Safety and efficacy of a programmed cell death 1 inhibitor combined with oxaliplatin plus S-1 in patients with Borrmann large type III and IV gastric cancers.

BACKGROUND: Gastric cancer (GC) is the fifth most common and the fourth most lethal malignant tumour in the world. Most patients are already in the advanced stage when they are diagnosed, which also leads to poor overall survival. The effect of postoperative adjuvant chemotherapy for advanced GC is unsatisfactory with a high rate of distant metastasis and local recurrence. AIM: To investigate the safety and efficacy of a programmed cell death 1 (PD-1) inhibitor combined with oxaliplatin and S-1 (SOX) in the treatment of Borrmann large type III and IV GCs. METHODS: A retrospective analysis (IRB-2022-371) was performed on 89 patients with Borrmann large type III and IV GCs who received neoadjuvant therapy (NAT) from January 2020 to December 2021. According to the different neoadjuvant treatment regimens, the patients were divided into the SOX group (61 patients) and the PD-1 + SOX (P-SOX) group (28 patients). RESULTS: The pathological response (tumor regression grade 0/1) in the P-SOX group was significantly higher than that in the SOX group (42.86% vs 18.03%, P = 0.013). The incidence of ypN0 in the P-SOX group was higher than that in the SOX group (39.29% vs 19.67%, P = 0.05). The use of PD-1 inhibitors was an independent factor affecting tumor regression grade. Meanwhile, the use of PD-1 did not increase postoperative complications or the adverse effects of NAT. CONCLUSION: A PD-1 inhibitor combined with SOX could significantly improve the rate of tumour regression during NAT for patients with Borrmann large type III and IV GCs.

Development and validation of a noninvasive prediction model of autoimmune hepatitis in patients with liver diseases.

BACKGROUND AND AIMS: There is no golden standard for the diagnosis of autoimmune hepatitis which still dependent on liver biopsy currently. So, we developed a noninvasive prediction model to help optimize the diagnosis of autoimmune hepatitis. METHODS: From January 2017 to December 2019, 1739 patients who had undergone liver biopsy were seen in the second hospital of Nanjing, of which 128 were here for consultation. Clinical, laboratory, and histologic data were obtained retrospectively. Multivariable logistic regression analysis was employed to create a nomogram model that predicting the risk of autoimmune hepatitis. Internal and external validation was both performed to evaluate the model. RESULTS: A total of 1288 patients with liver biopsy were enrolled (1184 from the second hospital of Nanjing, the remaining 104 from other centers). After the univariate and multivariate logistic regression analysis, nine variables including ALT, IgG, ALP/AST, ALB, ANA, AMA, HBsAg, age, and gender were selected to establish the noninvasive prediction model. The nomogram model exhibits good prediction in diagnosing autoimmune hepatitis with AUROC of 0.967 (95% CI: 0.776-0.891) in internal validation and 0.835 (95% CI: 0.752-0.919) in external validation. CONCLUSIONS: ALT, IgG, ALP/AST, ALB, ANA, AMA, HBsAg, age, and gender are predictive factors for the diagnosis of autoimmune hepatitis in patients with unexplained liver diseases. The predictive nomogram model built by the nine predictors achieved good prediction for diagnosing autoimmune hepatitis.

Fabricating Freestanding, Broadband Reflective Cholesteric Liquid-Crystal Networks via Topological Tailoring of the Sm-Ch Phase Transition.

Numerous biological systems in nature provide much inspiration for humanity to master diverse coloration strategies for creating stimuli-responsive materials and display devices, such as to access gorgeous structural colors from well-defined photonic structures. Cholesteric liquid crystals (CLCs) are a fascinating genre of photonic materials displaying iridescent colors responsive to circumstance changes; however, it is still a big challenge to design materials with broadband color variation as well as good flexibility and freestanding capacity. Herein, we report a feasible and flexible strategy to fabricate cholesteric liquid-crystal networks (CLCNs) with precise colors across the entire visible spectrum through molecular structure tailoring and topology engineering and demonstrate their application as smart displays and rewritable photonic paper. Influences of chiral and achiral LC monomers on the thermochromic behaviors of CLC precursors as well as on the topology of the polymerized CLCNs are systematically investigated, demonstrating that the monoacrylate achiral LC facilitated the formation of a smectic phase-chiral phase (Sm-Ch) pretransitional phase in the CLC mixture and improved the flexibility of the photopolymerized CLCNs. High-resolution multicolor patterns in one CLCN film are generated through photomask polymerization. In addition, the freestanding CLCN films show perceivable mechanochromic behaviors and repeated erasing-rewriting performances. This work opens avenues toward the realization of pixelated colorful patterns and rewritable CLCN films promising in technology fields ranging from information storage and smart camouflage to anti-counterfeiting and smart display.

Design, Synthesis, Herbicidal Activity, and Structure-Activity Relationship Study of Novel 6-(5-Aryl-Substituted-1-Pyrazolyl)-2-Picolinic Acid as Potential Herbicides.

Picolinic acid and picolinate compounds are a remarkable class of synthetic auxin herbicides. In recent years, two new picolinate compounds, halauxifen-methyl (ArylexTM active) and florpyrauxifen-benzyl (RinskorTM active), have been launched as novel herbicides. Using their structural skeleton as a template, 33 4-amino-3,5-dicholor-6-(5-aryl-substituted-1-pytazolyl)-2-picolinic acid compounds were designed and synthesized for the discovery of compounds with potent herbicidal activity. The compounds were tested for inhibitory activity against the growth of Arabidopsis thaliana roots, and the results demonstrated that the IC50 value of compound V-7 was 45 times lower than that of the halauxifen-methyl commercial herbicide. Molecular docking analyses revealed that compound V-7 docked with the receptor auxin-signaling F-box protein 5 (AFB5) more intensively than picloram. An adaptive three-dimensional quantitative structure-activity relationship model was constructed from these IC50 values to guide the next step of the synthetic strategy. Herbicidal tests of the new compounds indicated that compound V-8 exhibited better post-emergence herbicidal activity than picloram at a dosage of 300 gha-1, and it was also safe for corn, wheat, and sorghum at this dosage. These results demonstrated that 6-(5-aryl-substituted-1-pyrazolyl)-2-picolinic acid compounds could be used as potential lead structures in the discovery of novel synthetic auxin herbicides.

Integrative proteomic characterization of adenocarcinoma of esophagogastric junction.

The incidence of adenocarcinoma of the esophagogastric junction (AEG) has been rapidly increasing in recent decades, but its molecular alterations and subtypes are still obscure. Here, we conduct proteomics and phosphoproteomics profiling of 103 AEG tumors with paired normal adjacent tissues (NATs), whole exome sequencing of 94 tumor-NAT pairs, and RNA sequencing in 83 tumor-NAT pairs. Our analysis reveals an extensively altered proteome and 252 potential druggable proteins in AEG tumors. We identify three proteomic subtypes with significant clinical and molecular differences. The S-II subtype signature protein, FBXO44, is demonstrated to promote tumor progression and metastasis in vitro and in vivo. Our comparative analyses reveal distinct genomic features in AEG subtypes. We find a specific decrease of fibroblasts in the S-III subtype. Further phosphoproteomic comparisons reveal different kinase-phosphosubstrate regulatory networks among AEG subtypes. Our proteogenomics dataset provides valuable resources for understanding molecular mechanisms and developing precision treatment strategies of AEG.

Unravelling intrinsic descriptors based on a two-stage activity regulation of bimetallic 2D c-MOFs for CO2RR.

The bimetallic 2D conductive MOFs of M1Pc-M2-O, possessing dual metal sites to realize flexible molecular-level structural modification, are brilliant catalysts for electrochemical CO2 reduction. However, the bimetallic centers bring about the complex regulatory mechanism of catalytic activity and obscure principles for catalyst design. Herein, systematical theoretical investigation unravels intrinsic descriptors to design favorable M1Pc-M2-O catalysts based on the discovered coarse-fine two-stage activity regulation mechanism. The reaction site controls the M-COOH distance of the key intermediate and therefore affects the reaction kinetics for the first stage of coarse regulation. The other metal site influents the d-band center of the reaction site and thus constitutes the second stage of fine regulation. The coarse and fine regulation are related to the valence electrons (V), electronegativity (E), and bond length (LM-N/O) between the metal and coordination atoms. The intrinsic descriptor ϕ = (4 × VM1 × (EM1 + EN/O)/EN/O + VM2 × (EM2 + EN/O)/EN/O) × LM1-N/O (with a coefficient ratio of 4 : 1) was eventually established and correlated well with the reported experiments. On this basis, the favorable catalysts CoPc-Zn-O and CoPc-Co-O were located. The research results could contribute to the diversity of bimetallic 2D c-MOFs in CO2RR.

Design, Synthesis, Fungicidal and Insecticidal Activities of Novel Diamide Compounds Combining Pyrazolyl and Polyfluoro-Substituted Phenyl into Alanine or 2-Aminobutyric Acid Skeletons.

Thirty novel diamide compounds combining pyrazolyl and polyfluoro-substituted phenyl groups into alanine or 2-aminobutyric acid skeletons were designed and synthesized with pyflubumide as the lead compound to develop potent and environmentally friendly pesticides. The preliminary bioassay results indicated that the new compounds containing the para-hexa/heptafluoroisopropylphenyl moiety exhibit fungicidal, insecticidal, and acaricidal activities. This is the first time that the para-hexa/heptafluoroisopropylphenyl group is a key fragment of the fungicidal activity of new N-phenyl amide compounds. Most of the target compounds exhibited moderate to good insecticidal activity against Aphis craccivora at a concentration of 400 µg/mL, and some showed moderate activity at a concentration of 200 µg/mL; in particular, compounds I-4, II-a-10, and III-26 displayed higher than 78% lethal rates at 200 µg/mL. Compound II-a-14 exhibited a 61.1% inhibition at 200 µg/mL for Tetranychus cinnabarinus. In addition, some of the target compounds exhibited good insecticidal activities against Plutella xylostella at a concentration of 200 µg/mL; the mortalities of compounds I-1, and II-a-15 were 76.7% and 70.0%, respectively. Preliminary analysis of the structure-activity relationship (SAR) indicated that the insecticidal and acaricidal activities varied significantly depending on the type of substituent and substitution pattern. The fungicidal activity results showed that compounds I-1, II-a-10, II-a-17, and III-26 exhibited good antifungal effects. Enzymatic activity experiments and in vivo efficacy of compound II-a-10 were conducted and discussed.

Porous Photo-Fenton Catalysts Rapidly Triggered by Levodopa-Based Mussel-Inspired Coatings for Enhanced Dye Degradation and Sterilization.

The advanced oxidation process of the photo-Fenton reaction can produce hydroxyl radicals with extremely strong oxidizing properties for the efficient and green degradation of various chemical and microbial pollutants. Herein, we report an approach to fabricating heterogeneous Fenton catalysts of ß-FeOOH nanorods on porous substrates triggered by mussel-inspired coatings of levodopa (3,4-dihydroxy-phenyl-l-alanine, l-DOPA) and polyethylenimine (PEI) for efficient photocatalytic dyes' degradation and sterilization. The l-DOPA-based coatings not only promote the formation and immobilization of ß-FeOOH nanorods on the porous substrates by strong coordination between catechol/carboxyl groups and Fe3+ but also improve the energy band structure of the Fenton catalysts through a valence band blue shift and band gap narrowing. The photo-Fenton catalysts prepared by the l-DOPA-based coatings exhibit high electron transport efficiency and improved utilization of sunlight. Only 2 h of mineralization is needed to fabricate these catalysts with excellent photocatalytic efficiency, in which the degradation efficiency of methylene blue can reach 99% within 30 min, whereas the sterilization efficiency of E. coli/S. aureus can reach 93%/94% within 20 min of the photo-Fenton reaction. Additionally, the prepared catalysts reveal a high photodegradation performance for various dyes including methylene blue, methyl blue, methyl orange, direct yellow, and rhodamine B. Furthermore, the catalysts retain high dye degradation efficiencies of above 90% after five photodegradation cycles, indicating cycling performance and good stability.

[Clinical efficacy of combined therapy in children with stage 4 neuroblastoma]. / 儿童4期神经母细胞瘤联合治疗的临床疗效观察.

OBJECTIVES: To study the early clinical efficacy of combined therapy of stage 4 neuroblastoma. METHODS: A retrospective analysis was performed on the medical data and follow-up data of 14 children with stage 4 neuroblastoma who were diagnosed in Hong Kong University-Shenzhen Hospital from January 2016 to June 2021. RESULTS: The median age of onset was 3 years and 7.5 months in these 14 children. Among these children, 9 had positive results of bone marrow biopsy, 4 had N-Myc gene amplification, 13 had an increase in neuron-specific enolase, and 7 had an increase in vanilmandelic acid in urine. Based on the results of pathological examination, differentiated type was observed in 6 children, undifferentiated type in one child, mixed type, in one child and poorly differentiated type in 6 children. Of all the children, 10 received chemotherapy with the N7 regimen (including 2 children receiving arsenic trioxide in addition) and 4 received chemotherapy with the Rapid COJEC regimen. Thirteen children underwent surgery, 14 received hematopoietic stem cell transplantation, and 10 received radiotherapy. A total of 8 children received Ch14.18/CHO immunotherapy, among whom 1 child discontinued due to anaphylactic shock during immunotherapy, and the other 7 children completed Ch14.18/CHO treatment without serious adverse events, among whom 1 child was treated with Lu177 Dotatate 3 times after recurrence and is still undergoing chemotherapy at present. The median follow-up time was 45 months for all the 14 children. Four children experienced recurrence within 2 years, and the 2-year overall survival rate was 100%; 4 children experienced recurrence within 3 years, and 7 achieved disease-free survival within 3 years. CONCLUSIONS: Multidisciplinary combined therapy is recommended for children with stage 4 neuroblastoma and can help them achieve better survival and prognosis.

Trametes robiniophila Murr Sensitizes Gastric Cancer Cells to 5-Fluorouracil by Modulating Tumor Microenvironment.

Trametes robiniophila Murr (TRM) is a traditional Chinese medicine which has been used in clinics for enhancing immunity and improving the efficacy of chemotherapy. However, the mechanisms of action of TRM are unknown. In the previous study, we found that the Trametes robiniophila Murr n-butanol extract (TRMBE) comprises the major bioactive components of TRM. In the present study, we aimed to assess the combinational effects of TRMBE and 5-fluorouracil (5-FU) on the treatment of gastric cancer (GC) and explore its mechanism of action. It was found that TRMBE significantly potentiated the anticancer activity of 5-FU and prolonged the survival time of mice bearing Mouse Forestomach Carcinoma (MFC) xenograft tumors. We observed that the combination of TRMBE and 5-FU decreased the risk of liver metastasis in vivo. Furthermore, the combination of TRMBE and 5-FU reduced the levels of immune cytokines IL-6, IL-10, and TGF-ß and increased the level of IFN-γ in peripheral blood. This combination therapy also significantly decreased the levels of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and PD-1-positive CD8+ T cells and increased the levels of NK cells in tumor microenvironment (TME). However, TRMBE treatment was unable to enhance the chemosensitivity of GC to 5-FU in vivo after the depletion of CD8+ T and NK cells. Taken together, our results demonstrate that TRMBE can reshape the TME of GC by regulating PMN-MDSCs, CD8+ T cells, and NK cells, therefore improving the therapeutic effects of 5-FU. This study suggests that the combination of TRMBE and 5-FU could enhance immunity and could be a promising approach for GC treatment.

Current treatments and outlook in adenocarcinoma of the esophagogastric junction: a narrative review.

Background and Objective: Adenocarcinoma of the esophagogastric junction (AEG) is a tumor of the esophagogastric junction (EGJ). Research has suggested that AEG may be an independent tumor because of its peculiar site and biological behavior. During the past several decades, the incidence of AEG has increased globally. Therefore, it is necessary to explore appropriate treatments for AEG. The aim of this review is to summarize the current treatments for AEG and forecast their future developments. Methods: We critically conducted a literature search in PubMed (from the inception of the database to October 31, 2021). The keywords used in the search were "adenocarcinoma of the esophagogastric junction", "gastroesophageal adenocarcinoma and surgical treatment", "gastroesophageal adenocarcinoma and target therapy", "gastroesophageal adenocarcinoma and neoadjuvant therapy" and "gastroesophageal adenocarcinoma and immunotherapy". Key Content and Findings: This study introduced the existing treatments for AEG from the aspects of surgical therapy, neoadjuvant therapy and targeted therapy, and prospected the future research direction. Conclusions: Treatments for AEG often have different plans (such as surgical treatment, neoadjuvant therapy, targeted therapy and immunotherapy) according to the pathological type of patients, the status of metastasis, and the conditions of patients. Surgical treatment is the most commonly used treatment in clinical practice. Minimally invasive surgery promising potential for further development. Targeted therapy and immunotherapy can improve the quality of life and survival of patients. Currently, some drugs, such as trastuzumab, ramucirumab, pembrolizumab, and nivolumab have been approved by the Food and Drug Administration (FDA) for clinical treatment of AEG. However, targeted therapy and immunotherapy still have a long way to go and need to be further explored.

Management of Nasopharyngeal Carcinoma in Elderly Patients.

Nasopharyngeal cancer (NPC) is one of the most difficult cancers in the head and neck region due to the complex geometry of the tumour and the surrounding critical organs. High-dose radical radiotherapy with or without concurrent platinum-based chemotherapy is the primary treatment modality. Around 10%-15% of NPC patients have their diagnosis at age after 70. The management of NPC in elderly patients is particularly challenging as they encompass a broad range of patient phenotypes and are often prone to treatment-related toxicities. Chronologic age alone is insufficient to decide on the management plan. Comprehensive geriatric assessment with evaluation on patients' functional status, mental condition, estimated life expectancy, comorbidities, risks and benefits of the treatment, patients' preference, and family support is essential. In addition, little data from randomized controlled trials are available to guide treatment decisions in elderly patients with NPC. In deciding which treatment strategy would be suitable for an individual elderly patient, we reviewed the literature and reviewed the analysis of primary studies, reviews, and guidelines on management of NPC. This review also summarises the current evidence for NPC management in elderly adults from early to late stage of disease.

GPR30 Activation Promotes the Progression of Gastric Cancer and Plays a Significant Role in the Anti-GC Effect of Huaier.

Gastric cancer (GC) is one of the most common types of cancer. The n-butanol extract of Huaier (NEH) is the alcohol-soluble part extracted by the systematic solvent method, which is effective against gastric cancer (GC). However, the mechanism of action of NEH remains unclear. In this study, we aim to evaluate the clinical relevance of GPR30 expression in GC patients and the role of the GPR30/PI3K/AKT signalling pathway in the anti-GC effect of NEH. The expression of GPR30 was examined using immunohistochemistry. Cell counting kit 8 (CCK-8) assay, wound healing, and transwell experiments were used to investigate the viability, migration, and invasion of gastric cancer cells. Western blotting was used to detect the expression of GPR30 and its downstream signalling molecules of the PI3K/AKT signalling pathway. Gastric cancer patient-derived xenografts (PDX) mouse model was used to evaluate the antitumor effect of NEH in vivo. In addition, the graded doses and the maximum tolerated dose of NEH were administered intraperitoneally into the mice for acute toxicity test. We demonstrate that GPR30 expression in GC tissues was significantly higher than that in corresponding adjacent noncancerous tissues and the expression of GPR30 was correlated with a poor prognosis in GC patients. Moreover, GPR30 expression was involved in the migration and invasion of GC cells in vitro. Additionally, we found that NEH can suppress the growth of GC in patient-derived xenograft tumors in vivo. Furthermore, NEH inhibited the proliferation, migration, and invasion in GC cells in a concentration-dependent manner through inhibiting the GPR30-mediated PI3K/AKT signalling pathway in vitro. Acute toxicity test showed that NEH caused no toxic reaction or death and the maximum tolerated dose of NEH in mice was greater than 1600 mg/kg. Our results demonstrate that the high expression of GPR30 is an independent factor of poor prognosis in patients with GC and NEH could be a new agent for the treatment of gastric cancer.

PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy.

Proteolysis targeting chimeric (PROTAC) technology is an effective endogenous protein degradation tool developed in recent years that can ubiquitinate the target proteins through the ubiquitin-proteasome system (UPS) to achieve an effect on tumor growth. A number of literature studies on PROTAC technology have proved an insight into the feasibility of PROTAC technology to degrade target proteins. Additionally, the first oral PROTACs (ARV-110 and ARV-471) have shown encouraging results in clinical trials for prostate and breast cancer treatment, which inspires a greater enthusiasm for PROTAC research. Here we focus on the structures and mechanisms of PROTACs and describe several classes of effective PROTAC degraders based on E3 ligases.

Exosomal miR-590-5p in Serum as a Biomarker for the Diagnosis and Prognosis of Gastric Cancer.

The purpose of this study is to explore the expression of miRNA-590-5p, an exosome of gastric cancer (GC), and to evaluate the suitability of miR-590-5p, an exosome with its own clinical characteristics. Serum samples from 168 gastric cancer patients and 50 matched controls were collected and exosomal RNAs were extracted. After that, miR-590-5p is analyzed by quantitative polymerase chain reaction (qRT-PCR), which is more related to clinical and pathological parameters and patient monitoring data. MGC-803 and HGC-27 cells were treated by miR-590-5p mimics, and then the changes of cell fluidity and invasiveness were monitored. The results showed that the expression level of miR-590-5p in exosomes of healthy observation group, early (I and II) stage group, and late stage (III) group was 30.34 ± 6.35, 6.19 ± 0.81, and 2.9 ± 0.19, respectively (all p < 0.05). ROC (receiver-operating characteristic curve) showed that the AUC (area under the curve) of exosomal miR-590-5p was 0.810 with 63.7% sensitivity and 86% specificity. The expression of exosomal miR-590-5p in serum was related to clinical stage (p = 0.008), infiltration depth, and the expression level of ki-67 (p < 0.001). In addition, Kaplan-Meier analysis showed that the decrease of explicit level of exosomal miR-590-5p was related to the decrease of overall survival rate (p < 0.001). Cox regression analysis showed that miR-590-5p can be used as an independent predictor. Furthermore, upregulation of miR-590-5p inhibited cell migration and invasion in MGC-803 cells and HGC-27 cells. The serum expression level of exosomal miR-590-5p may be a biomarker, which is potentially useful and noninvasive for early detection and prediction of GC. In addition, miR-590-5p can play a role in eliminating carcinogens by actively regulating the malignant potential of gastric cancer.

p-MEK expression predicts prognosis of patients with adenocarcinoma of esophagogastric junction (AEG) and plays a role in anti-AEG efficacy of Huaier.

The incidence rate of adenocarcinoma of the esophagogastric junction (AEG) is increasing worldwide with poor prognosis and unclear pathogenesis. Trametes robiniophila Murr. (Huaier), a traditional Chinese medicine has been used in the clinical treatment of a variety of solid tumors, including AEG. However, its anticancer components and molecular mechanisms are still unclear. In our previous studies, we have found that Huaier n-butanol extract (HBE) shows the most potent anticancer activity among different extracts. In the present study, we aimed to investigate the clinical relevance of p-MEK expression in AEG patients and the role of the MEK/ERK signaling pathway in the anti-AEG efficacy of HBE in vitro and in vivo. We herein demonstrate that p-MEK expression in AEG tissues was significantly higher than that in paracancerous tissues and correlated with a poor prognosis in AEG patients. We further found that HBE inhibited the colony formation, migration, and invasion in AEG cell lines in a concentration-dependent manner in vitro. HBE also suppressed the growth of AEG xenograft tumors without causing any host toxicity in vivo. Mechanistically, HBE caused the inactivation of the MEK/ERK signaling pathway by dephosphorylating MEK1 at S298, ERK1 at T202, and ERK2 at T185 and modulating the expression of EMT-related proteins. In summary, our results demonstrate that the high expression of p-MEK may be an independent factor of poor prognosis in patients with AEG. The clinically used anticancer drug Huaier may exert its anti-AEG efficacy by inhibiting the MEK/ERK signaling pathway.

The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe?

Gastric cancer is the third most common cause of cancer-related death worldwide. Drug resistance is the main inevitable and vital factor leading to a low 5-year survival rate for patients with gastric cancer. Autophagy, as a highly conserved homeostatic pathway, is mainly regulated by different proteins and non-coding RNAs (ncRNAs) and plays dual roles in drug resistance of gastric cancer. Thus, targeting key regulatory nodes in the process of autophagy by small molecule inhibitors or activators has become one of the most promising strategies for the treatment of gastric cancer in recent years. In this review, we provide a systematic summary focusing on the relationship between autophagy and chemotherapy resistance in gastric cancer. We comprehensively discuss the roles and molecular mechanisms of multiple proteins and the emerging ncRNAs including miRNAs and lncRNAs in the regulation of autophagy pathways and gastric cancer chemoresistance. We also summarize the regulatory effects of autophagy inhibitor and activators on gastric cancer chemoresistance. Understanding the vital roles of autophagy in gastric cancer chemoresistance will provide novel opportunities to develop promising therapeutic strategies for gastric cancer.

New-Onset Atrial Fibrillation and Adverse In-Hospital Outcome in Patients with Acute Pulmonary Embolism.

Atrial fibrillation (AF) can be secondary to acute pulmonary embolism (PE). This study aimed to investigate the prognostic impact of new-onset AF on patients with acute PE. In this study, 4,288 consecutive patients who were diagnosed with acute PE were retrospectively screened. In total, 77 patients with acute PE and new-onset AF were analyzed. Another 154 acute PE patients without AF were selected as the age- and sex-matched control group. Adverse in-hospital outcome comprised one of the following conditions: all-cause death, endotracheal intubation, cardiopulmonary resuscitation, and intravenous catecholamine therapy. The patients with new-onset AF had higher prevalence of congestive heart failure, higher simplified PE severity index (sPESI), higher creatinine, and larger left atrium diameter. The incidences of adverse in-hospital outcomes were 10.4 and 2.6% in patients with new-onset AF and no AF, respectively (p = 0.02). Patients with sPESI ≥ 1 had higher incidence of adverse in-hospital outcomes than those with sPESI = 0 (9.4 vs. 0.9%, p < 0.01). The area under the receiver operating characteristic curve of sPESI and sPESI + AF (adding 1 point for new-onset AF) scores in assessing the adverse in-hospital outcome were 0.80 (95% confidence interval [CI]: 0.68-0.93) and 0.84 (95% CI: 0.72-0.96), respectively. In multivariable analysis, sPESI ≥ 1 (odds ratio, 8.88; 95% CI: 1.10-72.07; p = 0.04) was an independent predictor of adverse in-hospital outcome. However, new-onset AF was not an independent predictor. In the population studied, sPESI is an independent predictor of adverse in-hospital outcomes, whereas new-onset AF following acute PE is not, but it may add predictive value to sPESI.

Targeting MDMX for Cancer Therapy: Rationale, Strategies, and Challenges.

The oncogene MDMX, also known as MDM4 is a critical negative regulator of the tumor suppressor p53 and has been implicated in the initiation and progression of human cancers. Increasing evidence indicates that MDMX is often amplified and highly expressed in human cancers, promotes cancer cell growth, and inhibits apoptosis by dampening p53-mediated transcription of its target genes. Inhibiting MDMX-p53 interaction has been found to be effective for restoring the tumor suppressor activity of p53. Therefore, MDMX is becoming one of the most promising molecular targets for developing anticancer therapeutics. In the present review, we mainly focus on the current MDMX-targeting strategies and known MDMX inhibitors, as well as their mechanisms of action and in vitro and in vivo anticancer activities. We also propose other potential targeting strategies for developing more specific and effective MDMX inhibitors for cancer therapy.

Targeting ß-Catenin Signaling by Natural Products for Cancer Prevention and Therapy.

The mutations and deregulation of Wnt signaling pathway occur commonly in human cancer and cause the aberrant activation of ß-catenin and ß-catenin-dependent transcription, thus contributing to cancer development and progression. Therefore, ß-catenin has been demonstrated as a promising target for cancer prevention and therapy. Many natural products have been characterized as inhibitors of the ß-catenin signaling through down-regulating ß-catenin expression, modulating its phosphorylation, promoting its ubiquitination and proteasomal degradation, inhibiting its nuclear translocation, or other molecular mechanisms. These natural product inhibitors have shown preventive and therapeutic efficacy in various cancer models in vitro and in vivo. In the present review, we comprehensively discuss the natural product ß-catenin inhibitors, their in vitro and in vivo anticancer activities, and underlying molecular mechanisms. We also discuss the current ß-catenin-targeting strategies and other potential strategies that may be examined for identifying new ß-catenin inhibitors as cancer preventive and therapeutic drugs.