomy, liver metastasis occurred in 1 case and lung metastasis in 1 in the mesoesophageal group, whereas liver metastasis occurred in 2 cases, mediastinal metastasis in 2, and anastomotic recurrence in 1 in the non-mesoesophageal group. The mesoesophageal group had significantly better physical function (81.9 ± 7.3 vs. 78.3 ± 7.6), social function (65.1 ± 7.1 vs. 56.2 ± 18.2), global health status (65.3 ± 10.1 vs. 58.7 ± 12.4), and pain improvement (29.5 ± 9.5 vs. 35.6 ± 10.6). The overall survival rate was 82.2% (37/45) in the mesoesophageal group and 71.7% (38/53) in the non-mesoesophageal group (P = 0.26). The disease-free survival rate was 77.8% (35/45) for the mesoesophageal group and 62.3% (33/53) for the non-mesoesophageal group (P = 0.13). In conclusion:, the mesangium or membrane anatomy theory can be used safely and effectively to guide thoracolaparoscopic radical esophagectomy for esophageal cancer, with advantages of shorter surgical time, less bleeding, more lymph node harvest, fewer complications, and faster postoperative recovery.

Effects of proximal gastrectomy with narrow gastric tube anastomosis compared with total gastrectomy with Roux-en-Y anastomosis on upper gastric cancer.

OBJECTIVE: To investigate the clinical efficacy of proximal gastrectomy with narrow gastric tube anastomosis (PG-NGT) and total gastrectomy with Roux-en-Y anastomosis (TG-RY) for upper gastric cancer. MATERIALS AND METHODS: One hundred sixty-three upper gastric cancer patients were enrolled into the PG-NGT group and TG-RY group. The propensity score matching method was used to conduct a one-to-one match between the two groups with 38 patients in each group. RESULTS: Compared with the TG-RY group, the PG-NGT group had significantly (P < 0.05) shorter operation time, shorter hospital stay, and less intraoperative blood loss. The TG-RY group had significantly (P = 0.009) more lymph nodes dissected and greater (P = 0.014) total cost than the PG-NGT group, but no significant difference existed in the surgical cost between the two groups (P = 0.214). There was no significant (P > 0.05) difference in the incidence of anastomotic stenosis (10.5% vs. 13.1%) or the reflux esophagitis rate (8.6% vs. 9.1%) in the PG-NGT group and the TG-RY group. One year after surgery, the weight and hemoglobin and albumin levels in the PG-NGT group were significantly (P < 0.05) higher than those in the TG-RY group. CONCLUSIONS: PG-NGT may be better than TG-RY in improving patient weight loss and hemoglobin and albumin levels, without increasing the rate of anastomotic stenosis and reflux symptoms.

Laparoscopic total colectomy with ileorectal anastomosis and subtotal colectomy with antiperistaltic cecorectal anastomosis for slow transit constipation.

To investigate the clinical efficacy of laparoscopic total colectomy with ileorectal anastomosis (TC-IRA) and laparoscopic subtotal colectomy with antiperistaltic cecorectal anastomosis (SC-ACRA) on adults with slow transit constipation (STC). One hundred and three patients with STC were assigned to the TC-IRA group (n = 53) and the SC-ACRA group (n = 50). The clinical data were analyzed. The surgery was successful in all patients (100%). Significantly (P = 0.03) more patients took anti-laxatives during hospitalization in the TC-IRA than the SC-ACRA group (39.62% vs. 20.00%). Abdominal pain and distension was present in 33.96% and 32.00% patients in the TC-IRA and SC-ACRA group, respectively, which decreased insignificantly (P > 0.05) to 18.87% and 18.00% 24 months after surgery, respectively. The postoperative Wexner and gastrointestinal quality of life (GIQLI) scores were not significantly different (P > 0.05) at all times after surgery in both groups. The defecation frequency decreased in both groups, and the average defecation frequency was significantly (P < 0.05) higher in the TC-IRA than the SC-ACRA group (3.91 ± 1.23 vs. 3.14 ± 1.15 times/day) at 3 months. Three months after surgery, significantly (P < 0.05) fewer patients were satisfied with defecation frequency in the TC-IRA than the SC-ACRA group (29 vs. 37 patients), whereas the number of patients who were willing to choose the same procedure again was not significantly (P > 0.05) different between the two groups. The WIS score of patients was significantly (P = 0.035) higher in the TC-IRA than the SC-ACRA group (6 vs. 5) 3 months later. TC-IRA and SC-ACRA are both safe and effective for adult slow transit constipation, and can significantly improve the quality of life of patients. Even though SC-ACRA has better early defecation frequency, postoperative antidiarrheal application and satisfaction, the long-term follow-up effects are similar.

Thoracolaparoscopic radical resection of esophagogastric junction cancers with a NOSE-like approach to extract large specimens.

To investigate the efficacy and safety of combined thoracoscopic and laparoscopic radical resection of esophagogastric junction cancers using a natural orifice specimen extraction-like approach for extraction of large surgical specimens. Patients who had esophagogastric junction cancers treated with thoracolaparoscopic resection using the natural orifice specimen extraction-like approach for specimen extraction were retrospectively enrolled. A 5-cm transverse incision on the abdominal wall at the middle of the superior pubic symphysis was made for surgical specimen extraction. The clinical, surgical, complications, and follow-up data were analyzed. A total of 162 patients were enrolled, and the surgery was successful in all patients (100%). The total surgical duration ranged 165 to 270 minutes, with blood loss 20 to 150 mL, hospital stay 8 to 22 days, first flatus time 2 to 7 days, extubation time of drainage tubes 1 to 26 days, first oral feeding time 5 to 10 days, number of lymph nodes resected 15 to 39, postoperative ambulation time 1 to 2 days, and postoperative residual rate of cancerous cells at the surgical margins 0. Postoperative complications occurred in 14 (8.6%), including anastomotic leakage in 4 (2.5%), anastomotic stenosis in 3 (1.9%), hydrothorax in 4 (2.5%), and incision infection in 3 (1.9%). At follow-up (mean 12 months), all patients were alive, and the transverse incision was a linear scar concealed in the suprapubic pubic hair area. The combined laparoscopic and thoracoscopic surgery for radical resection of carcinomas at the esophagogastric junction is safe and effective, and a transverse incision at the suprapubic symphysis for specimen extraction results in improved minimal invasiveness and cosmesis.

Thoracolaparoscopic esophagectomy for esophageal cancer with a cervical incision to extract specimen.

BACKGROUND: Surgical treatment is the most important and effective therapy for resectable esophageal cancer. Minimally invasive esophagectomy (MIE) can reduce surgical trauma. A neck incision can be performed for extraction of surgical specimen. This study was performed to investigate the safety and feasibility of neck incision to extract surgical specimen in thoracolaparoscopic esophagectomy for esophageal cancer. MATERIALS AND METHODS: Thirty-four patients who experienced thoracolaparoscopic esophagectomy for esophageal cancer and a neck incision for extraction of surgical specimen were enrolled. The clinical, surgical and follow-up data were analyzed. RESULTS: The procedure was successful in all patients (100%), with a neck incision to extract the surgical specimen. The median surgical time was 309 min, and the median blood loss was 186 ml, with the mean length of hospital stay of 11.5 days. Pulmonary complications occurred in 8 patients (23.5%). Anastomotic leakage occurred in 5 patients (14.7%), with one patient being treated conservatively to recover and four (11.8%) who received interventional drainage. One patient with interventional drainage died of severe infection, resulting in a 30-day surgical mortality of 2.9% (n = 1). Gastrointestinal complications happened in 5 patients (14.7%), including ileus in three patients and anastomotic stenosis in two patients. Follow-up was performed at a median time of 20 months (interquartile range, 14-32 months), with no death during this period. No recurrence was found in the first 12 months after radical resection. CONCLUSION: The cervical incision to extract surgical specimen is safe and feasible with improved cosmetic effect in thoracolaparoscopic esophagectomy for esophageal cancer.

Comprehensive transcriptomic profiling and mutational landscape of primary gastric linitis plastica.

BACKGROUND: Primary gastric linitis plastica (GLP) is a distinct phenotype of gastric cancer with poor survival. Comprehensive molecular profiles and putative therapeutic targets of GLP remain undetermined. METHODS: We subjected 10 tumor-normal tissue pairs to whole exome sequencing (WES) and whole transcriptome sequencing (WTS). 10 tumor samples were all GLP which involves 100% of the gastric wall macroscopically. TCGA data were compared to generate the top mutated genes and the overexpressed genes in GLP. RESULTS: Our results reveal that GLP has distinctive genomic and transcriptomic features, dysfunction in the Hippo pathway is likely to be a key step during GLP development. 6 genes were identified as significantly highly mutated genes in GLP, including AOX1, ANKRD36C, CPXM1, PTPN14, RPAP1, and DCDC1). MUC6, as a previously identified gastric cancer driver gene, has a high mutation rate (20%) in GLP. 20% of patients in our GLP cohort had CDH1 mutations, while none had RHOA mutations. GLP exhibits high immunodeficiency and low AMPK pathway activity. Our WTS results showed that 3 PI3K-AKT pathway-related genes (PIK3R2, AKT3, and IGF1) were significantly up-regulated in GLP. Two genes were identified using immunohistochemistry (IHC), IGF2BP3 and MUC16, which specifically expressed in diffuse-type-related gastric cancer cell lines, and its knockdown inhibits PI3K-AKT pathway activity. CONCLUSIONS: We provide the first integrative genomic and transcriptomic profiles of GLP, which may facilitate its diagnosis, prognosis, and treatment.

Thoracolaparoscopic esophagectomy for esophageal cancer with a cervical or abdominal incision to extract specimen.

Surgery is the only curative approach for resectable esophageal cancer. This retrospective study was to investigate the immediate effect and operative complications of conventional and modified thoracolaparoscopic esophagectomy with a cervical or abdominal incision to extract specimen for the treatment of patients with esophageal cancer. Eighty-one patients were enrolled, among which 55 patients underwent conventional McKeown thoracolaparoscopic esophagectomy (conventional MTE) and 26 patients underwent modified MTE with a cerivical incision (modified MTE). The clinical, surgical, and postoperative data were analyzed. No significant (P > .05) difference was detected in the clinical data between two groups. The surgical procedure was successful in all patients (100%). The surgical time was significantly (P = .018) shorter in the conventional MTE group than in the modified MTE group (280 min vs 317 min). However, no significant (P > .05) difference was found in blood loss (200 mL vs 180 mL), intensive care unit (ICU) stay (31.3 ± 11.3 vs 25.2 ± 6.4 hours), first flatus after surgery (2.9 ± 1.9 vs 3.3 ± 1.6 days), postoperative hospital stay (12.9 ± 5.6 vs 12.6 ± 3.3 days), total number of lymph nodes dissected (27.9 ± 4.1 vs 26.7 ± 5.7), types of carcinoma, and pathological classification. No significant (P > .05) differences were detected in postoperative complications between the two groups. Assessment of postoperative pain using the visual analogue scale (VAS) score showed a significant (P < .05) difference in the VAS score at day 2 (4.81 ± 1.70 vs 3.87 ± 1.14) and day 3 (5.10 ± 0.83 vs 4.61 ± 1.12) between the conventional and modified MTE groups. The modified McKeown thoracolaparoscopic esophagectomy with only one cervical incision is more minimally invasive, more cosmetic, and less painful than the conventional approach.

Comparison of short-term surgical outcomes between complete mesenteric resection and traditional transhiatal laparoscopic surgery for Siewert type II/III esophagogastric junction adenocarcinoma.

PURPOSE: To explore the effectiveness and safety of laparoscopic transhiatal complete mesenteric resection (CME) surgery compared with those of the traditional laparoscopic transhiatal approach in the treatment of Siewert II/III adenocarcinoma of the esophagogastric junction (AEG). MATERIALS AND METHODS: Ninety-nine patients with Siewert type II/III AEG were enrolled and divided into two groups: the laparoscopic CME transhiatal approach (CEM-TH, n = 61) group and traditional laparoscopic transhiatal (TH, n = 38) group. Intraoperative and postoperative clinical data of both groups were analyzed. RESULTS: The laparoscopic trasihiatal surgery was technically successful in all patients. The surgical time, intraoperative bleeding, and hospital stay were all significantly (P < 0.05) reduced in the CME-TH group compared with those in the TH group. The levels of white blood cells on postoperative day (POD) 1 and 5, postoperative CRP on POD 3 and 5, and postoperative PCT were significantly (P < 0.05) lower while lymph nodes were harvested significantly (P < 0.05) more in the CME-TH group than in the TH group. Complications were not significantly (P > 0.05) different between two groups. No death occurred within 90 days. CONCLUSION: The CME theory could be safely and effectively applied laparoscopically to treat patients with Siewert II/III AEG. Mesogastrium and lower mesoesophagus can be completely resected together with the tumor, lymph nodes, adipose tissue, and blood vessels as an "intact package," leading to better short-term outcomes.

En bloc mesoesophageal esophagectomy through thoracoscopy combined with laparoscopy based on the mesoesophageal theory.

PURPOSE: To investigate the effectiveness and clinical significance of thoracolaparoscopic esophagectomy with mesoesophagus excision. MATERIALS AND METHODS: Patients who underwent en bloc mesoesophageal esophagectomy through thoracoscopy combined with laparoscopy were retrospectively enrolled. Carbon nanoparticles were used in some patients to label the esophageal drainage lymph nodes. The clinical data were analyzed. RESULTS: En bloc mesoesophageal esophagectomy was successfully performed in 135 patients (100%). The carbon nanoparticles were used in 10 patients, among which the left gastric arterial lymph nodes were labeled in all patients and excised together with the left gastric mesentery, mesoesophagus, esophageal cancer, lymph nodes, vessels, nerves, and adipose tissues as one intact package. The mean operation time was 182.5 ± 26.4 min, intraoperative blood loss 45.9 ± 17.6 ml, mean number of lymph nodes dissected 20.9 ± 8.12, extubation time of drainage tubes 7.5 ± 3.8 days, first oral feeding time 7.5 ± 1.8 days, and postoperative hospital stay 13 ± 5.11 days. Postoperatively, anastomotic leakage occurred in six patients (4.4%), anastomotic stenosis in eight (5.9%), hoarseness in seven (5.2%), and inflammation of the remnant stomach in four (3.0%), with a complication rate of 18.5%. Patients were followed up for 13-34 months (median 23). Eighteen patients presented with organ metastasis. No local recurrence or death during follow-up. CONCLUSION: Based on the membrane anatomy or mesoesophagus theory, thoracolaparoscopic en bloc mesoesophageal esophagectomy is safe, with decreased blood loss, and it is necessary to resect the left gastric artery lymph nodes together with the left gastric mesentery and its contents to completely remove the cancer.

Photoaffinity Probe Reveals the Potential Target of Harringtonolide for Cancer Cell Migration Inhibition.

Harringtonolide (HO, 1) is a bioactive diterpenoid tropone isolated from Cephalotaxus harringtonia with antiproliferation activity. Until now there have been no reports to elucidate its anticancer mechanism. Herein we report the synthesis of HO-derived probes (10, 11, and 12) to identify the possible target of HO. As a result, the application of a novel photoaffinity alkyne-tagged probe from HO (compound 12) showed direct engagement between HO and receptor for activated C kinase 1 (RACK1). Furthermore, HO could suppress the epithelial-mesenchymal transition (EMT) process and inhibit activation of the FAK/Src/STAT3 signaling pathway in A375 cells. This study provides a groundwork for HO as an effective antitumor agent that targets RACK1 to suppress cancer cell migration.

Lymph node metastasis pattern and significance of left gastric artery lymph node dissection in esophagectomy for esophageal cancers.

PURPOSE: To investigate the lymph node metastasis pattern and significance of dissection of the left gastric artery lymph nodes in radical en bloc esophagectomy for esophageal squamous carcinomas based on the lymphatic drainage pathway revealed by carbon nanoparticle labeling. MATERIALS AND METHODS: Patients who underwent en bloc esophagectomy endoscopically were retrospectively enrolled. Carbon nanoparticles were injected in the submucosa of upper thoracic esophagus to label the relevant draining lymph nodes. The clinical data, lymph nodes dissected, surgical technique, and complications were analyzed. RESULTS: En bloc esophagectomy was successful in all 179 patients. Metastases to the left gastric artery lymph nodes were positive in 42 patients (23.5%) but negative in 137 (76.5%). The left gastric lymph nodes were labeled, whereas no celiac lymph nodes were labeled by carbon nanoparticles. A total of 4652 lymph nodes were resected, with 26 lymph nodes per patient. Seventy-three patients had lymph node metastasis (73/179). Seventeen patients had metastasis to the recurrent laryngeal nerve lymph nodes (9.5%). The metastasis rate of the lower thoracic esophageal cancer to the left gastric artery lymph nodes was 37.0%, significantly greater than that at the middle (15.4%) or upper (6.7%) thoracic segment. The lymph node metastasis rate was significantly (P < 0.05) increased with the length of the cancerous lesion, infiltration depth, and poor differentiation. Univariate analysis revealed that the metastasis rate to the left gastric artery lymph nodes was significantly (P < 0.05) associated with paraesophageal lymph node metastasis, para-cardial lymph metastasis, and TNM classification. Multivariate analysis indicated that cancer location (odds ratio 8.32, 95% confidence interval 2.12-32.24) was significantly (P < 0.05) associated with metastasis to the left gastric artery lymph nodes, with the cancer at the middle and lower thoracic segments significantly more than in the upper thoracic segment. CONCLUSION: Certain patterns exist in lymph node metastasis of esophageal cancer, and in radical esophagectomy of esophageal cancers, dissection of the left gastric artery lymph nodes is necessary to prevent possible residual or metastasis of esophageal squamous carcinomas based on the lymphatic drainage pathway of esophageal carcinomas demonstrated by carbon nanoparticle labeling.

Upregulation of miR-133a-3p enhances Bufothionine-induced gastric cancer cell death by modulating IGF1R/PI3K/Akt signal pathway mediated ER stress.

AIMS: Bufothionine had been used for gastric cancer (GC) treatment, and this study managed to uncover the underlying mechanisms. MATERIALS AND METHODS: Cell proliferation was determined by CCK-8 assay and colony formation assay. Flow cytometry (FCM) and TUNEL assay were used to measure cell apoptosis ratio. Intracellular ROS was measured by DCFH-DA probes. qRT-PCR was used to determine miRNAs levels. Western Blot was performed to probe proteins. Dual-luciferase reporter gene system was employed to validate the binding sites of miR-133a-3p and 3'UTR regions of IGF1R mRNA. Immunohistochemistry (IHC) was used to determine the expressions of Ki-67 in mice tumor tissues. KEY FINDINGS: Bufothionine inhibited cell viability, triggered ER stress and promoted ROS production in GC cells, and both ER stress inhibitor Salburinal (Sal) and ROS scavenger (NAC) abrogated Bufothionine induced GC cell death. Besides, miR-133a-3p was upregulated by Bufothionine, and Bufothionine-induced cell death was enhanced by miR-133a-3p overexpression while alleviated by miR-133a-3p knockdown. Furthermore, miR-133a-3p inactivated PI3K/Akt signal pathway by sponging IGF1R, and Bufothionine inhibited insulin-like growth factor 1 receptor (IGF1R) and inactivated PI3K/Akt cascade by upregulating miR-133a-3p. Notably, the promoting effects of overexpressed miR-133a-3p on Bufothionine-induced GC cell death were abrogated by overexpressing IGF1R, and aggravated by the PI3K/Akt cascade inhibitor (LY294002). SIGNIFICANCE: Bufothionine promoted GC cell death by triggering miR-133a-3p/IGF1R/PI3K/Akt axis mediated ER stress and ROS production.

Taicrypnacids A and B, a Pair of C37 Heterodimeric Diterpenoid Stereoisomers from Taiwania cryptomerioides.

Two uncommon C37 heterodimeric diterpenoids, taicrypnacids A (1) and B (2), and a known labdane-type diterpenoid (3) were isolated from the leaves of Taiwania cryptomerioides. Several techniques, such as comprehensive spectroscopic analysis, chemical conversion, X-ray crystallography, and ECD data, were employed to define the structures. The two new compounds displayed cytotoxicity against human breast cancer (MCF-7), osteosarcoma (U-2 OS), and human colon carcinoma (HCT-116) cell lines, while the methyl ester 1a showed no activity. Compound 1 induced Ca2+-ROS pathway-mediated endoplasmic reticulum stress, and excessive stress led to cell death by activating apoptosis and autophagy.

Taiwanoids A-D, four dimeric diterpenoids featuring tetracyclic [7. 75, 9. 4. 05, 10. 08, 9] octodecane from Taiwania cryptomerioidesim.

Biogenesis-inspired chemical research of the leaves of Taiwania cryptomerioides afforded four unprecedented dimeric diterpenes, featuring a tetracyclic [7. 75, 9. 4. 05, 10. 08, 9] octodecane core: taiwanoids A-D (1-4). The structures of these compounds were determined on the basis of comprehensive spectral analysis, chemical conversions and X-ray crystallography. A possible biosynthetic pathway for compounds 1-4 was proposed. Compounds 2 and 3 exerted a 5.37 and 6.26-fold potentiation effect on bortezmib (BTZ) susceptibility at a tested concentration of 20 µM, respectively.