Prediction of biomarkers and therapeutic combinations for anti-PD-1 immunotherapy using the global gene network association

Owing to a lack of response to the anti-PD1 therapy for most cancer patients, we develop a network approach to infer genes, pathways, and potential therapeutic combinations that are associated with tumor response to anti-PD1. Here, our prediction identifies genes and pathways known to be associated with anti-PD1, and is further validated by 6 CRISPR gene sets associated with tumor resistance to cytotoxic T cells and targets of the 36 compounds that have been tested in clinical trials for combination treatments with anti-PD1. Integration of our top prediction and TCGA data identifies hundreds of genes whose expression and genetic alterations that could affect response to anti-PD1 in each TCGA cancer type, and the comparison of these genes across cancer types reveals that the tumor immunoregulation associated with response to anti-PD1 would be tissue-specific. In addition, the integration identifies the gene signature to calculate the MHC I association immunoscore (MIAS) that shows a good correlation with patient response to anti-PD1 for 411 melanoma samples complied from 6 cohorts. Furthermore, mapping drug target data to the top genes in our association prediction identifies inhibitors that could potentially enhance tumor response to anti-PD1, such as inhibitors of the encoded proteins of CDK4, GSK3B, and PTK2.

Comprehensive Analysis and Validation Reveal Potential MYCN Regulatory Biomarkers Associated with Prognosis of Neuroblastoma

Background Neuroblastoma (NB) is an embryonic malignant tumor that occurs in the sympathetic nervous system. The treatment effect of patients in the high-risk group is poor, and relapse and treatment failure can occur even with multiple combination treatments. MYCN is an independent prognostic factor for NB, and the proportion of MYCN amplification in tumor tissues of high-risk patients reaches 40-50%. Hence, exploring new MYCN targeting molecules is a meaningful way to treat high-risk NB patients. Methods The microarray datasets were obtained from Gene Expression Omnibus, and differentially expressed genes were identified. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and miRPathDB were used for function and pathway analysis. The STRING and Cytoscape were used to construct a protein-protein interaction network and modular analysis. The miRNet and NetworkAnalyst databases were used to predict and construct target gene-miRNA and target gene-TF networks. The R2 database was used for expression, correlation, and prognosis analysis. The diagnostic effect of the biomarkers was predicted by ROC analysis, and rt-PCR was used to verify the hub genes. Finally, used specific siRNA and plasmid to knockdown and overexpressed MYCN, the mRNA levels were verified. Results We identified 431 DEGs and FBXO9, HECW2, MIB2, RNF19B, RNF213, TRIM36, and ZBTB16 as novel biomarkers that affect the prognosis of the NB patients. In addition, FBXO9, RNF19B, and TRIM36 were preliminarily confirmed to be potential targeting molecules of MYCN. Conclusions Our results are expected to become novel biomarkers for the treatment of high-risk NB patients.

Assessment in vitro of the antimalarial and transmission blocking activities of Cipargamin and Ganaplacide in artemisinin resistant Plasmodium falciparum

Artemisinin resistance in Plasmodium falciparum has emerged and spread widely in the Greater Mekong Subregion threatening current first line artemisinin combination treatments. New antimalarial drugs are needed urgently. Cipargamin (KAE609) and ganaplacide (KAF156) are promising novel antimalarial compounds in advanced stages of development. Both compounds have potent asexual blood stage activities, inhibit P. falciparum gametocytogenesis and reduce oocyst development in anopheline mosquitoes. In this study, we compared the asexual and sexual stage activities of cipargamin, ganaplacide and artesunate in artemisinin resistant P. falciparum isolates (N=7, K13 mutation; C580Y, G449A and R539T) from Thailand and Cambodia. Asexual blood stage antimalarial activity was evaluated in a SYBR-green I based 72h in vitro assay, and the effects on male and female mature stage V gametocytes were assessed in the P. falciparum dual gamete formation assay. Ganaplacide had higher activities when compared to cipargamin and artesunate, with a mean (SD) IC50 against asexual stages of 5.5 (1.1) nM, 7.8 (3.9) nM for male gametocytes and 57.9 (59.6) nM for female gametocytes. Cipargamin had a similar potency against male and female gametocytes, with a mean (SD) IC50 of 123.1 (80.2) nM for male gametocytes, 88.5 (52.7) nM for female gametocytes and 2.4 (0.6) nM for asexual stages. Both cipargamin and ganaplacide showed significant transmission-blocking activities against artemisinin resistant P. falciparum in vitro .

HDAC inhibitors with potential to overcome drug resistance in castration-resistant prostate cancer

Epigenetic mechanisms play an important role in the development and persistence of cancer, and histone deacetylase (HDAC) inhibitors are promising anticancer drugs targeting epigenetic modes. Efficient anticancer drugs for the treatment of castration-resistant prostate cancer (CRPC) are sought, and approved HDAC inhibitors have shown promising results on the one hand and severe drawbacks on the other hand. Hence, ways to break the drug resistance mechanisms of existing HDAC inhibitors as well as the design of new promising HDAC inhibitors which can overcome the disadvantages of the classic HDAC inhibitors are of great importance. In this work, HDAC inhibitors with the potential to become a mainstay for the treatment of CRPC in the future as well as suitable combination treatments of HDAC inhibitors with other anticancer drugs leading to considerable synergistic effects in treated CRPCs are discussed.

Distinct cDC subsets co-operate in CD40 agonist response while suppressive microenvironments and lack of antigens subvert efficacy

Agonistic αCD40 therapy has shown to inhibit cancer progression, but only in a fraction of patients. Hence, understanding the cancer cell-intrinsic and microenvironmental determinants of αCD40 therapy response is crucial to identify responsive patient populations and design efficient combination treatments. Here, we showed that the therapeutic efficacy of αCD40 in responder melanoma tumours, relied on pre-existing cDC1-primed CD8+ T cells, however cDC1s were dispensable after αCD40 administration. Surprisingly, in response to αCD40 the abundance of activated cDCs, potentially derived from cDC2s increased, thereby further activating antitumour CD8+ T cells. Hence, distinct cDC subsets are required to induce αCD40 responses. By contrast, lung tumours, characterised by a high abundance of macrophages, were resistant to αCD40 therapy. Combining αCD40 therapy with macrophage depletion led to tumour growth inhibition only in the presence of strong neoantigens. Accordingly, treatment with immunogenic cell-death inducing chemotherapy sensitised non-immunogenic tumours to αCD40 therapy.

Barriers to Immunotherapy in Ovarian Cancer: Metabolic, Genomic, and Immune Perturbations in the Tumour Microenvironment

A lack of explicit early clinical signs and effective screening measures mean that ovarian cancer (OC) often presents as advanced, incurable disease. While conventional treatment combines maximal cytoreductive surgery and platinum-based chemotherapy, patients frequently develop chemoresistance and disease recurrence. The clinical application of immune checkpoint blockade (ICB) aims to restore anti-cancer T-cell function in the tumour microenvironment (TME). Disappointingly, even though tumour infiltrating lymphocytes are associated with superior survival in OC, ICB has offered limited therapeutic benefits. Herein, we discuss specific TME features that prevent ICB from reaching its full potential, focussing in particular on the challenges created by immune, genomic and metabolic alterations. We explore both recent and current therapeutic strategies aiming to overcome these hurdles, including the synergistic effect of combination treatments with immune-based strategies and review the status quo of current clinical trials aiming to maximise the success of immunotherapy in OC.

Infliximab for Anoperineal Lesions in Crohn's Disease: Remission Appears to be Based on Rapid Combination Therapy at High Doses

Study Aim The aim of the present study was to compare in real life the characteristics of treatment with infliximab according to the presence or absence of anoperineal involvement in Crohn's disease. Methods We performed a single-center, prospective, non-interventional study, on patients with Crohn's disease in remission who had been treated with infliximab for at least 1 year. Patients with poor treatment compliance, on antibiotics, or those with a stoma were excluded. Results We included 52 patients in this study: 34 with anoperineal lesions with or without luminal lesions, and 18 with luminal lesions only. Patients with anoperineal lesions were more likely to have undergone surgery (70.6% versus 38.9%, p = 0.027), had a shorter median time to infliximab treatment initiation (0.5 versus 5.5 years, p = 0.005), a higher mean dose of infliximab (6.6 versus 5.1 mg/kg, p = 0.015), and were more likely to receive combination treatments including infliximab (52.9% versus 11.1%, p = 0.008) than patients with luminal involvement only. Conclusions In our study, infliximab treatment was initiated more quickly, at higher doses, and more in combination therapy for anoperineal Crohn's disease than for luminal damage alone. Additional studies are required to confirm this finding and to assess the tolerance of this treatment throughout patient management.

Effect of Combination Treatments of Apigenin and Chemotherapy on Apoptosis- Related Genes and Proteins in Acute Leukaemia Cell Lines

Apigenin is a dietary polyphenol found abundantly in fruit and vegetables. It has been shown to sensitize acute lymphoid and myeloid leukaemia cells to topoisomerase inhibitor agents (e.g., etoposide), and alkylating agents (e.g., cyclophosphamide), reducing ATP levels and inducing apoptosis; whilst being protective to control haematopoietic stem cells. This study analysed the expression profiles of intrinsic and extrinsic apoptosis-related genes and proteins to help elucidate the mechanisms of action of apigenin when used in combination with etoposide or cyclophosphamide in acute lymphoid and myeloid leukaemia cells (Jurkat and THP-1). Expression of apoptosis-related genes were measured using a TaqMan® Human Apoptosis Array and the StepOne Plus RT-qPCR System, whilst apoptosis-related proteins were determined using a protein profilerTM-human apoptosis array and the LI-COR OdysseyR Infrared Imaging System. Apigenin when combined with etoposide or cyclophosphamide-induced apoptosis via the mitochondrial pathway, increasing the expression of pro-apoptotic cytochrome c, SMAC/DIABLO, and HTRA2/OMI, which promoted caspase-9 and -3 activation. Targeting anti-apoptotic and/or pro-apoptotic members of the apoptotic pathways is a promising strategy to induce cancer cell death and improve sensitivity to chemotherapy agents.Here apigenin in combination with etoposide or cyclophosphamide induced apoptosis in leukaemia cells and may have clinical potential in the treatment of leukaemia.

Analysis of Clinical Research Trends for Acupotomy Treatment of Peripheral Facial Palsy

The purpose of this review was to investigate acupotomy treatment for peripheral facial palsy. By reviewing recent clinical trends, this may contribute to standardizing acupotomy treatment methods. There were 7 randomized controlled trials and 6 case series using acupotomy treatment for peripheral facial palsy published between January 01, 2014 and April 05, 2021, which were retrieved from 9 online databases. The number and characteristics of participants, main treatment sites, combination treatments, size of acupotomy needle, frequency and total period of treatment, evaluation indices, efficacy, and adverse events were analyzed. “Tender point or induration,” “infraorbical foramen,” and “buccal mucosa” were the most used treatment sites. The sizes of acupotomy needles varied from 20 mm to 80 mm in length, and 0.35 mm to 1.0 mm in diameter. One treatment cycle was performed every 3 to 5-7 days, and the number of treatments per treatment session ranged from 3 to 5-9 cycles. The results were evaluated using 1 to 4 evaluation indices and 9 different evaluation indices were used overall. The efficacy rate was the most used index, followed by the House-Brackmann grade, and electrocardiography. The “Risk of Bias 2,” categorized most studies as having “some concerns.” There were few adverse events reported.

EFFECT OF FERTILIZERRS WITH UREASE AND NITRIFICATION INHIBITORS ON DURUM WHEAT CROP ON YIELD AND QUALITY (Triticum turgidum L. subsp. durum)

Conventional agricultural has a significant role in climate change. For this reason, farmers choose more innovative practices such as fertilizers inhibitors. Durum wheat (Triticum turgidum L. subsp. durum) is the most cultivated winter crop in the Mediterranean basin. The scope of this study is to determine the improvement of the fertilizer yield by adding nitrification (DMPSA) and urease (NBPT) inhibitor in urea in durum wheat crop. Meridiano variety was evaluated for one growing period through 2019–2020 under two basic fertilization (20-20-0 and 12-40-0 (+10S +Zn). The experiments were designed according to split-plot design, 2 main plots (basic fertilization) and 7 subplots (top fertilization). The top fertilization were the various urea combination treatments (urea, urea + urease inhibitor thiophosphoric-triamide (NBPT) (UI), urea + nitrogen inhibitor 3,4- dimethylpyrazole succinic (DMPSA) and control. Nitrogen markers, such as nitrogen use efficiency (NUE), nitrogen harvest index and nitrogen agronomic efficiency (NAE) were used to evaluate nitrogen release. The length of the inflorescences was over 20 cm for all fertilizations. Regarding basic fertilization, larger inflorescences were recorded with 12-40-0 (+10S +Zn). The grain protein content and nitrogen were higher by 1-2% under basic basic fertilization 20-20-0. Grain and biomass production were increased with both fertilizers’ inhibitors (NBPT and DMPSA). Between two inhibitors, urease inhibitor (NBPT) yielded higher than DMPSA.