Predicting the Prognosis of Gastric Cancer by Albumin/Globulin Ratio and the Prognostic Nutritional Index.

Background: Albumin-to-globulin ratio (AGR) and the prognostic nutrition index (PNI) are used to assess the nutritional status and severity of disease for a cancer patient. However, the clinical significance of combining these two predictors in gastric cancer (GC) remains unclear. This study evaluated the prognostic value of pretreatment serum AGR and the PNI for GC.Methods: A total of 273 patients with GC, diagnosed between January 2010 and January 2014, were enrolled. The association of AGR, PNI with clinicopathological characters and prognosis were assessed by Cox regression and Kaplan-Meier methods.Results: Both low AGR group and low PNI group had poor overall survival (OS) and progression-free survival (PFS) (all p < 0.001), while patients with low AGR and PNI had the lowest OS rate. Multivariate analyses revealed that AGR (for OS HR = 0.657, 95%CI: 0.449-0.962, p = 0.031; for PFS HR = 0.684, 95%CI: 0.528-0.895, p = 0.035) was an independent prognostic factor for OS and PFS in patients with GC, and PNI was verified as a predictor for OS (HR = 0.782, 95%CI: 0.503 -0.997, p = 0.048).Conclusions: Low level of pretreatment AGR and PNI may be independent prognostic factors for patients with GC, and patients with both factors indicated the worst OS.

Elevated serum levels of interleukin-37 correlate with poor prognosis in gastric cancer.

BACKGROUND: interleukin-37 (IL-37) is as a natural suppressor of the innate inflammatory and immune responses. It has also been reported to be involved in carcinogenesis and metastasis. The present case-control study was designed to investigate the role of serum levels of IL-37 in patients with gastric cancer. METHODS: serum IL-37 levels were determined using the enzyme-linked immunosorbent assay in 180 patients diagnosed with gastric cancer and 100 healthy controls. The association between IL-37 levels and clinical factors was assessed. Univariate and multivariate analyses were performed to investigate the prognostic significance of these parameters in gastric cancer. RESULTS: serum IL-37 levels in gastric cancer patients (5.606 ± 0.837 pg/ml) were significantly higher than those in healthy controls (2.364 ± 0.210 pg/ml, p < 0.001). High serum IL-37 levels were related to a poorly differentiated histologic type (p = 0.046) and advanced T stage (p = 0.003). The Kaplan-Meier survival analysis indicated that the high-IL-37 group had a poorer overall survival and progression-free survival (overall survival [OS]: 39.0 months vs 13.0 months, p < 0.001, progression-free survival [PFS]: 25.0 months vs 10.0 months, p < 0.001). Multivariate analyses showed serum IL-37 to be an independent prognostic factor for gastric cancer patients (OS: hazard ratios [HR] = 1.842, 95% CI: 1.190-2.854, p = 0.006; PFS: HR = 1.547, 95% CI: 1.014-2.359, p = 0.043). CONCLUSIONS: in conclusion, serum IL-37 levels were associated with poor overall survival and progression-free survival in gastric cancer patients. IL-37 may be a potential predictor of prognosis in gastric cancer.

Genetic variations in PRKAA1 predict the risk and progression of gastric Cancer.

BACKGROUND: PRKAA1 encodes α-subunit of 5-AMP-activated protein kinase (AMPK), which has been implicated in the pathogenesis of carcinoma of the stomach. Previous works have suggested that polymorphisms in the PRKAA1 may be associated with the risk of non-cardiac gastric cancer (NCGC), but whether PRKAA1 polymorphisms are related to clinical pathologic characteristics of gastric cancer and its clinical outcome is largely unknown. METHODS: We carried out a case-control study including a total of 481 gastric cancer patients and 490 healthy controls. The genotypes of enrolled polymorphisms were identified with Sequenom MassARRAY platform. RESULTS: This study showed that rs10074991 GG genotype (adjusted OR = 1.44, 95%CI:0.99-2.09, p = 0.056) has a borderline significantly increased risk for gastric cancer, which was consistent with the result of additive model (adjusted OR = 1.21, 95%CI:1.01-1.46, p = 0.042). In similar, an increased risk of gastric cancer was also observed for rs13361707 TC genotype (adjusted OR = 1.47, 95%CI: 1.01-2.14, p = 0.043; additive model: adjusted OR = 1.22, 95%CI: 1.02-1.47, p = 0.033). Furthermore, the rs154268 and rs461404 were also found associated with increased gastric cancer risk, which may be influenced by age, tumor type and differentiation, and tumor stage. Haplotype analysis indicated A-G-C-T-C-G haplotype (rs6882903, rs10074991, rs13361707, rs3805490, rs154268 and rs461404) is associated with increased risk of gastric cancer (OR = 1.29, 95%CI: 1.02-1.62, p = 0.035). The univariate analysis for overall survival (OS) revealed that both of rs10074991 and rs13361707 variants are associated with poor OS in patients with NCGC. CONCLUSION: This case-control study provided the evidence thatrs13361707CC, rs10074991GG, rs461404GG, and rs154268CC are associated with increased gastric cancer risk, especially for NCGC, and that patients with rs10074991 G or rs13361707 C allele have a poor OS.

C6 ceramide dramatically increases vincristine sensitivity both in vivo and in vitro, involving AMP-activated protein kinase-p53 signaling.

Use of the conventional cancer chemotherapy (i.e. vincristine) is limited in tumor cells exhibiting pre-existing or acquired resistance. Here, we found that C6 ceramide (C6) dramatically sensitized vincristine's activity. In vitro, C6 and vincristine coadministration induced substantial necrosis and apoptosis in multiple human cancer cell lines, which were accompanied by a profound AMP-activated protein kinase (AMPK) activation, subsequent p53 activation, mTORC1 inactivation and Bcl-2/HIF-1α downregulation. Such synergistic effects were attenuated by AMPK inactivation through genetic mutation or short hairpin RNA silencing. Coadministration-activated p53 translocated to mitochondria, and formed a complex with cyclophilin-D, leading to mitochondrial permeability transition pore opening and cell necrosis. Disrupting p53-Cyp-D complexation through pharmacological or genetic means reduced costimulation-induced cytotoxicity. In vivo, a liposomal C6 was synthesized, which dramatically enhanced the antiproliferative activity of vincristine on HCT-116 or A2780 xenografts. Together, C6 sensitizes vincristine-induced anticancer activity in vivo and in vitro, involving activating AMPK-p53 signaling.

MicroRNA-101 down-regulates sphingosine kinase 1 in colorectal cancer cells.

MicroRNAs (miRs) dysregulation is a general feature of colorectal cancer (CRC) and other solid tumors, and is associated cancer progression. In the current study, we demonstrate that microRNA-101 (miR-101) inhibits CRC cells probably through down-regulating sphingosine kinase 1 (SphK1). Our results showed that exogenously expressing miR-101 inhibited CRC cell (HT-29 and HCT-116 lines) growth in vitro. At the molecular level, miR-101 dramatically down-regulated SphK1 mRNA and protein expression, causing pro-apoptotic ceramide production in above CRC cells. On the other hand, inhibition of miR-101 through expressing antagomiR-101 increased SphK1 expression to down-regulate ceramide level in HT-29 cells. miR-101 expression increased the in vitro anti-CRC activity of conventional chemo-agents: paclitaxel and doxorubicin. CRC cells with SphK1-shRNA knockdown showed similar phenotypes as the miR-101-expressed CRC cells, presenting with elevated level of ceramide and high sensitivity to paclitaxel or doxorubicin. In vivo, HCT-116 xenograft growth in severe combined immuno-deficient (SCID) mice was dramatically inhibited by over-expressing miR-101. Further, miR-101 enhanced paclitaxel-induced anti-HCT-116 activity in vivo. Together, these results indicate that miR-101 exerts its anti-CRC activities probably through down-regulating SphK1.

Association of Interleukin-10 -3575T>A and -1082A>G polymorphisms with non-Hodgkin lymphoma susceptibility: a comprehensive review and meta-analysis.

A number of studies have investigated the associations between IL-10 polymorphisms and non-Hodgkin lymphoma (NHL) susceptibility; however, the conclusions were still contradictory. To acquire a more precise estimation of the association, we performed the current meta-analysis. We systematically searched publications from EMBASE and MEDLINE, and calculated pooled odds ratios (ORs) and 95 % confidence intervals (CIs) using either fixed-effects or random-effects model. Genotype-based IL-10 mRNA expression analysis was performed using online public database of 270 individuals with three different ethnicities. A total of 10,703 cases and 11,823 controls from 10 studies were included for the -3575T>A polymorphism, 10,226 cases and 12,215 controls from 17 studies for the -1082A>G polymorphism. Pooled results indicated that IL-10 -3575T>A was associated with increased risk of diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), especially for Caucasians and hospital-based population. There was no association between IL-10 -1082A>G and NHL risk. However, subgroup analysis showed that IL-10 -1082GG might confer increased susceptibility to FL. In summary, this meta-analysis indicated that -3575T>A polymorphism was associated with altered NHL susceptibility for Caucasians and hospital-based population, especially for DLBCL and FL subtypes. The -1082A>G polymorphism may contribute to increased FL risk. Further large-scale population studies among different ethnicities are needed to validate these results.

The association between NQO1 Pro187Ser polymorphism and urinary system cancer susceptibility: a meta-analysis of 22 studies.

Numerous studies have investigated the association between NQO1 Pro187Ser polymorphism and urinary system cancer risk, but the findings are inconsistent. To derive a more precise estimation of such association, we performed a meta-analysis based on 22 publications encompassing 5,274 cases and 6,459 controls. Overall, significant association was found between NQO1 Pro187Ser polymorphism and urinary system cancer risk. Moreover, stratified analysis observed a statistically significant association for bladder cancer, prostate cancer, renal cell carcinoma, Caucasians, Asians, and hospital-based studies. In summary, this meta-analysis indicated that NQO1 Pro187Ser polymorphism conferred genetic susceptibility to urinary system cancer.

Prognostic value of TROP2 expression in patients with gallbladder cancer.

Altered expression of TROP2 is observed in various types of human cancers. However, the clinical significance and pathological role of TROP2 in gallbladder cancer (GBC) remains unclear. The main objective of this investigation was to clarify the relationships between TROP2 expression and the clinicopathological features of patients with GBC. Immunohistochemistry was performed to investigate the expression of TROP2 and epithelial-mesenchymal transition (EMT) indicator proteins in 93 patients with GBC. Immunohistochemistry showed that the protein expression level of TROP2 was significantly higher in GBC tissues than in adjacent noncancerous tissues. In addition, immunohistochemistry analysis showed that TROP2 expression was significantly correlated with histologic grade (P=0.038), tumor stage (P=0.015), and lymph node metastasis (P=0.007). Furthermore, high TROP2 expression was significantly associated with a loss of the epithelial marker E-cadherin (P=0.013) and acquisition of expression of the mesenchymal marker vimentin (P=0.031). Kaplan-Meier analysis and Cox proportional hazards regression models were used to investigate the correlation between TROP2 expression and prognosis of GBC patients. Kaplan-Meier analysis indicated that patients with high TROP2 expression had poor overall survival (P<0.001). Multivariate analysis showed that high TROP2 expression was an independent predictor of overall survival. In conclusion, our data suggest for the first time that the increased expression of TROP2 in GBC is associated significantly with aggressive progression and poor prognosis. In conclusion, this study confirmed that TROP2 might be involved in regulating the EMT and malignant progression in GBC. It also provided the first evidence that TROP2 expression in GBC was an independent prognostic factor of patients, which might be a potential diagnostic and therapeutic target of GBC.

Crosstalk between ferroptosis and cuproptosis: From mechanism to potential clinical application.

Ferroptosis and cuproptosis, regulated forms of cell death resulting from metal ion accumulation, are closely related in terms of occurrence, cell metabolism, signaling pathways, and drug resistance. Notably, it is now understood that these processes play crucial roles in regulating physiological and pathological processes, especially in tumor development. Consequently, ferroptosis and cuproptosis have gained increasing significance as potential targets for anti-cancer drug development. This article systematically outlines the molecular mechanisms and cross-talk components of both ferroptosis and cuproptosis, elucidating their impacts on cancer. Furthermore, it investigates the clinical perspective of targeted ferroptosis and cuproptosis in cancer chemotherapy, immunotherapy, and radiotherapy. Our discussion extends to a comparative analysis of nanoparticles developed based on the mechanisms of ferroptosis and cuproptosis in cancer, contrasting them with current conventional therapies. Opportunities and challenges in cancer treatment are explored, emphasizing the potential therapeutic direction of co-targeting ferroptosis and cuproptosis. The article also attempts to analyze the clinical applications of this co-targeting approach for cancer treatment while summarizing the existing barriers that require overcoming.

FOXA1 and FOXA2: the regulatory mechanisms and therapeutic implications in cancer.

FOXA1 (Forkhead Box A1) and FOXA2 (Forkhead Box A2) serve as pioneering transcription factors that build gene expression capacity and play a central role in biological processes, including organogenesis and differentiation, glycolipid metabolism, proliferation, migration and invasion, and drug resistance. Notably, FOXA1 and FOXA2 may exert antagonistic, synergistic, or complementary effects in the aforementioned biological processes. This article focuses on the molecular mechanisms and clinical relevance of FOXA1 and FOXA2 in steroid hormone-induced malignancies and highlights potential strategies for targeting FOXA1 and FOXA2 for cancer therapy. Furthermore, the article describes the prospect of targeting upstream regulators of FOXA1/FOXA2 to regulate its expression for cancer therapy because of the drug untargetability of FOXA1/FOXA2.

A dual-radiomics model for overall survival prediction in early-stage NSCLC patient using pre-treatment CT images.

Introduction: Radiation therapy (RT) is one of the primary treatment options for early-stage non-small cell lung cancer (ES-NSCLC). Therefore, accurately predicting the overall survival (OS) rate following radiotherapy is crucial for implementing personalized treatment strategies. This work aims to develop a dual-radiomics (DR) model to (1) predict 3-year OS in ES-NSCLC patients receiving RT using pre-treatment CT images, and (2) provide explanations between feature importanceand model prediction performance. Methods: The publicly available TCIA Lung1 dataset with 132 ES-NSCLC patients received RT were studied: 89/43 patients in the under/over 3-year OS group. For each patient, two types of radiomic features were examined: 56 handcrafted radiomic features (HRFs) extracted within gross tumor volume, and 512 image deep features (IDFs) extracted using a pre-trained U-Net encoder. They were combined as inputs to an explainable boosting machine (EBM) model for OS prediction. The EBM's mean absolute scores for HRFs and IDFs were used as feature importance explanations. To evaluate identified feature importance, the DR model was compared with EBM using either (1) key or (2) non-key feature type only. Comparison studies with other models, including supporting vector machine (SVM) and random forest (RF), were also included. The performance was evaluated by the area under the receiver operating characteristic curve (AUCROC), accuracy, sensitivity, and specificity with a 100-fold Monte Carlo cross-validation. Results: The DR model showed highestperformance in predicting 3-year OS (AUCROC=0.81 ± 0.04), and EBM scores suggested that IDFs showed significantly greater importance (normalized mean score=0.0019) than HRFs (score=0.0008). The comparison studies showed that EBM with key feature type (IDFs-only demonstrated comparable AUCROC results (0.81 ± 0.04), while EBM with non-key feature type (HRFs-only) showed limited AUCROC (0.64 ± 0.10). The results suggested that feature importance score identified by EBM is highly correlated with OS prediction performance. Both SVM and RF models were unable to explain key feature type while showing limited overall AUCROC=0.66 ± 0.07 and 0.77 ± 0.06, respectively. Accuracy, sensitivity, and specificity showed a similar trend. Discussion: In conclusion, a DR model was successfully developed to predict ES-NSCLC OS based on pre-treatment CT images. The results suggested that the feature importance from DR model is highly correlated to the model prediction power.

A multicenter, prospective, non-interventional real-world study to assess the effectiveness of mecapegfilgrastim in preventing neutropenia in patients with gastrointestinal cancer.

BACKGROUND: Mecapegfilgrastim, a long-acting granulocyte-colony stimulating factor has been approved for reducing the incidence of infection, particularly febrile neutropenia (FN), in China. OBJECTIVE: We conducted a multicenter prospective observational study to examine the safety and effectiveness of mecapegfilgrastim in preventing neutropenia in gastrointestinal patients receiving the chemotherapy, including S-1/capecitabine-based regimens or the fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)/fluorouracil, leucovorin, and oxaliplatin (FOLFOX)/fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) regimens. METHOD: Five hundred and sixty-one gastrointestinal patients from 40 sites across China, between May 2019 and November 2021, were included. The administration of mecapegfilgrastim was prescribed at the discretion of local physicians. RESULTS: The most common adverse drug reactions (ADRs) of any grade for all patients was increased white blood cells (2.9%). Grade 3/4 ADRs were observed for anemia (0.2%), decreased white blood cells (0.2%), and decreased neutrophil count (0.2%). Among the 116 patients who received S-1/capecitabine-based chemotherapy throughout all cycles, ADRs of any grade included anemia (1.7%), myalgia (0.9%), and increased alanine aminotransferase (0.9%). No grade 3/4 ADRs were observed. In 414 cycles of patients who underwent S-1/capecitabine-based regimens, only one (0.2%) cycle experienced grade 4 neutropenia. In the FOLFIRINOX, FOLFOXIRI, and FOLFOX chemotherapy regimens, grade 4 neutropenia occurred in one (2.7%) of 37 cycles, four (4.7%) of 85 cycles, and two (1.2%) of 167 cycles, respectively. CONCLUSION: In a real-world setting, mecapegfilgrastim has proven effective in preventing severe neutropenia in gastrointestinal patients following chemotherapy. This includes commonly used moderate or high-risk FN regimens or regimens containing S1/capecitabine, all of which have demonstrated favorable efficacy and safety profiles.

Identification of G protein subunit alpha i2 as a promising therapeutic target of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a global health problem. Its incidence and mortality are increasing. Exploring novel therapeutic targets against HCC is important and urgent. We here explored the expression and potential function of Gαi2 (G protein subunit alpha i2) in HCC. The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) database shows that the number of Gαi2 transcripts in HCC tissues is significantly higher than that in the normal liver tissues. Moreover, Gαi2 overexpression in HCC correlates with poor prognosis of the patients. Gαi2 mRNA and protein expression are also elevated in local HCC tissues and different human HCC cells. In patient-derived primary HCC cells and immortalized HepG2 cells, Gαi2 silencing (by targeted shRNA) or knockout (KO, by the dCas9-sgRNA method) largely suppressed cell proliferation and motility, while inducing cell cycle arrest and caspase-apoptosis activation. Moreover, Gαi2 silencing or KO-induced reactive oxygen species (ROS) production and oxidative injury in primary and HepG2 HCC cells. Whereas different antioxidants ameliorated Gαi2-shRNA-induced anti-HCC cell activity. Using a lentiviral construct, Gαi2 overexpression further augmented proliferation and motility of primary and immortalized HCC cells. Further studies revealed that the binding between the transcription factor early growth response zinc finger transcription factor 1 (EGR1) and Gαi2 DNA promoter was significantly increased in HCC tissues and cells. In vivo, intratumoral injection of Gαi2 shRNA adeno-associated virus significantly hindered HCC xenograft growth in nude mice. Moreover, the growth of Gαi2-KO HCC xenografts in the nude mice was remarkably slow. Gαi2 depletion, oxidative injury, and apoptosis induction were detected in Gαi2-silenced or Gαi2-KO HCC xenografts. Together, overexpressed Gαi2 is required for HCC cell growth in vitro and in vivo, representing as a novel and promising diagnosis marker and therapeutic target of HCC.

Identification of matrix-remodeling associated 5 as a possible molecular oncotarget of pancreatic cancer.

Pancreatic cancer has an extremely poor prognosis. Here we examined expression, potential functions and underlying mechanisms of MXRA5 (matrix remodeling associated 5) in pancreatic cancer. Bioinformatics studies revealed that MXRA5 transcripts are significantly elevated in pancreatic cancer tissues, correlating with the poor overall survival, high T-stage, N1 and pathologic stage of the patients. MXRA5 mRNA and protein expression is significantly elevated in microarray pancreatic cancer tissues and different pancreatic cancer cells. In primary and immortalized (BxPC-3 and PANC-1 lines) pancreatic cancer cells, shRNA-induced MXRA5 silencing or CRISPR/Cas9-mediated MXRA5 knockout suppressed cell survival, proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), while provoking cell apoptosis. Conversely, forced overexpression of MXRA5 further promoted pancreatic cancer cell progression and EMT. Bioinformatics studies and the protein chip analyses revealed that differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) in MXRA5-overexpressed primary pancreatic cancer cells were enriched in the PI3K-Akt-mTOR cascade. Indeed, Akt-mTOR activation in primary human pancreatic cancer cells was inhibited by MXRA5 shRNA or knockout, but was augmented following MXRA5 overexpression. In vivo, the growth of MXRA5 KO PANC-1 xenografts was largely inhibited in nude mice. Moreover, intratumoral injection of adeno-associated virus-packed MXRA5 shRNA potently inhibited primary pancreatic cancer cell growth in nude mice. Akt-mTOR activation was also largely inhibited in the MXRA5-depleted pancreatic cancer xenografts. Contrarily MXRA5 overexpression promoted primary pancreatic cancer cell growth in nude mice. Together, overexpressed MXRA5 is important for pancreatic cancer cell growth possibly through promoting EMT and Akt-mTOR activation. MXRA5 could be a potential therapeutic oncotarget for pancreatic cancer.

Perifosine sensitizes curcumin-induced anti-colorectal cancer effects by targeting multiple signaling pathways both in vivo and in vitro.

Our study shows that coadministration of curcumin and an orally bioactive alkylphospholipid perifosine results in a significant increase in colorectal cancer cell apoptosis and a marked inhibition of cell growth both in vitro and in vivo. This novel combinatorial regimen leads to changes of multiple cell signaling pathways including inactivation of Akt and nuclear factor-κB as well as activation of c-Jun N-terminal kinases and endoplasmic reticulum stress. Further, perifosine and curcumin synergistically increase intracellular level of reactive oxygen species and ceramide, and downregulate the expression of cyclin D1 and Bcl-2 in colorectal cancer cells. These changes at molecular level together account for the cancer cell apoptosis and growth inhibition. We conclude that perifosine sensitizes colorectal cancer cells to curcumin by modulating multiple signaling pathways. Adding perifosine with curcumin may represent an effective therapy regimen against colorectal cancers, and possible other aggressive tumors.

The association between polymorphisms in the leptin receptor gene and risk of breast cancer: a systematic review and pooled analysis.

Many epidemiological studies have found that leptin correlates to body fat extent and breast cancer. Leptin exerts its physiological action through the leptin receptor (LEPR). However, published data on the association between LEPR alleles and breast cancer occurrence have led to in contradictory results. A total of 10 studies were identified to the meta-analysis, including 4,644 cases and 5,485 controls for LEPR rs1137101 polymorphism, 5 studies with 2,759 cases and 4,464 controls for rs1137100 polymorphism, and 2 studies for rs8051542, rs8051542, and rs8051542 polymorphisms. The pooled odds ratios (OR) with 95 % confidence intervals (CI) for breast cancer risk associated with LEPR genotypes were estimated. Elevated breast cancer risk was associated with LEPR rs1137101 polymorphism when all studies were pooled in the meta-analysis (allele contrast model: OR = 0.71, 95 % CI = 0.551-0.997). In the stratified analysis by ethnicity, significantly increased risks were also found among Asians for allele contrast model (OR 0.414, 95 % CI 0.312-0.550) and dominant model (OR 0.537, 95 % CI 0.370-0.781); for Africans, significantly increased risks were also found for allele contrast model (OR 0.716, 95 % CI 0.595-0.861), homozygote codominant (OR 0.537, 95 % CI 0.370-0.781) and dominant model (OR 1.595, 95 % CI 1.207-2.108). And significantly elevated breast cancer risk was associated with LEPR rs1137100 polymorphism for allele contrast (OR = 0.666, 95 % CI = 0.603-0.720) and homozygote codominant models (OR = 0.344, 95 % CI = 0.282-0.421). For LEPR rs8179183, rs4655537, and rs3762274 polymorphisms, no significant associations were detected in all comparison models. This pooled analysis suggested that rs1137101 and rs1137100 polymorphisms were significantly correlated with breast cancer risk and the A allele of LEPR rs1137101 variant and the G allele of LEPR rs1137100 variant were low-penetrant risk factors for developing breast cancer. Further, no significant associations existed between LEPR rs8179183, rs4655537, and rs3762274 polymorphisms and risk of breast cancer.

Endothelial cell-specific molecule 1 drives cervical cancer progression.

The expression, biological functions and underlying molecular mechanisms of endothelial cell-specific molecule 1 (ESM1) in human cervical cancer remain unclear. Bioinformatics analysis revealed that ESM1 expression was significantly elevated in human cervical cancer tissues, correlating with patients' poor prognosis. Moreover, ESM1 mRNA and protein upregulation was detected in local cervical cancer tissues and various cervical cancer cells. In established and primary cervical cancer cells, ESM1 shRNA or CRISPR/Cas9-induced ESM1 KO hindered cell proliferation, cell cycle progression, in vitro cell migration and invasion, and induced significant apoptosis. Whereas ESM1 overexpression by a lentiviral construct accelerated proliferation and migration of cervical cancer cells. Further bioinformatics studies and RNA sequencing data discovered that ESM1-assocaited differentially expressed genes (DEGs) were enriched in PI3K-Akt and epithelial-mesenchymal transition (EMT) cascades. Indeed, PI3K-Akt cascade and expression of EMT-promoting proteins were decreased after ESM1 silencing in cervical cancer cells, but increased following ESM1 overexpression. Further studies demonstrated that SYT13 (synaptotagmin 13) could be a primary target gene of ESM1. SYT13 silencing potently inhibited ESM1-overexpression-induced PI3K-Akt cascade activation and cervical cancer cell migration/invasion. In vivo, ESM1 knockout hindered SiHa cervical cancer xenograft growth in mice. In ESM1-knockout xenografts tissues, PI3K-Akt inhibition, EMT-promoting proteins downregulation and apoptosis activation were detected. In conclusion, overexpressed ESM1 is important for cervical cancer growth in vitro and in vivo, possibly by promoting PI3K-Akt activation and EMT progression. ESM1 represents as a promising diagnostic marker and potential therapeutic target of cervical cancer.

Prognostic Nutritional Index Predicts Outcome of PD-L1 Negative and MSS Advanced Cancer Treated with PD-1 Inhibitors.

Purpose: Tumor mutational burden (TMB), microsatellite instability-high (MSI-H), and expression of programmed death ligand-1 (PD-L1) have emerged as predictive biomarkers for responsiveness to immune checkpoint inhibitors (ICIs) in several cancer types. However, for patients with negative PD-L1 expression, or microsatellite stability (MSS), some cases may experience favorable response to immunotherapy, and there is currently a lack of good relevant predictors. We tried to introduce several peripheral blood markers for predicting treatment outcome and immune-related adverse events (irAEs) in PD-L1 negative and MSS patients. Methods: A retrospective study of 142 PD-L1 negative and MSS patients was carried out. The association of peripheral blood markers including lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), albumin-to-globulin ratio (AGR), prognostic nutrition index (PNI), and other factors with clinicopathological characters and prognosis were assessed by Cox regression and Kaplan-Meier methods. Results: Lower level of PNI and poor performance status (ECOG score of 2) was correlated with significantly shorter overall survival (OS) and worse outcome of ICIs. The multivariate analysis revealed that PNI (for OS HR = 0.465, 95% CI: 0.236-0.916, p = 0.027; for PFS HR = 0.493, 95% CI: 0.251-0.936, p = 0.031) and ECOG score (for OS HR = 4.601, 95% CI: 2.676-7.910, p < 0.001; for PFS HR = 2.830, 95% CI: 1.707-4.691, p < 0.001) were independent prognostic factors for OS and PFS. NLR was related to the onset of irAEs. Conclusions: Pretreatment level of PNI and NLR, beyond PD-L1 expression and MSS, can improve the predictive accuracy for immunotherapy outcomes and has the potential to expand the candidate pool of patients for treatment with ICIs.

The sphingosine kinase inhibitor SKI-V suppresses cervical cancer cell growth.

Overexpression and/or overactivation of sphingosine kinase 1/2 (SphK1/2) is important for tumorigenesis and progression of cervical cancer. The current study examined the potential activity and signaling mechanisms of SKI-V, a non-lipid small molecule SphK inhibitor, against cervical cancer cells. In different primary and immortalized cervical cancer cells, SKI-V exerted significant anti-cancer activity by inhibiting cell viability, colony formation, proliferation, cell cycle progression and cell migration. Significant apoptosis activation was detected in SKI-V-treated cervical cancer cells. Significantly, SKI-V also provoked programmed necrosis cascade in cervical cancer cells, as it induced mitochondrial p53-cyclophilin-D-adenine nucleotide translocator-1 (ANT1) complexation, mitochondrial membrane potential collapse, reactive oxygen species production and the release of lactate dehydrogenase into the medium. Further, SKI-V blocked SphK activation and induced ceramide accumulation in primary cervical cancer cells, without affecting SphK1/2 expression. SKI-V-induced cytotoxicity in cervical cancer cells was largely inhibited by sphingosine-1-phosphate or the SphK1 activator K6PC-5, but was sensitized by adding the short-chain ceramide C6. Moreover, SKI-V inhibited Akt-mTOR (mammalian target of rapamycin) activation in primary cervical cancer cells, and its cytotoxicity was mitigated by a constitutively-active Akt. In vivo, daily intraperitoneal injection of SKI-V significantly inhibited subcutaneous primary cervical cancer xenograft growth in nude mice. Together, the SphK inhibitor SKI-V suppresses cervical cancer growth in vitro and in vivo.

The bevacizumab plus oxaliplatin-based chemotherapy regimen is more suitable for metastatic colorectal cancer patients with a history of schistosomiasis: a clinical retrospective analysis.

Background: The basic platelet counts of schistosomiasis patients are low. If it does not meet the requirements for chemotherapy, the patient's treatment will not be carried out, which directly affects their prognosis. Therefore the impact of treatment on platelet counts is critically important. The effects of bevacizumab plus oxaliplatin-based chemotherapy and bevacizumab plus irinotecan-based chemotherapy regimens on platelets are different but have not been determined. In order to find a more suitable plan for metastatic colorectal cancer (mCRC) patients with a history of schistosomiasis, we conducted a retrospective analysis of mCRC patients and evaluated the impact of bevacizumab on their platelets. Methods: The medical records of all mCRC patients with a history of schistosomiasis who received oxaliplatin-based chemotherapy or irinotecan-based chemotherapy as first-line treatment for no less than 4 cycles, with or without bevacizumab from September 1, 2017, to June 30, 2019, in Kunshan Hospital were reviewed. Six-month cumulative incidence rates of splenomegaly and thrombocytopenia of chemotherapy with and without bevacizumab groups, oxaliplatin-based chemotherapy with and without bevacizumab groups, irinotecan-based chemotherapy with and without bevacizumab groups were compared from the first cycle until the completion of chemotherapy using Kaplan-Meier analysis and Log-rank test. Results: Evaluable splenic enlargement and thrombocytopenia results were obtained from 153 mCRC patients. The 6-month cumulative incidence rates of splenomegaly (23.3% vs. 55%; P=0.01) and that of thrombocytopenia (43.8% vs. 57.5%; P=0.40) were lower in the bevacizumab group than the non-bevacizumab group, however there were no statistical differences for the rates of thrombocytopenia. For patients treated with oxaliplatin, the rates of splenomegaly (19.5% vs. 66.7%; P=0.01) and thrombocytopenia (31.7% vs. 77.2%; P=0.02) were lower in the bevacizumab-treated cohort than that in the non-bevacizumab cohort. When stratified for irinotecan, there were no statistical differences in the frequency of splenomegaly between the two groups. However, the rates of thrombocytopenia were higher in the bevacizumab-treated cohort than that in the non-bevacizumab cohort (59.4% vs. 8.7%; P=0.01). Conclusions: The bevacizumab plus oxaliplatin-based chemotherapy regimen is safer for mCRC patients with a history of schistosomiasis, especially for patients with a lower platelet count.