Sulfoxide-containing polymers conjugated prodrug micelles with enhanced anticancer activity and reduced intestinal toxicity.

Poly(ethylene glycol) (PEG) is widely utilized as a hydrophilic coating to extend the circulation time and improve the tumor accumulation of polymeric micelles. Nonetheless, PEGylated micelles often activate complement proteins, leading to accelerated blood clearance and negatively impacting drug efficacy and safety. Here, we have crafted amphiphilic block copolymers that merge hydrophilic sulfoxide-containing polymers (psulfoxides) with the hydrophobic drug 7-ethyl-10-hydroxylcamptothecin (SN38) into drug-conjugate micelles. Our findings show that the specific variant, PMSEA-PSN38 micelles, remarkably reduce protein fouling, prolong blood circulation, and improve intratumoral accumulation, culminating in significantly increased anti-cancer efficacy compared with PEG-PSN38 counterpart. Additionally, PMSEA-PSN38 micelles effectively inhibit complement activation, mitigate leukocyte uptake, and attenuate hyperactivation of inflammatory cells, diminishing their ability to stimulate tumor metastasis and cause inflammation. As a result, PMSEA-PSN38 micelles show exceptional promise in the realm of anti-metastasis and significantly abate SN38-induced intestinal toxicity. This study underscores the promising role of psulfoxides as viable PEG substitutes in the design of polymeric micelles for efficacious anti-cancer drug delivery.

Systemic knockout of Tmem175 results in aberrant differentiation but no effect on hematopoietic reconstitution.

Lysosomes play crucial roles in regulating cell metabolism, and K+ channels are critical for controlling various aspects of lysosomal function. Additionally, lysosomal activity is essential for maintaining the quiescence of hematopoietic stem cells (HSCs) under both steady-state and stress conditions. Tmem175 is a lysosomal potassium channel protein. To further investigate the role of K+ channels in HSCs, our study employed knockout mice to examine the function of Tmem175. Our research findings demonstrate that the deletion of Tmem175 does not disrupt the functionality of HSCs in both stable and stressed conditions, including irradiation and intraperitoneal 5-FU injections. However, we did observe that the absence of Tmem175 impairs the long-term differentiation capacity of HSCs into myeloid differentiated subpopulation cells（In this paper, it is referred to simply as M cells）in HSC transplantation test, while promoting their differentiation into T cells. This suggests that Tmem175 plays a role in the lineage differentiation of HSCs without being essential for their self-renewal or long-term regenerative capabilities.

Neutrophil Extracellular Traps-Inhibiting and Fouling-Resistant Polysulfoxides Potently Prevent Postoperative Adhesion, Tumor Recurrence, and Metastasis.

Peritoneal metastasis (PM) is considered one of the most dreaded forms of cancer metastases for both patients and physicians. Aggressive cytoreductive surgery (CRS) is the primary treatment for peritoneal metastasis. Unfortunately, this intensive treatment frequently causes clinical complications, such as postoperative recurrence, metastasis, and adhesion formation. Emerging evidence suggests that neutrophil extracellular traps (NETs) released by inflammatory neutrophils contribute to these complications. Effective NET-targeting strategies thus show considerable potential in counteracting these complications but remain challenging. Here, one type of sulfoxide-containing homopolymer, PMeSEA, with potent fouling-resistant and NET-inhibiting capabilities, is synthesized and screened. Hydrating sulfoxide groups endow PMeSEA with superior nonfouling ability, significantly inhibiting protein/cell adhesion. Besides, the polysulfoxides can be selectively oxidized by ClO- which is required to stabilize the NETs rather than H2O2, and ClO- scavenging effectively inhibits NETs formation without disturbing redox homeostasis in tumor cells and quiescent neutrophils. As a result, PMeSEA potently prevents postoperative adhesions, significantly suppresses peritoneal metastasis, and shows synergetic antitumor activity with chemotherapeutic 5-Fluorouracil. Moreover, coupling CRS with PMeSEA potently inhibits CRS-induced tumor metastatic relapse and postoperative adhesions. Notably, PMeSEA exhibits low in vivo acute and subacute toxicities, implying significant potential for clinical postoperative adjuvant treatment.

MAPK4 silencing in gastric cancer drives liver metastasis by positive feedback between cancer cells and macrophages.

Liver metastasis is a major cause of death in gastric cancer patients, but the underlying mechanisms are poorly understood. Through a combination of in vivo screening and transcriptome profiling followed by quantitative RT-PCR and tissue array analyses, we found that mitogen-activated protein kinase 4 (MAPK4) downregulation in gastric cancer tissues from patients is significantly associated with liver metastasis and poor prognosis. The knockdown of MAPK4 in gastric cancer cells promotes liver metastasis in orthotopic mouse models. MAPK4 depletion in gastric cancer cells induces the secretion of macrophage migration inhibitory factor (MIF) to polarize tumor-associated macrophages (TAMs) in orthotopic xenograft tumors. Moreover, TAMs activate epithelial-mesenchymal transition of gastric cancer cells to suppress MAPK4 expression, which further increases MIF secretion to polarize TAMs. Taken together, our results suggest a previously undescribed positive feedback loop between cancer cells and macrophages mediated by MAPK4 silencing that facilitates gastric cancer liver metastasis.

mTORC2 Facilitates Liver Regeneration Through Sphingolipid-Induced PPAR-α-Fatty Acid Oxidation.

BACKGROUND & AIMS: During liver regeneration after partial hepatectomy, the function and metabolic pathways governing transient lipid droplet accumulation in hepatocytes remain obscure. Mammalian target of rapamycin 2 (mTORC2) facilitates de novo synthesis of hepatic lipids. Under normal conditions and in tumorigenesis, decreased levels of triglyceride (TG) and fatty acids (FAs) are observed in the mTORC2-deficient liver. However, during liver regeneration, their levels increase in the absence of mTORC2. METHODS: Rictor liver-specific knockout and control mice underwent partial hepatectomy, followed by measurement of TG and FA contents during liver regeneration. FA metabolism was evaluated by analyzing the expression of FA metabolism-related genes and proteins. Intraperitoneal injection of the peroxisome proliferator-activated receptor α (PPAR-α) agonist, p53 inhibitor, and protein kinase B (AKT) activator was performed to verify the regulatory pathways involved. Lipid mass spectrometry was performed to identify the potential PPAR-α activators. RESULTS: The expression of FA metabolism-related genes and proteins suggested that FAs are mainly transported into hepatocytes during liver regeneration. The PPAR-α pathway is down-regulated significantly in the mTORC2-deficient liver, resulting in the accumulation of TGs. The PPAR-α agonist WY-14643 rescued deficient liver regeneration and survival in mTORC2-deficient mice. Furthermore, lipidomic analysis suggested that mTORC2 deficiency substantially reduced glucosylceramide (GluCer) content. GluCer activated PPAR-α. GluCer treatment in vivo restored the regenerative ability and survival rates in the mTORC2-deficient group. CONCLUSIONS: Our data suggest that FAs are mainly transported into hepatocytes during liver regeneration, and their metabolism is facilitated by mTORC2 through the GluCer-PPAR-α pathway, thereby establishing a novel role for mTORC2 in lipid metabolism.

Statin uses and mortality in colorectal cancer patients: An updated systematic review and meta-analysis.

BACKGROUND: Colorectal cancer (CRC) remains one of the most common types of cancer and a leading cause of death worldwide. Previous studies indicated that statins may have a potential protective effect on CRC. METHODS: We conducted this meta-analysis to systematically assess the overall and cancer-specific survival benefit of statin uses on CRC patients. Related references were identified through PubMed, the Cochrane Library, Web of Science, EMBASE, and SCOPUS from inception to August 2017. Adjusted hazard ratios (HRs) were adopted to calculate summary hazard ratios (HRs) with 95% confidence intervals (95% CIs), using a random-effects model. RESULTS: Total fourteen studies involving 130 994 patients were included in this meta-analysis. Six studies reported the association between pre-diagnosis statin uses and CRC mortality, while 11 studies investigated mortality in patients using statins after CRC diagnosis. For pre-diagnosis statin uses, the pooled HR of all-cause mortality (ACM) was 0.85 (95% CI, 0.79-0.92) and the pooled HR of cancer-specific mortality (CSM) was 0.82 (95% CI, 0.79-0.86). In terms of post-diagnosis statin uses, the pooled HR of ACM was 0.86 (95% CI, 0.76-0.98), and the pooled HR of CSM was 0.79 (95% CI, 0.70-0.89). For post-diagnosis statin uses, there is no difference in ACM when stratified by KRAS gene (KRAS) mutation status. Results of ACM and CSM did not markedly alter in other subgroup analyses. CONCLUSION: Our meta-analysis demonstrates that both pre-diagnosis and post-diagnosis statin uses are associated with reduced ACM and CSM for CRC patients.

Contrast-Enhanced EUS for Differential Diagnosis of Pancreatic Masses: A Meta-Analysis.

BACKGROUND: Though methods for the diagnosis of pancreatic masses are various, such as ultrasonography (US), computed tomography (CT), endoscopic ultrasonography (EUS), and contrast-enhanced computed tomography (CE-CT), their sensitivity, specificity, and accuracy are not quite satisfying. Contrast-enhanced endoscopic ultrasonography (CE-EUS), as a new technique, has its own unique advantages in diagnosing pancreatic disease. However, its sensitivity, specificity, and accuracy are still controversial. OBJECTIVE: To evaluate the accuracy of CE-EUS for differential diagnosis between benign and malignant pancreatic mass lesions. DESIGN: Eighteen relevant articles systemically searched from PubMed, Web of Science, Ovid, Scopus, and MEDLINE were selected. The pooled results were calculated in a fixed effects model. MAIN OUTCOME MEASUREMENT: The pooled sensitivity, specificity, positive likelihood ratio (LR), negative likelihood ratio, diagnostic odds ratio (OR), and summary receiver operating characteristic (SROC) curve. RESULTS: The pooled sensitivity, specificity, and diagnostic odds ratio of CE-EUS for the differential diagnosis of pancreatic adenocarcinomas were 0.91 (95% confidence interval (CI), 0.89-0.93), 0.86 (95% CI, 0.83-0.89), and 69.50 (95% CI, 48.89-98.80), respectively. The SROC area under the curve was 0.9545. The subgroup analysis based on excluding the outliers showed that the heterogeneity was eliminated and the pooled sensitivity and specificity were 0.92 (95% CI, 0.90-0.93) and 0.87 (95% CI, 0.84-0.89), respectively. The SROC area under the curve was 0.9569. CONCLUSION: CE-EUS is a useful method to distinguish pancreatic adenocarcinoma from other pancreatic diseases. Compared with EUS elastography, it has higher specificity. However, it is still not superior to pathological diagnosis for the identification of pancreatic carcinomas.

Different Anatomical Subsites of Colon Cancer and Mortality: A Population-Based Study.

BACKGROUND: In terms of incidence and pathogenesis, right-sided colon cancer (RCC) and left-sided colon cancer (LCC) exhibit several differences. However, whether existing differences could reflect the different survival outcomes remains unclear. Therefore, we aimed to ascertain the role of location in the prognosis. METHODS: We identified colon cancer cases from the Surveillance, Epidemiology, and End Results database between 1973 and 2012. Differences among subsites of colon cancer regarding clinical features and metastatic patterns were compared. The Kaplan-Meier curves were conducted to compare overall and disease-specific survival in relation to cancer location. The effect of tumour location on overall and cancer-specific survival was analysed by Cox proportional hazards model. RESULTS: A total of 377,849 patients from SEER database were included in the current study, with 180,889 (47.9%) RCC and 196,960 (52.1%) LCC. LCC was more likely to metastasize to the liver and lung. Kaplan-Meier curves demonstrated that LCC patients had better overall and cancer-specific survival outcomes. Among Cox multivariate analyses, LCC was associated with a slightly reduced risk of overall survival (HR, 0.92; 95% CI, 0.92-0.93) and cancer-specific survival (HR, 0.92; 95% CI, 0.91-0.93), even after adjusted for other variables. However, the relationship between location and prognosis was varied by subgroups defined by age, year at diagnosis, stage, and therapies. CONCLUSIONS: We demonstrated that LCC was associated with better prognosis, especially for patients with distant metastasis. Future trails should seek to identify the underlying mechanism.

The impact of a history of cancer on pancreatic ductal adenocarcinoma survival.

BACKGROUND AND OBJECTIVE: Previous studies indicated cancer survivors had a higher risk of developing subsequent pancreatic ductal adenocarcinoma. However, the influence of prior cancer on survival outcomes of current pancreatic cancer remains unclear. METHODS: Eligible populations were selected from the Surveillance, Epidemiology, and End Results programs from 2000 to 2012. We adopted Kaplan-Meier curves and Cox analysis to compare survival differences between patients with and without prior cancer. RESULTS: Overall, 67,555 pancreatic cancer patients, including 5582 (8.26%) with and 61,973 (91.74%) without prior cancer, were included. The most common types of prior cancers were prostate, breast, and colorectal cancers. The median time from diagnosis of an initial malignancy to subsequent pancreatic cancer was 59.8 months. Patients with a prior cancer had higher overall one-year and three-year survival rates compared with those without a prior cancer. Multivariable Cox analysis demonstrated that a history of prior malignancy could independently predict the better overall survival outcome of pancreatic cancer (HR = 0.92, 95% CI, 0.89-0.94, p < 0.001), especially for colorectal, breast, corpus uteri and prostate cancer survivors. CONCLUSIONS: A history of cancer did not contribute to a poor survival outcome for patients with pancreatic cancer. More prospective trials might be warranted to validate our findings.

Rectal Indomethacin Is Protective against Pancreatitis after Endoscopic Retrograde Cholangiopancreatography: Systematic Review and Meta-Analysis.

BACKGROUND AND AIM: Rectal indomethacin was reported to be effective for postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) prophylaxis. However, the preventive effect of indomethacin for average-risk patients remains unclear. Recently, some conflicting evidence was addressed by recent articles. We aimed to determine the protective role of indomethacin in PEP based on the latest available literature. METHODS: A systematic literature search was conducted using PubMed, Embase, Web of Science, and the Cochrane Library to identify related articles published before October 2016. Studies that evaluated the administration of indomethacin in the prevention of PEP were included in the analysis. We adopted a random-effects model to calculate the overall relative risk (RR) and 95% confidence interval (CI). RESULTS: Ten trials from an initial search were finally included in the meta-analysis. The administration of rectal indomethacin significantly reduced the incidence of PEP in consecutive ERCP population (RR, 0.63; 95% CI, 0.50-0.77). There was no significant heterogeneity across included studies (I2 = 14.2%, P = 0.31). Further subgroup analyses also revealed that rectal indomethacin could protect the individuals at high and average risks and reduced severity of PEP. Pre-ERCP administration of indomethacin seemed to be better than the post-ERCP given. There was no evidence of significant publication bias. CONCLUSIONS: Rectal administration of indomethacin is an effective approach to prevent the incidence of PEP in both high- and average-risk populations undergoing ERCP. However, more high-quality RCTs are needed to further investigate the optimal timing for the administration of indomethacin.

Excessive risk of second primary cancers in young-onset colorectal cancer survivors.

With an increasing trend of patients with young-onset colorectal cancer (CRC), risks of second primary cancers (SPCs) among them become a concerning issue. We aimed to define the detailed risk and site-distributed patterns of SPCs in young CRC individuals (age ≤50). A population-based cohort were identified from the Surveillance, Epidemiology, and End Results database between 1973 and 2013. Standardized incidence ratios (SIRs) and absolute excess risk (AER) were calculated to assess the risk for SPCs compared with the general population. A total of 44,106 patients, including 3245 (7.4%) the young and 40,861 (92.6%) the old, developed 50,679 secondary malignancies subsequently. With increased age, the risk of secondary cancers gradually decreased. A significant 44% excess risk of SPCs was observed in the young (SIR = 1.44, AER = 34.23), while a slightly increased risk was noted in the old (SIR = 1.02, AER = 4.29). For young survivors, the small intestine (SIR = 8.49), bile ducts (SIR = 3.77), corpus, and uterus (SIR = 2.45) were the most common sites of SPCs. Significantly, excess SIRs in the young were persisted regardless of other factors. For the young, secondary cancer-related deaths were responsible for 51.2% of overall deaths and secondary stomach, liver and bile, pancreas cancers were top three causes. An excessive risk of SPCs existed in young CRC survivors, and this trend was consistent among different subgroups. We hope our findings may inform future targeted screening strategies among young-onset CRC survivors.

Validation of the American Joint Committee on Cancer (AJCC) 8th edition stage system for gastric cancer patients: a population-based analysis.

BACKGROUND: Our aim was to validate the American Joint Committee on Cancer (AJCC) 8th edition stage system for gastric cancer in the Western world and to compare several modifications between the 7th and 8th edition systems. METHODS: Eligible patients having undergone surgical resection of gastric cancer during 2004-2011 from the Surveillance, Epidemiology, and End Results (SEER) database were included in the current study. Survival differences were assessed by Kaplan-Meier curve and log-rank tests. The discriminative power of the AJCC 8th and 7th editions was compared by Harrell's concordance index (c-index). RESULTS: Patients with pN3a and pN3b presented distinct survival outcomes, especially for cases in which more than 15 lymph nodes were examined. The overall (OS) and cancer-specific survival (CSS) c-indices for the 8th edition were largely comparable with c-indices for the 7th edition throughout the cohort. Notably, the new edition improved the power of discrimination slightly in OS and CSS (c-indices: 0.717, 0.744) compared with the 7th edition (c-indices: 0.712, 0.739) for patients for whom 15 or more lymph nodes were examined. The analysis of stage migration in the new edition revealed nonhomogeneous survival outcomes in stages IIIB and IIIC. CONCLUSION: The AJCC 8th stage system for gastric cancer performs as well as the AJCC 7th edition in the United States (USA). Importantly, when more than 15 lymph nodes are examined, the discriminatory performance of the new edition is improved.

Marital status and survival in patients with primary liver cancer.

BACKGROUND: Marital status is viewed as an independent prognostic factor for survival in various cancer types. However, its role in primary liver cancer has yet to be thoroughly explored. OBJECTIVE: To investigate the impact of marital status on survival outcomes among liver cancer patients. RESULTS: We finally identified 40,809 eligible liver cancer patients between 2004 and 2012, including 21,939 (53.8%) patients were married at diagnosis and 18,870 (46.2%) were unmarried (including 5,871 divorced/separated, 4,338 widowed and 8,660 single). Married patients enjoyed overall and cause-specific survival outcomes compared with patients who were divorced/separated, widowed, single, respectively. The survival benefit associated with marriage still persisted even after adjusted for known confounders. Widowed individuals were at greater risk of overall and cancer-specific mortality compared to other groups. Similar associations were observed in subgroup analyses according to SEER stage. MATERIALS AND METHODS: We used the Surveillance, Epidemiology and End Results (SEER) database to identify 40,809 patients diagnosed with primary liver cancer between 2004 and 2012. Kaplan-Meier analysis and Cox regression were performed to identify the influence of marital status on overall survival (OS) and liver cancer-specific survival (CSS). CONCLUSIONS: In primary liver cancer patients, married patients enjoyed survival benefits while widowed persons suffered survival disadvantages in both overall survival and cancer-specific survival.

Contrast-enhanced endoscopic ultrasound for differential diagnosis of pancreatic cancer: an updated meta-analysis.

AIM: We aim to assess the diagnostic value of contrast-enhanced endoscopic ultrasound (CE-EUS) for pancreatic cancer and inflammatory lesions by pooling current evidence. MATERIALS AND METHODS: A systematical search of PubMed, Web of Science and the Cochrane Library was performed from inception to January 2016. Two authors independently screened and extracted detailed data from included studies. A random effect model was adopted to estimate the pooled sensitivity, specificity in order to determine the diagnostic ablitity of CE-EUS. Furthermore, we conducted the meta-regression and subgroup analyses to explore possible heterogeneity. RESULTS: Eighteen eligible studies enrolling 1668 patients were finally included in the study. The pooled sensitivity of CE-EUS for distinguishing pancreatic cancers from solid inflammatory masses was 0.93 (95% CI, 0.91-0.94), and the specificity was 0.88 (95% CI, 0.84-0.90). The area under summary receiver operating characteristic curve yielded 0.97. No publication bias was observed by Deeks' funnel plot in current meta-analysis. CONCLUSIONS: We provided evidence that CE-EUS is a promising modality for differential diagnosis of pancreatic adenocarcinomas. Further multicenter prospective studies should be carried out to certify its utility.

Survival benefits of gastrectomy in gastric cancer patients with stage IV: a population-based study.

OBJECTIVE: The aim of the current study is to investigate the role of gastrectomy for survival among metastatic gastric cancer patients. RESULTS: We finally identified 12,986 eligible patients with stage IV GC between 2004 and 2012, including 1,981 (15.3%) patients with gastrectomy and 11,005 (84.7%) without surgery. The median overall survival time for patients with and without surgery were 9.0 (95%, 8.3-9.7) and 4.0 (95%, 3.9-4.1) months respectively. Patients who received gastrectomy had a significantly better survival outcome compared with those without surgery (P < 0.05). In the multivariate Cox analysis, gastrectomy was associated with decreased overall mortality (HR, 0.47, 95% CI 0.44-0.49, P < 0.001) and cancer-specific mortality (HR, 0.46, 95% CI 0.44-0.50, P < 0.001). The survival benefits associated with surgery persisted even after performing the propensity score matching analysis (overall survival, HR, 0.47, 95% CI 0.43-0.50, cancer-specific survival, HR, 0.47, 95% CI 0.44-0.50). CONCLUSIONS: Based on population-based study, we demonstrated that there was a survival advantage of gastrectomy in stage IV GC patients. Further prospective trials need to verify our findings. MATERIALS AND METHODS: We included an eligible cohort of stage IV gastric cancer (GC) patients in the Surveillance, Epidemiology and End Results (SEER) database from 2004 to 2012. The survival difference of patients with and without gastrectomy were assessed by Kaplan-Meier analysis and log-rank test. Multivariate Cox analyses were performed to analyze the effect of gastrectomy on overall and cancer-specific mortality. Furthermore, we performed propensity score matching (PSM) to reduce the potential selection bias.

A retrospective study of pyogenic liver abscess focusing on Klebsiella pneumoniae as a primary pathogen in China from 1994 to 2015.

Pyogenic liver abscess (PLA) is a common intra-abdominal infection in adults. In this study, we aim to explore demographic and clinical characteristics of PLA focusing on Klebsiella pneumoniae (K. pneumoniae) induced PLA (KP-PLA) in mainland China. A retrospective review of medical records from all patients with KP-PLA admitted to a tertiary teaching hospital over a 21-year period (1994-2015) was performed. Among 296 PLA cases with confirmed culture-positive data, K. pneumoniae was revealed as the predominant pathogen (n = 189, 63.9%), followed by Escherichia coli (n = 39, 13.2%). Strikingly, KP-PLA patients had a higher incidence of metabolic disorders, such as diabetes mellitus (49.7% vs. 36.4%, P = 0.027; odds ratio (OR): 1.725; 95% confidence interval (CI): 1.061-2.805), hypertension (38.1% vs. 19.6%, P = 0.001; OR: 2.520; 95% CI: 1.439-4.413), and fatty liver (32.3% vs. 14.0%, P = 0.001; OR: 2.923; 95% CI: 1.564-5.462) than those with non-K. pneumoniae induced PLA (non-KP-PLA). Moreover, patients with KP-PLA had higher susceptibility to septic metastatic infection at distant sites compared to those with non-KP-PLA (10.6% vs. 3.7%, p = 0.038). Our results indicate that K. pneumoniae is the predominant pathogen of PLA in mainland China. KP-PLA is frequently diagnosed in patients with metabolic diseases and has a higher risk for septic metastatic infection.