DNAJC24 acts directly with PCNA and promotes malignant progression of LUAD by activating phosphorylation of AKT.

Heat shock proteins (HSPs) are a group of highly conserved proteins found in a wide range of organisms. In recent years, members of the HSP family were overexpressed in various tumors and widely involved in oncogenesis, tumor development, and therapeutic resistance. In our previous study, DNAJC24, a member of the DNAJ/HSP40 family of HSPs, was found to be closely associated with the malignant phenotype of hepatocellular carcinoma. However, its relationship with other malignancies needs to be further explored. Herein, we demonstrated that DNAJC24 exhibited upregulated expression in LUAD tissue samples and predicted poor survival in LUAD patients. The upregulation of DNAJC24 expression promoted proliferation and invasion of LUAD cells in A549 and NCI-H1299 cell lines. Further studies revealed that DNAJC24 could regulate the PI3K/AKT signaling pathway by affecting AKT phosphorylation. In addition, a series of experiments such as Co-IP and mass spectrometry confirmed that DNAJC24 could directly interact with PCNA and promoted the malignant phenotypic transformation of LUAD. In conclusion, our results suggested that DNAJC24 played an important role in the progression of LUAD and may serve as a specific prognostic biomarker for LUAD patients. The DNAJC24/PCNA/AKT axis may be a potential target for future individualized and precise treatment of LUAD patients.

Etiological analysis of 167 cases of drug-resistant epilepsy in children.

BACKGROUND: To analyze the etiological distribution characteristics of drug-resistant epilepsy (DRE) in children, with the aim of providing valuable perspectives to enhance clinical practice. METHODS: In this retrospective study, clinical data were collected on 167 children with DRE who were hospitalized between January 2020 and December 2022, including gender, age of onset, seizure types, video electroencephalogram(VEEG) recordings, neuroimaging, and genetic testing results. Based on the etiology of epilepsy, the enrolled children were categorized into different groups. The rank-sum test was conducted to compare the age of onset for different etiologies. RESULTS: Of the 167 cases, 89 (53.3%) had a clear etiology. Among them, structural factors account for 23.4%, genetic factors for 19.2%, multiple factors for 7.2%, and immunological factors for 3.6%. The age of onset was significantly earlier in children with genetic causes than those with structural (P < 0.001) or immunological (P = 0.001) causes. CONCLUSIONS: More than half of children with DRE have a distinct underlying cause, predominantly attributed to structural factors, followed by genetic factors. Genetic etiology primarily manifests at an early age, especially among children aged less than one year. This underscores the need for proactive enhancements in genetic testing to unveil the underlying causes and subsequently guide treatment protocols.

OVOL2 induces autophagy-mediated epithelial-mesenchymal transition by the ERK1/2 MAPK signaling in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the leading causes of cancer-related death worldwide. Epithelial-mesenchymal transition (EMT) plays an important role in malignant tumor progression. Recently, accumulating evidence has shown that autophagy is involved in the regulation of EMT-induced migration. Therefore, the exploration of targets to inhibit EMT by targeting autophagy is important. In this study, we found that OVO-like zinc finger 2 (OVOL2) may be a key target for regulating autophagy-induced EMT. Firstly, we found that OVOL2 expression was dramatically downregulated in LUAD. Low expression of OVOL2 is an indicator of poor prognosis in LUAD. In vitro experiments have shown that downregulation of OVOL2 expression induces EMT, thereby promoting malignant biological behavior, such as proliferation, migration, and invasion of LUAD cells. Interestingly, autophagy is a key step in regulating OVOL2 and inducing EMT. Furthermore, OVOL2 regulates autophagy through the MAPK signaling pathway, ultimately inhibiting the malignant progression of LUAD.

A high concentrate diet inhibits forkhead box protein A2 expression, and induces oxidative stress, mitochondrial dysfunction and mitochondrial unfolded protein response in the liver of dairy cows.

High-concentrate diet induce subacute ruminal acidosis (SARA) and cause liver damage in ruminants. It has been reported that forkhead box protein A2 (FOXA2) can enhance mitochondrial membrane potential but its function in mitochondrial dysfunction induced by high concentrate diets is still unknown. Therefore, the aim of this study was to elucidate the effect of high-concentrate (HC) diet on hepatic FOXA2 expression, mitochondrial unfolded protein response (UPRmt), mitochondrial dysfunction and oxidative stress. A total of 12 healthy mid-lactation Holstein cows were selected and randomized into 2 groups: the low concentrate (LC) diet group (concentrate:forage = 4:6) and HC diet group (concentrate:forage = 6:4). The trial lasted 21 d. The rumen fluid, blood and liver tissue were collected at the end of the experiment. The results showed that the rumen fluid pH level was reduced in the HC group and the pH was lower than 5.6 for more than 4 h/d, indicating that feeding HC diets successfully induced SARA in dairy cows. Both FOXA2 mRNA and protein abundance were significantly reduced in the liver of the HC group compared with the LC group. The activity of antioxidant enzymes (CAT, G6PDH, T-SOD, Cu/Zn SOD, Mn SOD) and mtDNA copy number in the liver tissue of the HC group decreased, while the level of H2O2 significantly increased, this increase was accompanied by a decrease in oxidative phosphorylation (OXPHOS). The balance of mitochondrial division and fusion was disrupted in the HC group, as evidenced by the decreased mRNA level of OPA1, MFN1, and MFN2 and increased mRNA level of Drp1, Fis1, and MFF. At the same time, HC diet downregulated the expression level of SIRT1, SIRT3, PGC-1α, TFAM, and Nrf 1 to inhibit mitochondrial biogenesis. The HC group induced UPRmt in liver tissue by upregulating the mRNA and protein levels of CLPP, LONP1, CHOP, Hsp10, and Hsp60. In addition, HC diet could increase the protein abundance of Bax, CytoC, Caspase 3 and Cleaved-Caspase 3, while decrease the protein abundance of Bcl-2 and the Bcl-2/Bax ratio. Overall, our study suggests that the decreased expression of FOXA2 may be related to UPRmt, mitochondrial dysfunction, oxidative stress, and apoptosis in the liver of dairy cows fed a high concentrate diet.

Inetetamab, a novel anti-HER2 monoclonal antibody, exhibits potent synergistic anticancer effects with cisplatin by inducing pyroptosis in lung adenocarcinoma.

Cisplatin is a first-line chemotherapy drug for lung adenocarcinoma (LUAD). However, its therapeutic efficacy is limited because of serious side effects and acquired drug resistance. Targeting HER2 has been proven to be a viable therapeutic strategy against LUAD. Moreover, inetetamab, an innovative anti-HER2 monoclonal antibody, has a more potent antibody-dependent cell-mediated cytotoxicity (ADCC)-inducing effect than trastuzumab, which has been shown to be an effective and rational strategy in the clinic when combined with multiple chemotherapeutic agents. Thus, the present study aimed to explore the synergistic effects of cisplatin (DDP) and inetetamab in LUAD cells and investigate the detailed underlying mechanisms. Here, in vitro and in vivo, we found that the combination of inetetamab and cisplatin induced synergistic effects, including induction of pyroptosis, in LUAD. Mechanistic studies revealed that inetetamab combined with cisplatin inhibited HER2/AKT/Nrf2 signaling to increase ROS levels, which triggered NLRP3/caspase-1/GSDMB-mediated pyroptosis to synergistically enhance antitumor efficacy in LUAD cells. In addition, cisplatin enhanced the PBMC-killing ability of inetetamab by inducing GSDMB-mediated pyroptosis, which can be explained by increased secretion of IFN-γ. Our study reveals that the anti-HER2 monoclonal antibody inetetamab may be an attractive candidate for LUAD therapy, which opens new avenues for therapeutic interventions for LUAD.

TWF1 induces autophagy and accelerates malignant phenotype in lung adenocarcinoma via inhibiting the cAMP signaling pathway.

Many studies have shown that the actin cytoskeleton plays an essential role in the initiation and progression of cancer. As an actin-binding protein, Twinfilin1 (TWF1) plays an important role in regulating cytoskeleton-related functions. However, little is known about the expression and function of TWF1 in human tumors. The present study aimed to investigate the functional roles and the underlying molecular mechanisms of TWF1 in human lung adenocarcinoma (LUAD). By using bioinformatics databases and tumor tissues, TWF1 expression was found to be higher in LUAD tissues than in adjacent tissues and poor survival was predicted in patients with LUAD. In vitro and in vivo assays indicated that downregulation of TWF1 expression suppressed LUAD cells invasion and migration. Further studies revealed that TWF1 interacted with p62 and was involved in the regulation of autophagy. The molecular mechanisms underlying TWF1 were investigated by RNA-seq analysis and a series of functional experiments. The results showed that downregulation of TWF1 suppressed LUAD progression through the cAMP signaling pathway. Therefore, overexpression of TWF1 in LUAD promoted migration, invasion, and autophagy through the cAMP signaling pathway.

The response prediction and prognostic values of systemic inflammation response index in patients with advanced lung adenocarcinoma.

PURPOSE: This study aimed to assess the response prediction and prognostic values of different peripheral blood cell biomarkers for advanced lung adenocarcinoma (LUAD) patients receiving first-line therapy. METHODS: Patients diagnosed with advanced LUAD as well as healthy controls and patients with benign pulmonary diseases were collected in this retrospective study. Propensity score matching (PSM) was performed in a 1:1 ratio. Survival state was estimated by the Kaplan-Meier method and the Cox proportional hazard model was used to assess the prognostic factors. RESULTS: Compared with the control groups, the level of peripheral blood leucocyte, neutrophil, monocyte, platelet, and neutrophil to lymphocyte ratio, monocyte to lymphocyte ratio, platelet to lymphocyte ratio, and systemic inflammation response index (SIRI) were higher in LUAD patients (all p < 0.001). Some inflammatory markers decreased at the time of optimal response and then increased again as the disease progressed. Multivariate analysis revealed that SIRI and lactate dehydrogenase (LDH) were independent prognostic factors no matter before or after PSM analysis. Area under the curve (AUC) of SIRI and LDH were 0.625 (p < 0.001) and 0.596 (p = 0.008), respectively. When SIRI and LDH were combined, the AUC reached 0.649 (p < 0.001). CONCLUSIONS: Pretreatment SIRI was an independent prognostic factor of progression free survival (PFS) in advanced LUAD patients. Dynamic monitoring of inflammatory index changes could help to predict therapeutic efficacy. The combination of SIRI and LDH is expected to be a promising clinically accessible biomarker in the future.

Fine-Grained Video Retrieval With Scene Sketches.

Benefiting from the intuitiveness and naturalness of sketch interaction, sketch-based video retrieval (SBVR) has received considerable attention in the video retrieval research area. However, most existing SBVR research still lacks the capability of accurate video retrieval with fine-grained scene content. To address this problem, in this paper we investigate a new task, which focuses on retrieving the target video by utilizing a fine-grained storyboard sketch depicting the scene layout and major foreground instances' visual characteristics (e.g., appearance, size, pose, etc.) of video; we call such a task "fine-grained scene-level SBVR". The most challenging issue in this task is how to perform scene-level cross-modal alignment between sketch and video. Our solution consists of two parts. First, we construct a scene-level sketch-video dataset called SketchVideo, in which sketch-video pairs are provided and each pair contains a clip-level storyboard sketch and several keyframe sketches (corresponding to video frames). Second, we propose a novel deep learning architecture called Sketch Query Graph Convolutional Network (SQ-GCN). In SQ-GCN, we first adaptively sample the video frames to improve video encoding efficiency, and then construct appearance and category graphs to jointly model visual and semantic alignment between sketch and video. Experiments show that our fine-grained scene-level SBVR framework with SQ-GCN architecture outperforms the state-of-the-art fine-grained retrieval methods. The SketchVideo dataset and SQ-GCN code are available in the project webpage https://iscas-mmsketch.github.io/FG-SL-SBVR/.

The Combination of R848 with Sorafenib Enhances Antitumor Effects by Reprogramming the Tumor Immune Microenvironment and Facilitating Vascular Normalization in Hepatocellular Carcinoma.

Novel promising strategies for combination with sorafenib are urgently needed to enhance its clinical benefit and overcome toxicity in hepatocellular carcinoma (HCC). the molecular and immunomodulatory antitumor effects of sorafenib alone and in combination with the new immunotherapeutic agent R848 are presented. Syngeneic HCC mouse model is presented to explore the antitumor effect and safety of three sorafenib doses alone, R848 alone, or their combination in vivo. R848 significantly enhances the sorafenib antitumor activity at a low subclinical dose with no obvious toxic side effects. Furthermore, the combination therapy reprograms the tumor immune microenvironment by increasing antitumor macrophages and neutrophils and preventing immunosuppressive signaling. Combination treatment promotes classical M1 macrophage-to-FTH1high M1 macrophage transition. The close interaction between neutrophils/classical M1 macrophages and dendritic cells promotes tumor antigen presentation to T cells, inducing cytotoxic CD8+ T cell-mediated antitumor immunity. Additionally, low-dose sorafenib, alone or combined with R848, normalizes the tumor vasculature, generating a positive feedback loop to support the antitumor immune environment. Therefore, the combination therapy reprograms the HCC immune microenvironment and normalizes the vasculature, improving the therapeutic benefit of low-dose sorafenib and minimizing toxicity, suggesting a promising novel immunotherapy (R848) and targeted therapy (tyrosine kinase inhibitors) combination strategy for HCC treatment.

High incidence and reversible bradycardia events following alectinib initiation.

BACKGROUND: With the widespread use of alectinib in patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC), its cardiotoxicity has gradually emerged, including new-onset sinus bradycardia (SB). However, the incidence, timing, severity, and risk factors of alectinib-induced bradycardia remain unknown. METHODS: From January 2020 to June 2022, 93 patients with ALK-positive NSCLC treated with alectinib were enrolled in this retrospective analysis. These patients had heart rate (HR) recorded before and after alectinib administration. By reviewing electronic medical records and follow-up, the HR changes of patients during medication were recorded. The potential risk factors associated with alectinib-induced SB were explored. RESULTS: According to an HR cut-off of 60 beats per minute (bpm), 47 patients (50.54%) experienced at least one recorded bradycardia. The mean HR of total participants before alectinib administration was 78.32 (standard deviation [SD], 9.48) and after was 64.88 (SD, 12.21). The median maximum change in HR (range) for all patients was 11 (-55, +4) bpm. For the bradycardia subgroup, the HR of most patients (76.60%) hovered around 50-60 bpm, and 61.70% of SB occurred within 3 months after alectinib administration. Multivariate analysis indicated that baseline HR (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.79-0.93, p < 0.001) and history of hypertension (OR 13.71, 95% CI 2.49-76.38, p = 0.003) were independent risk factors for alectinib-related bradycardia. CONCLUSIONS: Alectinib-induced bradycardia had a high incidence, appeared relatively early, and was reversible by dose reduction or withdrawal.

SceneSketcher-v2: Fine-Grained Scene-Level Sketch-Based Image Retrieval Using Adaptive GCNs.

Sketch-based image retrieval (SBIR) is a long-standing research topic in computer vision. Existing methods mainly focus on category-level or instance-level image retrieval. This paper investigates the fine-grained scene-level SBIR problem where a free-hand sketch depicting a scene is used to retrieve desired images. This problem is useful yet challenging mainly because of two entangled facts: 1) achieving an effective representation of the input query data and scene-level images is difficult as it requires to model the information across multiple modalities such as object layout, relative size and visual appearances, and 2) there is a great domain gap between the query sketch input and target images. We present SceneSketcher-v2, a Graph Convolutional Network (GCN) based architecture to address these challenges. SceneSketcher-v2 employs a carefully designed graph convolution network to fuse the multi-modality information in the query sketch and target images and uses a triplet training process and end-to-end training manner to alleviate the domain gap. Extensive experiments demonstrate SceneSketcher-v2 outperforms state-of-the-art scene-level SBIR models with a significant margin.

Poor response to selpercatinib plus crizotinib in a rearranged during transfection fusion-positive patient with acquired selpercatinib-resistant MNNG HOS transforming amplification: a case report.

Selpercatinib has been approved by most major regulatory bodies in 2020 and become the standard therapy for rearranged during transfection ( RET )-rearranged nonsmall-cell lung cancer (NSCLC). Knowledge is limited regarding mechanisms of resistance to selpercatinib and effective treatment. One study identified MNNG HOS transforming ( MET ) amplification as intrinsic or secondary resistance mechanism from four patients, and three of them showed ~40% tumor reduction when treated with selpercatinib plus crizotinib. We report a 30-year-old female nonsmoker diagnosed in 2019 with stage IV lung adenocarcinoma harboring KIF5B-RET and a novel FOXD1-RET fusion. Frontline therapy consisted of bevacizumab combined with pemetrexed and carboplatin and achieved a progression-free survival (PFS) of 14 months with best response of stable disease. The patient then enrolled in the LIBRETTO-321 trial (NCT03157129) and started selpercatinib, which elicited a PFS of 9 months with best response of partial response. MNNG HOS transforming ( MET ) amplification was subsequently detected upon progression on selpercatinib, and the patient was placed on third-line treatment with selpercatinib plus crizotinib. However, her health deteriorated rapidly and died of cancer 4 months later. We provided additional evidence supporting MET amplification as an acquired mechanism of resistance to selective RET inhibition. In addition, the apparent lack of response to selpercatinib plus crizotinib in this case highlights the need for future cohort studies for examining the value of combining RET and MET inhibitors in treating RET -rearranged, MET -amplified NSCLC.

Application of SNP in Genetic Sex Identification and Effect of Estradiol on Gene Expression of Sex-Related Genes in Strongylocentrotus intermedius.

Sea urchin (Strongylocentrotus intermedius) is an economically important mariculture species in Asia, and its gonads are the only edible part. The efficiency of genetic breeding in sea urchins is hampered due to the inability to distinguish gender by appearance. In this study, we first identified a sex-associated single nucleotide polymorphism (SNP) by combining type IIB endonuclease restriction site-associated DNA sequencing (2b-RAD-seq) and genome survey. Importantly, this SNP is located within spata4, a gene specifically expressed in male. Knocking down of spata4 by RNA interference (RNAi) in male individuals led to the downregulation of other conserved testis differentiation-related genes and germ cell marker genes. We also revealed that sex ratio in this validated culture population of S. intermedius is not 1:1. Moreover, after a 58-day feeding experiment with estradiol, the expression levels of several conserved genes that are related to testis differentiation, ovary differentiation, and estrogen metabolism were dynamically changed. Taken together, our results will contribute toward improving breeding efficiency, developing sex-controlled breeding, and providing a solid base for understanding sex determination mechanisms in sea urchins.

CEBPG promotes acute myeloid leukemia progression by enhancing EIF4EBP1.

BACKGROUND: Acute myeloid leukemia (AML) is a myeloid neoplasm accounts for 7.6% of hematopoietic malignancies. AML is a complex disease, and understanding its pathophysiology is contributing to the improvement in the treatment and prognosis of AML. In this study, we assessed the expression profile and molecular functions of CCAAT enhancer binding protein gamma (CEBPG), a gene implicated in myeloid differentiation and AML progression. METHODS: shRNA mediated gene interference was used to down-regulate the expression of CEBPG in AML cell lines, and knockdown efficiency was detected by RT-qPCR and western blotting. The effect of knockdown on the growth of AML cell lines was evaluated by CCK-8. Western blotting was used to detect PARP cleavage, and flow cytometry were used to determine the effect of knockdown on apoptosis of AML cells. Genes and pathways affected by knockdown of CEBPG were identified by gene expression analysis using RNA-seq. One of the genes affected by knockdown of CEBPG was Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1), a known repressor of translation. Knockdown of EIF4EBP1 was used to assess its potential role in AML progression downstream of CEBPG. RESULTS: We explored the ChIP-Seq data of AML cell lines and non-AML hematopoietic cells, and found CEBPG was activated through its distal enhancer in AML cell lines. Using the public transcriptomic dataset, the Cancer Cell Line Encyclopedia (CCLE) and western blotting, we also found CEBPG was overexpressed in AML. Moreover, we observed that CEBPG promotes AML cell proliferation by activating EIF4EBP1, thus contributing to the progression of AML. These findings indicate that CEBPG could act as a potential therapeutic target for AML patients. CONCLUSION: In summary, we systematically explored the molecular characteristics of CEBPG in AML and identified CEBPG as a potential therapeutic target for AML patients. Our findings provide novel insights into the pathophysiology of AML and indicate a key role for CEBPG in promoting AML progression.

MI-773, a breaker of the MDM2/p53 axis, exhibits anticancer effects in neuroblastoma via downregulation of INSM1.

Neuroblastoma (NB) is a common pediatric malignancy associated with poor outcomes. Recent studies have shown that murine double minute2 homolog (MDM2) protein inhibitors are promising anticancer agents. MI-773 is a novel and specific antagonist of MDM2, however, the molecular mechanism of its anti-NB activity remains unclear. NB cell viability was measured by Cell Counting Kit-8 assay following MI-773 treatment. Cell cycle progression was analyzed using PI staining and apoptosis was assessed using Annexin V/PI staining. The molecular mechanisms by which MI-773 exerted its effects were investigated using a microarray. The results showed that disturbance of the MDM2/p53 axis by MI-773 resulted in potent suppression of proliferation, induction of apoptosis and cell cycle arrest in NB cells. In addition, microarray analysis showed that MI-773 led to significant downregulation of genes involved in the G2/M phase checkpoint and upregulation of hallmark gene associated with the p53 pathway. Meanwhile, knockdown of insulinoma-associated 1 decreased proliferation and increased apoptosis of NB cells. In conclusion, the present study demonstrated that MI-773 exhibited high selectivity and blockade affinity for the interaction between MDM2 and TP53 and may serve as a novel strategy for the treatment of NB.

PrbP modulates biofilm formation in Liberibacter crescens.

In Liberibacter asiaticus, PrbP is a transcriptional regulatory protein involved in survival and persistence during host infection. Tolfenamic acid was previously found to inhibit interactions between PrbP and the promotor region of rplK, resulting in reduced survival of L. asiaticus in the citrus host. In this study, we performed transcriptome analyses to elucidate the PrbP regulon in L. crescens, as it is phylogenetically the closest related species to L. asiaticus that can be grown in laboratory conditions. Chemical inhibition of PrbP with tolfenamic acid revealed that PrbP is involved in the regulation of diverse cellular processes, including stress response, cell motility, cell cycle and biofilm formation. In vitro DNA binding and bacterial two-hybrid assays also suggested that PrbP is a global regulator of multiple transcription factors (RpoH, VisN, PleD, MucR, MocR and CtrA) at both transcriptional and/or post-transcriptional levels. Sub-lethal concentrations of tolfenamic acid significantly reduced the attachment of L. crescens during biofilm formation and decreased long-term persistence in biofilm structures. Overall, our findings show the importance of PrbP in regulating diverse biological processes through direct and indirect interactions with other transcriptional regulators in L. crescens.

Glycosylation of a Nonfibrillizing Appendage Alters the Self-Assembly Pathway of a Synthetic ß-Sheet Fibrillizing Peptide.

Owing to their biocompatibility and biodegradability, short synthetic peptides that self-assemble into elongated ß-sheet fibers (i.e., peptide nanofibers) are widely used to create biomaterials for diverse medical and biotechnology applications. Glycosylation, which is a common protein post-translational modification, is gaining interest for creating peptide nanofibers that can mimic the function of natural carbohydrate-modified proteins. Recent reports have shown that glycosylation can disrupt the fibrillization of natural amyloid-forming peptides. Here, using transmission electron microscopy, fluorescence microscopy, and thioflavin T spectroscopy, we show that glycosylation at a site external to the fibrillization domain can alter the self-assembly pathway of a synthetic fibrillizing peptide, NSGSGQQKFQFQFEQQ (NQ11). Specifically, an NQ11 variant modified with N-linked N-acetylglucosamine, N(GlcNAc)SGSG-Q11 (GQ11), formed ß-sheet nanofibers more slowly than NQ11 in deionized water (pH 5.8), which correlated to the tendency of GQ11 to form a combination of short fibrils and nonfibrillar aggregates, whereas NQ11 formed extended nanofibers. Acidic phosphate buffer slowed the rate of GQ11 fibrillization and altered the morphology of the structures formed yet had no effect on NQ11 fibrillization rate or morphology. The buffer ionic strength had no effect on the fibrillization rate of either peptide, while the diphosphate anion had a similar effect on the rate of fibrillization of both peptides. Collectively, these data demonstrate that a glycan moiety located external to the ß-sheet fibrillizing domain can alter the pH-dependent self-assembly pathway of a synthetic peptide, leading to significant changes in the fibril mass and morphology of the structures formed. These observations add to the understanding of the effect of glycosylation on peptide self-assembly and should guide future efforts to develop biomaterials from synthetic ß-sheet fibrillizing glycopeptides.

A Pan-Cancer Analysis of the Oncogenic Role of Twinfilin Actin Binding Protein 1 in Human Tumors.

BACKGROUND: Understanding common and unique mechanisms driving oncogenic processes in human tumors is indispensable to develop efficient therapies. Recent studies have proposed Twinfilin Actin Binding Protein 1 (TWF1) as a putative driver gene in lung cancer, pancreatic cancer and breast cancer, however a systematic pan-cancer analysis has not been carried out. METHODS: Here, we set out to explore the role of TWF1 in 33 tumor types using TCGA (The Cancer Genome Atlas), GEO (Gene Expression Omnibus) dataset, Human Protein Atlas (HPA), and several bioinformatic tools. RESULTS: As part of our analysis, we have assessed TWF1 expression across tumors. We found that over-expression of TWF1 generally predicted poor OS for patients with tumors with high TWF1 expression, such as mesothelioma, lung adenocarcinoma, cervical cancer and pancreatic adenocarcinoma. We also assessed the mutation burden of TWF1 in cancer and the TWF1-associated survival of cancer patients, compared the phosphorylation of TWF1 between normal and primary tumor tissues and explored putative functional mechanisms in TWF1-mediated oncogenesis. CONCLUSIONS: Our pan-cancer analysis provides a comprehensive overview of the oncogenic roles of TWF1 in multiple human cancers.

Effect of antibiotic use on the efficacy of nivolumab in the treatment of advanced/metastatic non-small cell lung cancer: A meta-analysis.

This study evaluates the impact of the use of antibiotics on the effectiveness of nivolumab in the treatment of advanced/metastatic non-small cell lung cancer (NSCLC). A literature search was conducted in various electronic databases to identify studies, which evaluated the impact of antibiotic use on the survival of patients with advanced/metastatic NSCLC who have been treated with nivolumab. Six studies, comprising a total of 787 patients with 37.2% females and of age range 30-90 years, were included in the study. A lack of smoking history was reported in 14.4% of the patients. A meta-analysis was conducted in 678 and 713 patients for PFS and OS, respectively. The pooled HR was 1.95 (95% CI: 1.13-3.37, P = 0.016) for PFS and 2.70 (95% CI: 1.81-4.02, P < 0.001) for OS. Among patients exposed to antibiotics, the median PFS and OS were reduced by 1.6 months (95% CI: 1.5-1.7) and 8.8 months (95% CI: 8.5-9.1), respectively. Our study indicates that, among patients with advanced/metastatic NSCLC, the use of antibiotics with nivolumab led to a decrease in the median OS by more than 8 months. Studying the mechanism of the effect of antibiotics on the efficacy of nivolumab in patients with NSCLC should also be prioritized.

Harnessing molecular recognition for localized drug delivery.

A grand challenge in drug delivery is providing the right dose, at the right anatomic location, for the right duration of time to maximize therapeutic efficacy while minimizing off-target toxicity and other deleterious side-effects. Two general modalities are receiving broad attention for localized drug delivery. In the first, referred to as "targeted accumulation", drugs or drug carriers are engineered to have targeting moieties that promote their accumulation at a specific tissue site from circulation. In the second, referred to as "local anchoring", drugs or drug carriers are inserted directly into the tissue site of interest where they persist for a specified duration of time. This review surveys recent advances in harnessing molecular recognition between proteins, peptides, nucleic acids, lipids, and carbohydrates to mediate targeted accumulation and local anchoring of drugs and drug carriers.