USP8-governed GPX4 homeostasis orchestrates ferroptosis and cancer immunotherapy.

Ferroptosis is an iron-dependent type of regulated cell death resulting from extensive lipid peroxidation and plays a critical role in various physiological and pathological processes. However, the regulatory mechanisms for ferroptosis sensitivity remain incompletely understood. Here, we report that homozygous deletion of Usp8 (ubiquitin-specific protease 8) in intestinal epithelial cells (IECs) leads to architectural changes in the colonic epithelium and shortens mouse lifespan accompanied by increased IEC death and signs of lipid peroxidation. However, mice with heterozygous deletion of Usp8 in IECs display normal phenotype and become resistant to azoxymethane/dextran sodium sulfate-induced colorectal tumorigenesis. Mechanistically, USP8 interacts with and deubiquitinates glutathione peroxidase 4 (GPX4), leading to GPX4 stabilization. Thus, USP8 inhibition destabilizes GPX4 and sensitizes cancer cells to ferroptosis in vitro. Notably, USP8 inhibition in combination with ferroptosis inducers retards tumor growth and enhances CD8+ T cell infiltration, which potentiates tumor response to anti-PD-1 immunotherapy in vivo. These findings uncover that USP8 counteracts ferroptosis by stabilizing GPX4 and highlight targeting USP8 as a potential therapeutic strategy to boost ferroptosis for enhancing cancer immunotherapy.

Postnatal eye size in mice is controlled by SREBP2-mediated transcriptional repression of Lrp2 and Bmp2.

Eye size is a key parameter of visual function, but the precise mechanisms of eye size control remain poorly understood. Here, we discovered that the lipogenic transcription factor sterol regulatory element-binding protein 2 (SREBP2) has an unanticipated function in the retinal pigment epithelium (RPE) to promote eye size in postnatal mice. SREBP2 transcriptionally represses low density lipoprotein receptor-related protein 2 (Lrp2), which has been shown to restrict eye overgrowth. Bone morphogenetic protein 2 (BMP2) is the downstream effector of Srebp2 and Lrp2, and Bmp2 is suppressed by SREBP2 transcriptionally but activated by Lrp2. During postnatal development, SREBP2 protein expression in the RPE decreases whereas that of Lrp2 and Bmp2 increases as the eye growth rate reduces. Bmp2 is the key determinant of eye size such that its level in mouse RPE inversely correlates with eye size. Notably, RPE-specific Bmp2 overexpression by adeno-associated virus effectively prevents the phenotypes caused by Lrp2 knock out. Together, our study shows that rapid postnatal eye size increase is governed by an RPE-derived signaling pathway, which consists of both positive and negative regulators of eye growth.

Transthoracic single-port-assisted laparoscopic gastrectomy versus laparoscopic transhiatal approach for Siewert type II adenocarcinoma of the esophagogastric junction: a single-center retrospective study.

BACKGROUND: The surgical approach for patients with Siewert type II AEG remains controversial. Several studies have described a new laparoscopic radical resection approach of Siewert type II AEG through the left diaphragm. However, the technical safety and feasibility of the new surgical approach compared with the transhiatal approach have not yet been tested. STUDY DESIGN: We retrospectively reviewed patients with AEG who underwent TSLG and LTH operations in the Guangdong Provincial Hospital of Chinese Medicine between January 2017 and April 2021. Histologically confirmed AEG and D2 lymphadenectomy with curative R0 patients were included, and patients with Siewert I/III AEG or distant metastasis were excluded. Blood loss, the amount of harvested lymph node, and complications related to surgery were evaluated. RESULTS: A total of 99 patients with Siewert type II AEG were analyzed, 44 in the TSLG group and 55 in the LTH group. There was no difference in clinicopathological features between the two groups. The more harvested lymph node (23.33 ± 11.41 vs. 32.18 ± 12.85, p < 0.01), lower mediastinal lymph node (1.07 ± 2.08 vs. 3.25 ± 3.31, p < 0.01), and longer proximal margin length (3.08 ± 1.19 vs. 4.47 ± 0.95 cm, p < 0.01) were observed in the TSLG group. The rate of cure (R0 gastrectomy) in the TSLG group was higher than that in the LTH group (100% vs. 89.09%, p = 0.03). CONCLUSION: The TSLG approach is associated with improved surgical views, simplified lymphatic dissection in the inferior mediastinum, and more reliable margins. TSLG surgery may be an effective addition to LTH surgery, particularly when lower mediastinal lymph node metastases are suspected.

Construction of Tetrahymena strains with highly active arsenic methyltransferase genes for arsenic detoxification in aquatic environments.

Biomethylation is an effective means of arsenic detoxification by organisms living in aquatic environments. Ciliated protozoa (including Tetrahymena species) play an important role in the biochemical cycles of aquatic ecosystems and have a potential application in arsenic biotransformation. This study compared arsenic tolerance, accumulation, methylation, and efflux in 11 Tetrahymena species. Nineteen arsenite (As(III)) S-adenosylmethionine (SAM) methyltransferase (arsM) genes, of which 12 are new discoveries, were identified, and protein sequences were studied. We then constructed recombinant cell lines based on the Tetrahymena thermophila (T. thermophila) wild-type SB210 strain and expressed each of the 19 arsM genes under the control of the metal-responsive the MTT1 promoter. In the presence of Cd2+ and As(V), expression of the arsM genes in the recombinant cell lines was much higher than in the donor species. Evaluation of the recombinant cell line identified one with ultra-high arsenic methylation enzyme activity, significantly higher arsenic methylation capacity and much faster methylation rate than other reported arsenic methylated organisms, which methylated 89% of arsenic within 6.5 h. It also had an excellent capacity for the arsenic detoxification of lake water containing As(V), 56% of arsenic was methylated at 250 µg/L As(V) in 48 h. This study has made a significant contribution to our knowledge on arsenic metabolism in protozoa and demonstrates the great potential to use Tetrahymena species in the arsenic biotransformation of aquatic environments.

Pharmacologic inhibition of IL11/STAT3 signaling increases MHC-I expression and T cell infiltration.

BACKGROUND: Recent studies have discovered an emerging role of IL11 in various colitis-associated cancers, suggesting that IL11 mainly promotes tumor cell survival and proliferation in regulating tumorigenesis. Herein we aimed to reveal a novel function of IL-11 through STAT3 signaling in regulating tumor immune evasion. METHODS: AOM/DSS model in Il11-/- and Apcmin/+/Il11-/- mice were used to detect tumor growth and CD8+ T infiltration. STAT1/3 phosphorylation and MHC-I, CXCL9, H2-K1 and H2-D1 expression were detected in MC38 cells and intestine organoids treated with/without recombinant IL11 to explore effect of IL11/STAT3 signaling, with IL11 mutein used to competitively inhibit IL11 and rescue inhibited STAT1 activation. Correlation between IL11 and CD8+ T infiltration was analyzed using TIMER2.0 website. IL11 expression and survival prognosis was analyzed in clinical data of patient cohort from Nanfang Hospital. RESULTS: IL11 is highly expressed in CRC and indicates unfavorable prognosis. IL11 knockout increased CD8+ T cell infiltration and reduced intestinal and colon formation. Tumors were significantly suppressed while MHC-I and CXCL9 expression for CD8+ T infiltration were remarkably increased in the tumor tissues of Apcmin/+/Il11-/- mice or Il11-/- mice induced by AOM/DSS. IL11/STAT3 signaling downregulated MHC-I and CXCL9 by inhibiting IFNγ-induced STAT1 phosphorylation. IL11 mutein competitively inhibit IL11 to upregulate CXCL9 and MHC-I in tumor and attenuated tumor growth. CONCLUSIONS: This study ascribes for a new immunomodulatory role for IL11 during tumor development that is amenable to anti-cytokine based therapy of colon cancer.

Hand-sewn esophagojejunostomy in transthoracic single-port assisted laparoscopic esophagogastrectomy for Siewert type II adenocarcinoma of the esophagogastric junction with esophageal invasion > 3 cm.

BACKGROUND: An optimal method for digestive tract reconstruction (DTR) in laparoscopic radical resection of Siewert type II adenocarcinoma of esophagogastric junction (AEG) has not yet been standardized. The aim of this study was to evaluate the safety and feasibility of a hand-sewn esophagojejunostomy (EJ) technique during transthoracic single-port assisted laparoscopic esophagogastrectomy (TSLE) for Siewert type II AEG with esophageal invasion > 3 cm. METHODS: The perioperative clinical data and short-term outcomes for patients who underwent TSLE using hand-sewn EJ for Siewert type II AEG with esophageal invasion > 3 cm between March 2019 and April 2022 have been retrospectively reviewed. RESULTS: A total of 25 patients were eligible. All 25 patients were successfully operated. None was converted to open surgery or mortality. 84.00% of patients were male and 16.00% were female. The mean age, body mass index (BMI), and the American Society of Anesthesiologists (ASA) score were 67.88 ± 8.10 years, 21.30 ± 2.80 kg/m2, and 2.08, respectively. The average incorporated operative and hand-sewn EJ procedural times were 274.92 ± 57.46 and 23.36 ± 3.00 min, respectively. The length of extracorporeal esophageal involvement and proximal margin was 3.31 ± 0.26 cm and 3.12 ± 0.12 cm, respectively. The average time for the first oral feeding and hospital stay were 6 (3-14) and 7 (3-18) days, respectively. Two patients (8.00%) developed postoperative grade IIIa complications according to the Clavien-Dindo classification, including 1 case of pleural effusion and 1 case of anastomotic leakage, both of whom were cured by puncture drainage. CONCLUSION: Hand-sewn EJ in TSLE is safe and feasible for Siewert type II AEG. This method can ensure safe proximal margins and could be a good option with an advanced endoscopic suture technique for type II tumor with esophageal invasion > 3 cm.

CRISPR/Cas-Based Techniques for Live-Cell Imaging and Bioanalysis.

CRISPR/Cas systems have found widespread applications in gene editing due to their high accuracy, high programmability, ease of use, and affordability. Benefiting from the cleavage properties (trans- or cis-) of Cas enzymes, the scope of CRISPR/Cas systems has expanded beyond gene editing and they have been utilized in various fields, particularly in live-cell imaging and bioanalysis. In this review, we summarize some fundamental working mechanisms and concepts of the CRISPR/Cas systems, describe the recent advances and design principles of CRISPR/Cas mediated techniques employed in live-cell imaging and bioanalysis, highlight the main applications in the imaging and biosensing of a wide range of molecular targets, and discuss the challenges and prospects of CRISPR/Cas systems in live-cell imaging and biosensing. By illustrating the imaging and bio-sensing processes, we hope this review will guide the best use of the CRISPR/Cas in imaging and quantifying biological and clinical elements and inspire new ideas for better tool design in live-cell imaging and bioanalysis.

Blockade of IL-6 inhibits tumor immune evasion and improves anti-PD-1 immunotherapy.

Long-standing inflammatory bowel disease predisposes to the development of colorectal cancer (CRC). Interleukin (IL) -6, a pivotal link between chronic inflammation and tumor progression, has recently been recognized as a potential therapeutic target. The effect of IL-6 on proliferation and metastasis of CRC by activating the STAT3 pathway has been widely demonstrated in recent years, but few on mediating tumor immune evasion. In this study, we found that IL-6 was remarkably overexpressed in CRC and its elevation was associated with a poor prognosis. We studied CRC tumorigenesis in vivo by inoculating MC38 tumors and induced-CRC model via AOM/DSS (azoxymethane/dextransulfate sodium) in IL-6 deficient (IL-6-/-) and wild-type (WT) mice and found that IL-6-/- mice were less susceptible to develop tumors, compared to WT mice. We detected CD8+ T cells via immunofluorescence and found they exhibit high expression in tumor of IL-6-/- mice. High level of IL-6 was found in colitis model, with down-regulation of MHC-I molecules. In in vitro experiments, we found that IL-6 may act as a negative regulator in IFNγ-STAT1-MHC-I signaling. In addition, vivo trials also confirmed that MHC-I mRNA level was negatively related to the existence of IL-6. Furthermore, the blockade of IL-6 also activated CD8+T-cell accumulation and led to the high PD-L1 expression in CRC, which can sensitize animals to anti-PD-1 therapy. Our study provides a research basis for the significant role of IL-6 in tumor evasion and highlights a novel target to improve the efficacy of immunotherapy.

Whether the infracardiac bursa protect right pleura during laparoscopic radical operation of Siewert type II adenocarcinoma of esophagogastric junction?

BACKGROUND: Transthoracic single-port assisted laparoscopic five-step maneuver inferior mediastinal lymphadenectomy for Siewert type II adenocarcinoma of esophagogastric junction (AEG) has superiority in lower mediastinal lymph nodes dissection and digestive tract reconstruction. However, the right pleura was probably ruptured in this surgical technique. The aim of this study was to explore whether the infracardiac bursa (ICB) exposed could protect right pleura. METHODS: We retrospectively collected and evaluated the clinical and pathological data of patients who underwent five-step maneuver of transthoracic single-port assisted laparoscopic lower mediastinal lymphadenectomy for Siewert II AEG at Guangdong Provincial Hospital of Chinese Medicine between May 2017 and February 2022. RESULTS: A total of 49 patients were eligible, including 31 patients in ICB exposed group (group A) and 18 patients in ICB unexposed group (group B). There were no statistically significant differences in baseline characteristics between the two groups. 4 patients (12.9%) had right pleura rupture in group A, while 14 patients (77.8%) in group B, and the difference was statistically significant (p < 0.001). Compared with group B, the extubation time of endotracheal intubation (10.0 (6.0 ~ 12.0) vs. 13.0 (8.0 ~ 15.0) min, p = 0.003) and thoracic drainage tube stay (6.0 (5.0 ~ 7.0) vs. 8.0 (6.0 ~ 10.5) days, p = 0.041) were significantly shorted in the group A. The drainage volume of thorax (351.61 ± 125.00 vs. 418.61 ± 207.86 mL, p = 0.146) was non-significant less and the rate of complications (3.2% vs. 11.1%, p = 0.074) was non-significant lower in group A compared with group B. The postoperative hospital stay (9.0 (8.0,13.0) vs. 9.0 (8.0,12.0) days, p = 0.983) were similar in two groups. No serious adverse event occurred in any patient. CONCLUSIONS: The ICB exposed could protect the right pleura and may promote postoperative recovery, which may be used as an anatomical marker in inferior mediastinal lymphadenectomy.

Loss of TMEM106B and PGRN leads to severe lysosomal abnormalities and neurodegeneration in mice.

Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). Loss of PGRN leads to lysosome dysfunction during aging. TMEM106B, a gene encoding a lysosomal membrane protein, is the main risk factor for FTLD with PGRN haploinsufficiency. But how TMEM106B affects FTLD disease progression remains to be determined. Here, we report that TMEM106B deficiency in mice leads to accumulation of lysosome vacuoles at the distal end of the axon initial segment in motor neurons and the development of FTLD-related pathology during aging. Ablation of both PGRN and TMEM106B in mice results in severe neuronal loss and glial activation in the spinal cord, retina, and brain. Enlarged lysosomes are frequently found in both microglia and astrocytes. Loss of both PGRN and TMEM106B results in an increased accumulation of lysosomal vacuoles in the axon initial segment of motor neurons and enhances the manifestation of FTLD phenotypes with a much earlier onset. These results provide novel insights into the role of TMEM106B in the lysosome, in brain aging, and in FTLD pathogenesis.

Neutrophil percentage-to-albumin ratio and monocyte-to-lymphocyte ratio as predictors of free-wall rupture in patients with acute myocardial infarction.

BACKGROUNDS: Free-wall rupture (FWR) has a high mortality rate. We aimed to find sensitive predictive indicators to identify high-risk FWR patients by exploring the predictive values of neutrophil percentage-to-albumin ratio (NPAR) and monocyte-to-lymphocyte ratio (MLR) on patients with acute myocardial infarction (AMI). METHODS: 76 FWR patients with AMI were collected, and then 228 non-CR patients with AMI were randomly selected (1:3 ratio) in this retrospective study. The independent influencing factors of FWR were evaluated by univariate and multivariate logistic regression analysis. The receiver-operating characteristic (ROC) curve analysis was applied to evaluate the predictive value of NPAR and MLR for FWR. RESULTS: According to the results of multivariate logistic regression analysis, emergency percutaneous coronary intervention (PCI) (OR = 0.27, 95% CI: 0.094-0.751, p = 0.012), angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) treatment (OR = 0.17, 95% CI: 0.044-0.659, p = 0.010), NPAR (OR = 2.69, 95% CI: 1.031-7.044, p = 0.043), and MLR (OR = 5.99, 95% CI: 2.09-17.168, p = 0.001) were the influencing factors of the FWR patients with AMI, independently. Additionally, the NPAR and MLR were the predictors of FWR patients, with AUC of 0.811 and 0.778, respectively (both p < 0.001). CONCLUSIONS: In summary, the emergency PCI and ACEI/ARB treatment were independent protective factors for FWR patients with AMI, while the increase of MLR and NPAR were independent risk factors. What's more, NPAR and MLR are good indicators for predicting FWR.

Rationally engineered Staphylococcus aureus Cas9 nucleases with high genome-wide specificity.

RNA-guided CRISPR-Cas9 proteins have been widely used for genome editing, but their off-target activities limit broad application. The minimal Cas9 ortholog from Staphylococcus aureus (SaCas9) is commonly used for in vivo genome editing; however, no variant conferring high genome-wide specificity is available. Here, we report rationally engineered SaCas9 variants with highly specific genome-wide activity in human cells without compromising on-target efficiency. One engineered variant, referred to as SaCas9-HF, dramatically improved genome-wide targeting accuracy based on the genome-wide unbiased identification of double-stranded breaks enabled by sequencing (GUIDE-seq) method and targeted deep sequencing analyses. Among 15 tested human endogenous sites with the canonical NNGRRT protospacer adjacent motif (PAM), SaCas9-HF rendered no detectable off-target activities at 9 sites, minimal off-target activities at 6 sites, and comparable on-target efficiencies to those of wild-type SaCas9. Furthermore, among 4 known promiscuous targeting sites, SaCas9-HF profoundly reduced off-target activities compared with wild type. When delivered by an adeno-associated virus vector, SaCas9-HF also showed reduced off-target effects when targeting VEGFA in a human retinal pigmented epithelium cell line compared with wild type. Then, we further altered a previously described variant named KKH-SaCas9 that has a wider PAM recognition range. Similarly, the resulting KKH-HF remarkably reduced off-target activities and increased on- to off-target editing ratios. Our finding provides an alternative to wild-type SaCas9 for genome editing applications requiring exceptional genome-wide precision.

AAV cis-regulatory sequences are correlated with ocular toxicity.

Adeno-associated viral vectors (AAVs) have become popular for gene therapy, given their many advantages, including their reduced inflammatory profile compared with that of other viruses. However, even in areas of immune privilege such as the eye, AAV vectors are capable of eliciting host-cell responses. To investigate the effects of such responses on several ocular cell types, we tested multiple AAV genome structures and capsid types using subretinal injections in mice. Assays of morphology, inflammation, and physiology were performed. Pathological effects on photoreceptors and the retinal pigment epithelium (RPE) were observed. Müller glia and microglia were activated, and the proinflammatory cytokines TNF-α and IL-1ß were up-regulated. There was a strong correlation between cis-regulatory sequences and toxicity. AAVs with any one of three broadly active promoters, or an RPE-specific promoter, were toxic, while AAVs with four different photoreceptor-specific promoters were not toxic at the highest doses tested. There was little correlation between toxicity and transgene, capsid type, preparation method, or cellular contaminants within a preparation. The toxic effect was dose-dependent, with the RPE being more sensitive than photoreceptors. Our results suggest that ocular AAV toxicity is associated with certain AAV cis-regulatory sequences and/or their activity and that retinal damage occurs due to responses by the RPE and/or microglia. By applying multiple, sensitive assays of toxicity, AAV vectors can be designed so that they can be used safely at high dose, potentially providing greater therapeutic efficacy.

Group analysis of distance matrices.

Distance-based regression model has become a powerful approach to identifying phenotypic associations in many fields. It is found to be particularly useful for high-dimensional biological and genetic data with proper distance or similarity measures being available. The pseudo F statistic used in this model accumulates information and is effective when the signals, that is the variations represented by the eigenvalues of the similarity matrix, scatter evenly along the eigenvectors of the similarity matrix. However, it might lose power for the uneven signals. To deal with this issue, we propose a group analysis on the variations of signals along the eigenvalues of the similarity matrix and take the maximum among them. The new procedure can automatically choose an optimal grouping point on some given thresholds and thus can improve the power evidence. Extensive computer simulations and applications to a prostate cancer data and an aging human brain data illustrate the effectiveness of the proposed method.

Laparoscopic vs. open surgery for gastrointestinal stromal tumors of esophagogastric junction: A multicenter, retrospective cohort analysis with propensity score weighting.

OBJECTIVE: Laparoscopic resection is increasingly performed for gastrointestinal stromal tumors (GISTs). However, the laparoscopic approach for GISTs located in the esophagogastric junction (EGJ-GIST) is surgically challenging. This study compares the efficacy of laparoscopic surgery and the open procedure for EGJ-GIST through the propensity score weighting (PSW) method. METHODS: Between April 2006 and April 2018, 1,824 surgical patients were diagnosed with primary gastric GIST at four medical centers in South China. Of these patients, 228 were identified as EGJ-GISTs and retrospectively reviewed clinicopathological characteristics, operative information, and long-term outcomes. PSW was used to create the balanced cohorts. RESULTS: PSW was carried out in laparoscopic and open-surgery cohorts according to year of surgery, sex, age, body mass index (BMI), tumor size, mitotic rates and recurrence risk. After PSW, 438 patients consisting of 213 laparoscopic (L group) and 225 open surgery (O group) patients were enrolled. After PSW, the following measures in the L group were superior to those in the O group: median operative time [interquartile range (IQR)]: 100.0 (64.5-141.5)vs. 149.0 (104.0-197.5) min, P<0.001; median blood loss (IQR): 30.0 (10.0-50.0)vs. 50.0 (20.0-100.0) mL, P=0.002; median time to liquid intake (IQR): 3.0 (2.0-4.0)vs. 4.0 (3.0-5.0) d, P<0.001; median hospital stay (IQR): 6.0 (4.0-8.0)vs. 7.0 (5.0-12.0) d, P<0.001; and postoperative complications (10.3%vs. 22.7%, P=0.001). The median follow-up was 55 (range, 2-153) months in the entire cohort. No significant differences were detected in either relapse-free survival (RFS) [hazard ratio (HR): 0.372, 95% confidence interval (95% CI): 0.072-1.910, P=0.236) or overall survival (OS) (HR: 0.400, 95% CI: 0.119-1.343, P=0.138) between the two groups. CONCLUSIONS: Laparoscopic surgery for EGJ-GIST is associated with the advantages of shorter operative time, reduced blood loss, shorter time to liquid intake, and shorter length of stay, all without compromising postoperative outcomes and long-term survival.

Two-Tier PSO Based Data Routing Employing Bayesian Compressive Sensing in Underwater Sensor Networks.

Underwater acoustic sensor networks play an important role in assisting humans to explore information under the sea. In this work, we consider the combination of sensor selection and data routing in three dimensional underwater wireless sensor networks based on Bayesian compressive sensing and particle swarm optimization. The algorithm we proposed is a two-tier PSO approach. In the first tier, a PSO-based clustering protocol is proposed to synthetically consider the energy consumption and uniformity of cluster head distribution. Then in the second tier, a PSO-based routing protocol is proposed to implement inner-cluster one-hop routing and outer-cluster multi-hop routing. The nodes selected to constitute i-th effective routing path decide which positions in the i-th row of the measurement matrix are nonzero. As a result, in this tier the protocol comprehensively considers energy efficiency, network balance and data recovery quality. The Bayesian Cramér-Rao Bound (BCRB) in such a case is analyzed and added in the fitness function to monitor the mean square error of the reconstructed signal. The experimental results validate that our algorithm maintains a longer life time and postpones the appearance of the first dead node while keeps the reconstruction error lower compared with the cutting-edge algorithms which are also based on distributed multi-hop compressive sensing approaches.

Oncometabolic surgery: Emergence and legitimacy for investigation.

Studies on morbid obesity have shown remarkable improvement of diabetes in patients who have undergone bariatric operations. It was subsequently shown that these operations induce diabetes remission independent of the resultant weight loss; as a result, surgeons began to investigate whether operations for gastric cancer (GC) could have the same beneficial effect on diabetes as bariatric operations. It was then shown in multiple reports that followed that certain operations for GC were able to improve or even cure type 2 diabetes mellitus (T2DM) in GC patients. This finding gave rise to the concept of "oncometabolic surgery", in which a patient diagnosed with both GC and T2DM undergo a single operation with the purpose of treating both diseases. With the increasing incidence of T2DM, oncometabolic surgery has the potential to improve the quality of life and even extend survival of many GC patients. However, because the GC patient population and the bariatric patient population are wildly different and because different GC operations have different properties, the effect of oncometabolic surgery must be carefully assessed and engineered in order to maximize benefit and avoid harm. This manuscript aims to summarize the findings made so far in the field of oncometabolic surgery and to provide an outlook regarding the possibility of oncometabolic surgery being incorporated into standard clinical practice.

Downregulation of KMT2D suppresses proliferation and induces apoptosis of gastric cancer.

PURPOSE: Histone lysine methyltransferase 2D (KMT2D/MLL2) is a known cancer-related protein; however, its function in gastric cancer (GC) remains uncharacterized. The present study sought to investigate the expression pattern and the role of KMT2D in GC. METHODS: The expression of KMT2D were evaluated at mRNA and protein levels, while its clinico-pathological value were further explored. GC cells were transfected with KMT2D knockdown siRNAs or lentiviruses, and then detected by cell counting kit-8, plate clone formation, cell apoptosis, cycle, migration, invasion, and tumorigenesis assays. RESULTS: Overexpression of KMT2D was observed in GC samples, and was strongly associated with poor survival. Depletion of KMT2D suppressed cell proliferation and induced apoptosis. CONCLUSION: Our study demonstrated the upregulation of KMT2D in GC tissue, and KMT2D modulates proliferation and apoptosis in GC. Therefore, KMT2D might represent a novel oncogene for prognosis and optimal treatment of GC patients.

Kallistatin inhibits lymphangiogenesis and lymphatic metastasis of gastric cancer by downregulating VEGF-C expression and secretion.

BACKGROUND: Tumor-induced lymphangiogenesis and lymphatic metastasis are predominant during the metastasis of many types of cancers. However, the endogenous inhibitors that counterbalance the lymphangiogenesis and lymphatic metastasis of tumors have not been well evaluated. Kallistatin has been recognized as an endogenous angiogenesis inhibitor. METHODS AND RESULTS: Our recent study showed for the first time that the lymphatic vessel density (LVD) was reduced in lung and stomach sections from kallistatin-overexpressing transgenic mice. Kallistatin expresses anti-lymphangiogenic activity by inhibiting the proliferation, migration, and tube formation of human lymphatic endothelial cells (hLECs). Therefore, the present study focuses on the relationships of changes in kallistatin expression with the lymphangiogenesis and lymphatic metastasis of gastric cancer and its underlying mechanisms. Our results revealed that the expression of kallistatin in cancer tissues, metastatic lymph nodes, and plasma of gastric cancer patients was significantly downregulated and that the plasma level of kallistatin was negatively associated with the phase of lymph node metastasis. Furthermore, treatment with kallistatin recombinant protein decreased LVD and lymph node metastases in the implanted gastric xenograft tumors of nude mice. Mechanically, kallistatin suppressed the lymphangiogenesis and lymphatic metastasis by downregulating VEGF-C expression and secretion through the LRP6/IKK/IÒ¡B/NF-Ò¡B signaling pathway in gastric cancer cells. CONCLUSIONS: These findings demonstrated that kallistatin functions as an endogenous lymphangiogenesis inhibitor and has an important part in the lymphatic metastasis of gastric cancer.

Laparoscopic resection for gastrointestinal stromal tumors in esophagogastric junction (EGJ): how to protect the EGJ.

BACKGROUND: Laparoscopic surgery for gastric gastrointestinal stromal tumors (GISTs) is now widely performed. However, laparoscopic resection of GIST in the esophagogastric junction (EGJ) is technically difficult and rarely reported. Herein, we introduce four fashions of laparoscopic resection for EGJ-GIST. METHODS: A retrospective review of 42 consecutive patients with EGJ-GIST who underwent attempted laparoscopic surgery was conducted. EGJ-GIST was defined as GIST with an upper border of less than 5 cm from the esophagogastric line. Four fashions of laparoscopic resection were performed: fashion A, laparoscopic wedge resection using linear stapler; fashion B, laparoscopic complete resection by opening the stomach wall and closing with suture or linear stapler; fashion C, laparoscopic mucosa-preserving resection; and fashion D, laparoscopic proximal gastrectomy with pyloroplasty and gastric plication. Clinicopathologic characteristics, operative course, and short-term and long-term outcomes were analyzed. RESULTS: All procedures were completed successfully without operative complications. In 24 of 42 (57.1%) patients, tumors were located in the fundus or greater curvature. Out of those, 70.8% (17/24) received fashion A and 29.2% (7/24) received fashion B. Tumors in 16 of 42 (38.1%) patients were located in the lesser curvature. Of those, 81.3% (13/16) underwent fashion B and 18.7% (3/16) underwent fashion D. One tumor in the anterior stomach wall and one in the posterior wall received fashion C. The mean operative time was 103.8 ± 22.1 min and the mean estimated blood loss was 22.4 ± 13.5 ml. The mean time to flatus was 40.3 ± 12.9 h and the time to fluid intake was 43.2 ± 14.3 h. The mean hospital stay was 4.8 ± 2.1 days. CONCLUSIONS: Laparoscopic surgery for EGJ-GIST is safe and feasible. The selection of various laparoscopic resection fashions should be chosen based on tumor location and the surgeon's experience.