Surgical quality determines the long-term survival superiority of right over left thoracic esophagectomy for localized esophageal squamous cell carcinoma patients: a real-world multicenter study.

OBJECTIVE: The objective was to compare the long-term overall survival (OS) of right versus left thoracic esophagectomy, and to evaluate whether surgical quality impacts comparison result. BACKGROUND: Controversy regarding the optimal thoracic esophagectomy approach persists for esophageal squamous cell carcinoma (ESCC). No study has assessed the effect of surgical quality in comparison between right and left approaches. METHODS: The authors consecutively recruited 5556 operable ESCC patients from two high-volume centers in China, of whom 2220 and 3336 received right and left thoracic esophagectomy, respectively. Cumulative sum was used to evaluate the learning curve for operation time of right approach, as the indicator of surgical proficiency. RESULTS: With a median follow-up of 83.1 months, right approach, harvesting more lymph nodes, tended to have a better OS than left approach (Mean: 23.8 vs. 16.7 nodes; adjusted hazard ratio (HR)=0.93, 95% CI: 0.85-1.02). Subset analysis by the extent of lymphadenectomy demonstrated that right approach with adequate lymphadenectomy (≥15 nodes) resulted in statistically significant OS benefit compared with left approach (adjusted HR=0.86, 95% CI: 0.77-0.95), but not with limited lymphadenectomy. Subset analysis by surgical proficiency showed that proficient right approach conferred a better OS than left approach (adjusted HR=0.75, 95% CI: 0.64-0.88), but improficient right approach did not have such survival advantage. CONCLUSIONS: Surgical quality plays a crucial role in survival comparison between surgical procedures. Right thoracic esophagectomy performed with adequate lymphadenectomy and surgical proficiency, conferring more favorable survival than left approach, should be recommended as the preferred surgical procedure for localized ESCC.

Oral Microbiota: A New Insight into Cancer Progression, Diagnosis and Treatment.

The polymorphic microbiome has been defined as one of the "Hallmarks of Cancer". Extensive studies have now uncovered the role of oral microbiota in cancer development and progression. Bacteria, fungi, archaea, and viruses in the oral cavity interact dynamically with the oral microenvironment to maintain the oral micro-ecological homeostasis. This complex interaction is influenced by many factors, such as maternal transmission, personal factors and environmental factors. Dysbiosis of oral microbiota can disturbed this host-microbiota interaction, leading to systemic diseases. Numerous studies have shown the potential associations between oral microbiota and a variety of cancers. However, the underlying mechanisms and therapeutic insights are still poorly understood. In this review, we mainly focus on the following aspects: (1) the factors affect oral microbiota composition and function; (2) the interaction between microenvironment and oral microbiota; (3) the role of multi-kingdom oral microbiota in human health; (4) the potential underlying mechanisms and therapeutic benefits of oral microbiota against cancer. Finally, we aim to describe the impact of oral microbiota on cancer progression and provide novel therapeutic insights into cancer prevention and treatment by targeting oral microbiota.

Controllable vortex lasing arrays in a geometrically frustrated exciton-polariton lattice at room temperature.

Quantized vortices appearing in topological excitations of quantum phase transition play a pivotal role in strongly correlated physics involving the underlying confluence of superfluids, Bose-Einstein condensates and superconductors. Exciton polaritons as bosonic quasiparticles have enabled studies of non-equilibrium quantum gases and superfluidity. Exciton-polariton condensates in artificial lattices intuitively emulate energy-band structures and quantum many-body effects of condensed matter, underpinning constructing vortex lattices and controlling quantum fluidic circuits. Here, we harness exciton-polariton quantum fluids of light in a frustrated kagome lattice based on robust metal-halide perovskite microcavities, to demonstrate vortex lasing arrays and modulate their configurations at room temperature. Tomographic energy-momentum spectra unambiguously reveal massless Dirac bands and quenched kinetic-energy flat bands coexisting in kagome lattices, where polariton condensates exhibit prototypical honeycomb and kagome spatial patterns. Spatial coherence investigations illustrate two types of phase textures of polariton condensates carrying ordered quantized-vortex arrays and π-phase shifts, which could be selected when needed using lasing emission energy. Our findings offer a promising platform on which it is possible to study quantum-fluid correlations in complex polaritonic lattices and highlight feasible applications of structured light.

mTORC2 orchestrates monocytic and granulocytic lineage commitment by an ATF5-mediated pathway.

Myeloid hematopoiesis is a finely controlled consecutive developmental process, which is essential to maintain peripheral innate immune homeostasis. Herein, we found that Rictor deletion caused the remarkable reduction of granulocyte-monocyte progenitors (GMPs), monocytes, and macrophages, while the levels of neutrophils were unaffected. Adoptive transfer of Rictor-deleted GMPs or common myeloid progenitors (CMPs) in syngeneic mice showed poor re-constitution of monocytes compared to wild-type GMPs or CMPs. In addition to decreasing the proliferation of CMPs/GMPs, Rictor deletion preferentially inhibited Ly6C+ monocyte differentiation, while enhancing neutrophil differentiation, as determined by colony formation assays. mTORC2 promotes monocyte development by downregulation of the AKT-Foxo4-activating transcription factor 5 (ATF5)-mitochondrial unfolded protein response (mtUPR) pathway. Genetic overexpression of ATF5 or exposure to ethidium bromide significantly rescued monocyte/macrophage differentiation defects of Rictor-deficient myeloid progenitors. Therefore, Rictor is required for CMP/GMP proliferation and acts as an important switch to balance monocytic and granulocytic lineage commitment in bone marrow.

Is Adjuvant Therapy a Better Option for Esophageal Squamous Cell Carcinoma Patients Treated With Esophagectomy? A Prognosis Prediction Model Based on Multicenter Real-World Data.

OBJECTIVE: To construct a prediction model for more precise evaluation of prognosis which will allow personalized treatment recommendations for adjuvant therapy in patients following resection of ESCC. BACKGROUND: Marked heterogeneity of patient prognosis and limited evidence regarding survival benefit of various adjuvant therapy regimens pose challenges in the clinical treatment of ESCC. METHODS: Based on comprehensive clinical data obtained from 4129 consecutive patients with resected ESCC in a high-risk region in China, we identified predictors for overall survival through a 2-phase selection based on Cox proportional hazard regression and minimization of Akaike information criterion. The model was internally validated using bootstrapping and externally validated in 1815 patients from a non-high-risk region in China. RESULTS: The final model incorporates 9 variables: age, sex, primary site, T stage, N stage, number of lymph nodes harvested, tumor size, adjuvant treatment, and hemoglobin level. A significant interaction was also observed between N stage and adjuvant treatment. N1+ stage patients were likely to benefit from addition of adjuvant therapy as opposed to surgery alone, but adjuvant therapy did not improve overall survival for N0 stage patients. The C -index of the model was 0.729 in the training cohort, 0.723 after bootstrapping, and 0.695 in the external validation cohort. This model outperformed the seventh edition American Joint Committee on Cancer staging system in prognostic prediction and risk stratification. CONCLUSIONS: The prediction model constructed in this study may facilitate precise prediction of survival and inform decision-making about adjuvant therapy according to N stage.

Minimally Invasive or Open Esophagectomy for Treatment of Resectable Esophageal Squamous Cell Carcinoma? Answer From a Real-world Multicenter Study.

OBJECTIVE: To evaluate the long-term and short-term outcomes of MIE compared with OE in localized ESCC patients in real-world settings. BACKGROUND: MIE is an alternative to OE, despite the limited evidence regarding its effect on long-term survival. METHODS: We recruited 5822 consecutive patients with resectable ESCC in 2 typical high-volume centers in southern and northern China, 1453 of whom underwent MIE. Propensity score-based overlap weighted regression adjusted for multifaceted confounding factors was used to compare outcomes in the MIE and OE groups. RESULTS: Five-year OS was 62.7% in the MIE group and 57.7% in the OE group. The overlap weighted Cox regression showed slightly better OS in the MIE group (hazard ratio 0.93, 95% confidence interval: 0.82-1.06). Although duration of surgery was longer and treatment cost higher in the MIE group than in the OE group, the number of lymph nodes harvested was larger, the proportion of intraoperative blood transfusions lower, and postoperative complications less in the MIE group. 30-day (risk ratio [RR] 0.77, 0.381.55) and 90-day (RR 0.79, 0.46-1.35) mortality were lower in the MIE group versus the OE group, although not statistically significant. These findings were consistent across different analytic approaches and subgroups, notably in the subset of ESCC patients with large tumors. CONCLUSIONS: MIE can be performed safely with OS comparable to OE for patients with localized ESCC, indicating MIE may be recommended as the primary surgical approach for resectable ESCC in health facilities with requisite technical capacity.

Tuberous Sclerosis Complex 1 Deficiency in Macrophages Promotes Unclassical Inflammatory Response to Lipopolysaccharide In Vitro and Dextran Sodium Sulfate-Induced Colitis in Mice.

Human tuberous sclerosis (TSC) is mainly caused by genetic mutations of tuberous TSC1or TSC2. Recent studies found that TSC1 deficiency promoted classical M1 macrophage polarization. However, whether TSC1 regulates other inflammatory cytokine expression in lipopolysaccharidem (LPS)-stimulated macrophages is unknown. Herein, we studied the cytokine expression profile of wild-type (WT) and TSC1-deleted macrophages after LPS stimulation in vitro and the pathogenesis of dextran sodium sulfate (DSS)-induced colitis in mice with myeloid-specific TSC1 deletion (TSC1cKO mice). We found that TSC1-deficient macrophages exhibited the enhanced secretion of interleukin-17A (IL-17A), IL-17F, and interferon-gamma (IFN-γ) in response to LPS stimulation in vitro. This is in contrast to LPS-stimulated WT macrophages, which usually do not. Importantly, TSC1cKO mice exhibited exacerbated DSS-induced acute colitis with severer symptoms. MTOR deletion or rapamycin treatment significantly reversed the enhanced expressions of IL-17A, IL-17F, and IFN-γ in LPS-stimulated TSC1-deficient macrophages in vitro and rescued the enhanced DSS-induced colitis in TSC1cKO mice, indicating that TSC1 deficiency increased these cytokine productions in an mTOR-dependent manner. RNA-sequencing and molecular studies indicated that TSC1 deficiency enhanced the aerobic glycolysis process and the activities of mTOR-STAT3-RORγT pathway in LPS-stimulated macrophages. Inhibition of aerobic glycolysis, STAT3, or RORγT reversed IL-17 and IFN-γ expression in LPS-treated TSC1-deficient macrophages. Thus, TSC1 is essential for macrophages to shut down IL-17A, IL-17F, and IFN-γ expression during LPS stimulation by suppressing the aerobic glycolysis process and mTOR-STAT3, RORγT, and T-bet pathways. The present study uncovered the key role of TSC1 in shutting down IL-17A, IL-17F, and IFN-γ expressions in LPS-treated macrophages.

FABP5 Deficiency Impaired Macrophage Inflammation by Regulating AMPK/NF-κB Signaling Pathway.

Fatty acid binding protein 5 (FABP5) is mainly involved in the uptake, transport, and metabolism of fatty acid in the cytoplasm, and its role in immune cells has been recognized in recent years. However, the role of FABP5 in macrophage inflammation and its underlying mechanisms were not fully addressed. In our study, the acute liver injury and sepsis mouse models were induced by i.p. injection of LPS and cecal contents, respectively. Oleic acid (0.6 g/kg) was injected four times by intragastric administration every week, and this lasted for 1 wk before the LPS or cecal content challenge. We found that myeloid-specific deletion of FABP5 mitigated LPS-induced acute liver injury with reduced mortality of mice, histological liver damage, alanine aminotransferase, and proinflammatory factor levels. Metabolic analysis showed that FABP5 deletion increased the intracellular unsaturated fatty acids, especially oleic acid, in LPS-induced macrophages. The addition of oleic acid also decreased LPS-stimulated macrophage inflammation in vitro and reduced acute liver injury in LPS-induced or cecal content-induced sepsis mice. RNA-sequencing and molecular mechanism studies showed that FABP5 deletion or oleic acid supplementation increased the AMP/ATP ratio and AMP-activated protein kinase (AMPK) activation and inhibited the NF-κB pathway during the inflammatory response to LPS stimulation of macrophages. Inhibiting AMPK activation or expression by chemical or genetic approaches significantly rescued the decreased NF-κB signaling pathway and inflammatory response in LPS-treated FABP5-knockout macrophages. Our present study indicated that inhibiting FABP5 or supplementation of oleic acid might be used for the treatment of sepsis-caused acute liver injury.

Combined Mean Corpuscular Hemoglobin, Fibrinogen, and Albumin (MF-A) Is a Novel Prognostic Marker in Patients with Resectable Esophageal Squamous Cell Carcinoma.

BACKGROUND: The aim was to systematically select blood markers routinely tested in clinical settings, which are independently associated with overall survival (OS) and are able to stratify prognosis of esophageal squamous cell carcinoma (ESCC) patients undergoing esophagectomy. METHODS: We selected optimal blood markers for prognostic stratification from 60 candidates in a clinical cohort of 1819 consecutive patients with resectable ESCC in China. Selection was carried out using two-step multivariable Cox proportional hazards regression adjusted for multifaceted confounders. A composite index was developed by multiplying risk factors and dividing them by protective factors. RESULTS: With a median follow-up of 48.07 months, 641 deaths occurred in the 1819 patients and the 5-year OS was 56.30%. Two risk factors (mean corpuscular hemoglobin, fibrinogen) and a protective factor (albumin), all dichotomized and assigned values 1 and 2, were used to construct the composite index marker "MF-A". Three risk groups were created based on the MF-A score including low- (0.5), moderate- (1), and high-risk groups (2 and 4). Compared with patients in the low-risk group (1184/1778, 66.59%), those in the moderate- (488, 27.45%), and high-risk (106, 5.96%) groups were at elevated risk of death (adjusted HR: 1.32, 95% CI: 1.11-1.57; adjusted HR: 2.08, 95% CI: 1.56-2.75; Ptrend < 10-7). Within each TNM stage grouping, OS also trended to be significantly worse as the MF-A score increased. CONCLUSIONS: "MF-A" is a novel independent predictor which may be used to estimate and stratify prognosis for ESCC patients undergoing esophagectomy.

Spontaneously coherent orbital coupling of counterrotating exciton polaritons in annular perovskite microcavities.

Exciton-polariton condensation is regarded as a spontaneous macroscopic quantum phenomenon with phase ordering and collective coherence. By engineering artificial annular potential landscapes in halide perovskite semiconductor microcavities, we experimentally and theoretically demonstrate the room-temperature spontaneous formation of a coherent superposition of exciton-polariton orbital states with symmetric petal-shaped patterns in real space, resulting from symmetry breaking due to the anisotropic effective potential of the birefringent perovskite crystals. The lobe numbers of such petal-shaped polariton condensates can be precisely controlled by tuning the annular potential geometry. These petal-shaped condensates form in multiple orbital states, carrying locked alternating π phase shifts and vortex-antivortex superposition cores, arising from the coupling of counterrotating exciton-polaritons in the confined circular waveguide. Our geometrically patterned microcavity exhibits promise for realizing room-temperature topological polaritonic devices and optical polaritonic switches based on periodic annular potentials.

Estimating cancer incidence based on claims data from medical insurance systems in two areas lacking cancer registries in China.

BACKGROUND: We aimed to establish a Medical-Insurance-System-based Cancer Surveillance System (MIS-CASS) in China and evaluate the completeness and timeliness of this system through reporting cancer incidence rates using claims data in two regions in northern and southern China. METHODS: We extracted claims data from medical insurance systems in Hua County of Henan Province, and Shantou City in Guangdong Province in China from Jan 1, 2012 to Jun 30, 2019. These two regions have been considered to be high risk regions for oesophageal cancer. We developed a rigorous procedure to establish the MIS-CASS, which includes data extraction, cleaning, processing, case ascertainment, privacy protection, etc. Text-based diagnosis in conjunction with ICD-10 codes were used to determine cancer diagnosis. FINDINGS: In 2018, the overall age-standardised (Segi population) incidence rates (ASR World) of cancer in Hua County and Shantou City were 167·39/100,000 and 159·78/100,000 respectively. In both of these areas, lung cancer and breast cancer were the most common cancers in males and females respectively. Hua County is a high-risk region for oesophageal cancer (ASR World: 25·95/100,000), whereas Shantou City is not a high-risk region for oesophageal cancer (ASR World: 11·43/100,000). However, Nanao island had the highest incidence of oesophageal cancer among all districts and counties in Shantou (ASR World: 36·39/100,000). The age-standardised male-to-female ratio for oesophageal cancer was lower in Hua County than in Shantou (1·69 vs. 4·02). A six-month lag time was needed to report these cancer incidences for the MIS-CASS. INTERPRETATION: MIS-CASS efficiently reflects cancer burden in real-time, and has the potential to provide insight for improvement of cancer surveillance in China. FUNDING: The National Key R&D Program of China (2016YFC0901404), the Digestive Medical Coordinated Development Center of Beijing Municipal Administration of Hospitals (XXZ0204), the Sanming Project of Shenzhen (SZSM201612061), and the Shantou Science and Technology Bureau (190829105556145, 180918114960704).

Brusatol inhibits amyloid-ß-induced neurotoxicity in U-251 cells via regulating the Nrf2/HO-1 pathway.

Amyloid-ß (Aß) has been reported to cause oxidative damage of neurons leading to neurotoxicity in a variety of diseases and cancers. As an anticancer drug, brusatol (BR) has been shown to have potent cytotoxic effects on various cancer cell lines. In this study, the effect and mechanism of BR on Aß-induced neurotoxicity was investigated in U-251 glioma cells. Using the MTT assay, the results suggest that BR ameliorated cell injury induced by Aß in U-251 cells. After running Hoechst and Western blot assays, BR prevented cell apoptosis induced by Aß in U-251 cells. In addition, BR inhibited the increased reactive oxygen species and mitochondrial membrane potential levels induced by Aß in U-251 cells using the DCFH-DA and Rh123 method. Furthermore, BR induced the Nrf2/HO-1 pathway by inhibiting the PI3K/AKT/mTOR pathway to inhibit neurotoxicity elicited by Aß. These results suggest that brustasol is a valuable potential antitumor drug available for chemotherapy.

Epigenetic Regulation of Gene Expression Induced by Butyrate in Colorectal Cancer: Involvement of MicroRNA.

Colorectal cancer (CRC) is the third most common cause of cancer mortality globally. Development of CRC is closely associated with lifestyle, and diet may modulate risk. A Western-style diet is characterised by a high intake of red meat but low consumption of fruit, vegetables, and whole cereals. Such a diet is associated with CRC risks. It has been demonstrated that butyrate, produced by the fermentation of dietary plant fibre, can alter both genetic and epigenetic expressions. MicroRNAs (miRNAs) are small non-coding RNAs that are commonly present in both normal and tumour cells. Aberrant miRNA expression is associated with CRC initiation, progression, and metastasis. In addition, butyrate can modulate cell proliferation, differentiation, apoptosis, and miRNA expression in CRC. In this review, the effects of butyrate on modulating miRNA expression in CRC will be discussed. Furthermore, evidence on the effect of butyrate on CRC risk through reducing oncogenic miRNA expression will be presented.