Important Cause Of Treatment Failure Research Articles

Engineered targeting OIP5 sensitizes bladder cancer to chemotherapy resistance via TRIP12-PPP1CB-YBX1 axis.

Chemoresistance is an important cause of treatment failure in bladder cancer, and identifying genes that confer drug resistance is an important step toward developing new therapeutic strategies to improve treatment outcomes. In the present study, we show that gemcitabine plus cisplatin (GEM/DDP) therapy induces NF-κB signaling, which promotes p65-mediated transcriptional activation of OIP5. OIP5 recruits the E3 ubiquitin ligase TRIP12 to bind to and degrade the phosphatase PPP1CB, thereby enhancing the transcription factor activity of YBX1. This in turn upregulates drug-resistance-related genes under the transcriptional control of YBX1, leading to chemoresistance. Moreover, PPP1CB degradation can enhance the phosphorylation activity of IKKβ, triggering the NF-κB signaling cascade, which further stimulates OIP5 gene expression, thus forming a negative feedback regulatory loop. Consistently, elevated OIP5 expression was associated with chemoresistance and poor prognosis in patients with bladder cancer. Furthermore, we used a CRISPR/Cas9-based engineered gene circuit, which can monitor the progression of chemoresistance in real-time, to induce OIP5 knockout upon detection of increased NF-κB signaling. The gene circuit significantly inhibited tumor cell growth in vivo, underscoring the potential for synergy between gene therapy and chemotherapy in the treatment of cancer.

Exploring the Molecular Mechanisms of Macrolide Resistance in Laboratory Mutant Helicobacter pylori.

Resistance to clarithromycin, a macrolide antibiotic used in the first-line treatment of Helicobacter pylori infection, is the most important cause of treatment failure. Although most cases of clarithromycin resistance in H. pylori are associated with point mutations in 23S ribosomal RNA (rRNA), the relationships of other mutations with resistance remain unclear. We examined possible new macrolide resistance mechanisms in resistant strains using next-generation sequencing. Two resistant strains were obtained from clarithromycin-susceptible H. pylori following exposure to low clarithromycin concentrations using the agar dilution method. Sanger sequencing and whole-genome sequencing were performed to detect resistance-related mutations. Both strains carried the A2142G mutation in 23S rRNA. Candidate mutations (T1495A, T1494A, T1490A, T1476A, and G1472T) for clarithromycin resistance were detected in the Mutant-1 strain. Furthermore, a novel mutation in the gene encoding for the sulfite exporter TauE/SafE family protein was considered to be linked to clarithromycin resistance or cross-resistance, being identified as a target for further investigations. In the Mutant-2 strain, a novel mutation in the gene that encodes DUF874 family protein that can be considered as relevant with antibiotic resistance was detected. These mutations were revealed in the H. pylori genome for the first time, emphasizing their potential as targets for advanced studies.

Real-time single-base specific detection of the Haemonchus contortus S168T variant associated with levamisole resistance using loop-primer endonuclease cleavage loop-mediated isothermal amplification

Haemonchus contortus is a parasitic haematophagous nematode that primarily affects small ruminants and causes significant economic loss to the global livestock industry. Treatment of haemonchosis typically relies on broad-spectrum anthelmintics, resistance to which is an important cause of treatment failure. Resistance to levamisole remains less widespread than to other major anthelmintic classes, prompting the need for more effective and accurate surveillance to maintain its efficacy. Loop-primer endonuclease cleavage loop-mediated isothermal amplification (LEC-LAMP) is a recently developed diagnostic method that facilitates multiplex target detection with single nucleotide polymorphism (SNP) specificity and portable onsite testing. In this study, we designed a new LEC-LAMP assay and applied it to detect the levamisole resistance marker S168T in H. contortus. We explored multiplexing probes for both the resistant S168T and the susceptible S168 alleles in a single-tube assay. We then included a generic probe to detect the acr-8 gene in the multiplex assay, which could facilitate the quantification of both resistance markers and overall genetic material from H. contortus in a single step. Our results showed promising application of these technologies, demonstrating a proof-of-concept assay which is amenable to detection of resistance alleles within the parasite population, with the potential for multiplex detection, and point-of-care application enabled by lateral flow end-point detection. However, further optimisation and validation is necessary.

Inhibitor of Wnt receptor 1 suppresses the effects of Wnt1, Wnt3a and β‑catenin on the proliferation and migration of C6 GSCs induced by low‑dose radiation.

The radioresistance of glioma is an important cause of treatment failure and tumor aggressiveness. In the present study, under performed with linear accelerator, the effects of 0.3 and 3.0Gy low‑dose radiation (LDR) on the proliferation and migration of C6 glioma stem cells invitro were examined by flow cytometric analysis, immunocytochemistry and western blot analysis. It was found that low‑dose ionizing radiation (0.3Gy) stimulated the proliferation and migration of these cells, while 3.0Gy ionizing radiation inhibited the proliferation of C6 glioma stem cells, which was mediated through enhanced Wnt/β‑catenin signaling, which is associated with glioma tumor aggressiveness. LDR treatment increased the expression of the DNA damage marker γ‑H2AX but promoted cell survival with a significant reduction in apoptotic and necrotic cells. When LDR cells were also treated with an inhibitor of Wnt receptor 1 (IWR1), cell proliferation and migration were significantly reduced. IWR1 treatment significantly inhibited Wnt1, Wnt3a and β‑catenin protein expression. Collectively, the current results demonstrated that IWR1 treatment effectively radio‑sensitizes glioma stem cells and helps to overcome the survival advantages promoted by LDR, which has significant implications for targeted treatment in radioresistant gliomas.

TRIM25 promotes temozolomide resistance in glioma by regulating oxidative stress and ferroptotic cell death via the ubiquitination of keap1.

Resistance to temozolomide (TMZ) remains an important cause of treatment failure in patients with glioblastoma multiforme (GBM). TRIM25, as a tripartite motif-containing (TRIM) family member, plays a significant role in cancer progression and chemoresistance. However, the function of TRIM25 and its precise mechanism in regulating GBM progression and TMZ resistance remain poorly understood. We found that the expression of TRIM25 was upregulated in GBM, and it was associated with tumor grade and TMZ resistance. Elevated TRIM25 expression predicted a poor prognosis in GBM patients and enhanced tumor growth in vitro and in vivo. Further analysis revealed that elevated TRIM25 expression inhibited oxidative stress and ferroptotic cell death in glioma cells under TMZ treatment. Mechanistically, TRIM25 regulates TMZ resistance by promoting the nuclear import of nuclear factor erythroid 2-related factor 2(Nrf2) via keap1 ubiquitination. Knockdown of Nrf2 abolished the ability of TRIM25 to promote glioma cell survival and TMZ resistance. Our results support the targeting of TRIM25 as a new therapeutic strategy for glioma.

TRPV1 inhibition overcomes cisplatin resistance by blocking autophagy-mediated hyperactivation of EGFR signaling pathway

Cisplatin resistance along with chemotherapy-induced neuropathic pain is an important cause of treatment failure for many cancer types and represents an unmet clinical need. Therefore, future studies should provide evidence regarding the mechanisms of potential targets that can overcome the resistance as well as alleviate pain. Here, we show that the emergence of cisplatin resistance is highly associated with EGFR hyperactivation, and that EGFR hyperactivation is arisen by a transcriptional increase in the pain-generating channel, TRPV1, via NANOG. Furthermore, TRPV1 promotes autophagy-mediated EGF secretion via Ca2+ influx, which activates the EGFR-AKT signaling and, consequentially, the acquisition of cisplatin resistance. Importantly, TRPV1 inhibition renders tumors susceptible to cisplatin. Thus, our findings indicate a link among cisplatin resistance, EGFR hyperactivation, and TRPV1-mediated autophagic secretion, and implicate that TRPV1 could be a crucial drug target that could not only overcome cisplatin resistance but also alleviate pain in NANOG+ cisplatin-resistant cancer.

HapE and hmg1 Mutations Are Drivers of cyp51A-Independent Pan-Triazole Resistance in an Aspergillus fumigatus Clinical Isolate.

Aspergillus fumigatus is a ubiquitous environmental mold that can cause severe disease in immunocompromised patients and chronic disease in individuals with underlying lung conditions. Triazoles are the most widely used class of antifungal drugs to treat A. fumigatus infections, but their use in the clinic is threatened by the emergence of triazole-resistant isolates worldwide, reinforcing the need for a better understanding of resistance mechanisms. The predominant mechanisms of A. fumigatus triazole resistance involve mutations affecting the promoter region or coding sequence of the target enzyme of the triazoles, Cyp51A. However, triazole-resistant isolates without cyp51A-associated mutations are frequently identified. In this study, we investigate a pan-triazole-resistant clinical isolate, DI15-105, that simultaneously carries the mutations hapEP88L and hmg1F262del, with no mutations in cyp51A. Using a Cas9-mediated gene-editing system, hapEP88L and hmg1F262del mutations were reverted in DI15-105. Here, we show that the combination of these mutations accounts for pan-triazole resistance in DI15-105. To our knowledge, DI15-105 is the first clinical isolate reported to simultaneously carry mutations in hapE and hmg1 and only the second with the hapEP88L mutation. IMPORTANCE Triazole resistance is an important cause of treatment failure and high mortality rates for A. fumigatus human infections. Although Cyp51A-associated mutations are frequently identified as the cause of A. fumigatus triazole resistance, they do not explain the resistance phenotypes for several isolates. In this study, we demonstrate that hapE and hmg1 mutations additively contribute to pan-triazole resistance in an A. fumigatus clinical isolate lacking cyp51-associated mutations. Our results exemplify the importance of and the need for a better understanding of cyp51A-independent triazole resistance mechanisms.

Lenalidomide Consolidation Added to Rituximab Maintenance Therapy in Patients Remaining PET Positive After Treatment for Relapsed Follicular Lymphoma: A Phase 2 Australasian Leukaemia & Lymphoma Group NHL26 Study.

Lenalidomide Consolidation Added to Rituximab Maintenance Therapy in Patients Remaining PET Positive After Treatment for Relapsed Follicular Lymphoma: A Phase 2 Australasian Leukaemia & Lymphoma Group NHL26 Study.

Development of antidrug antibodies against adalimumab maps to variation within the HLA-DR peptide-binding groove.

Targeted biologic therapies can elicit an undesirable host immune response characterized by the development of antidrug antibodies (ADA), an important cause of treatment failure. The most widely used biologic across immune-mediated diseases is adalimumab, a tumor necrosis factor inhibitor. This study aimed to identify genetic variants that contribute to the development of ADA against adalimumab, thereby influencing treatment failure. In patients with psoriasis on their first course of adalimumab, in whom serum ADA had been evaluated 6-36 months after starting treatment, we observed a genome-wide association with ADA against adalimumab within the major histocompatibility complex (MHC). The association signal mapped to the presence of tryptophan at position 9 and lysine at position 71 of the HLA-DR peptide-binding groove, with both residues conferring protection against ADA. Underscoring their clinical relevance, these residues were also protective against treatment failure. Our findings highlight antigenic peptide presentation via MHC class II as a critical mechanism in the development of ADA against biologic therapies and downstream treatment response.

Multifunctional immunotherapeutic gel prevented postoperative recurrence of hepatocellular carcinoma

Postoperative recurrence of hepatocellular carcinoma (HCC) remains an important cause of treatment failure. To mitigate the relapse of HCC, we have constructed an immunotherapeutic in situ fibrin gel to stimulate antitumor immune responses following HCC surgical resection. The gel consists of hollow mesoporous Prussian blue nanoparticles (HMPB) co-loaded with anti-SIRPα antibodies and the colony-stimulating factor 1 receptor (CSF-1R) small molecule inhibitor BLZ945, and differentiation inducer all-trans retinoic acid (ATRA). After the gel is formed in the surgical cavity, HMPB are released locally and then BLZ945 and anti-SIRPα antibody block the MCSF-CSF-1R and CD47-SIRPα signal axes respectively, which can repolarize tumor-associated macrophages (TAMs) from a tumorigenic M2 phenotype to an antitumor M1 phenotype, thus restoring their ability to kill cancer cells. In addition, ATRA released from the gel leads to the differentiation of cancer stem cells (CSCs) and increases their sensitivity to immunotherapy. Our findings indicate that this in situ immunotherapeutic gel can reshape the postoperative tumor microenvironment (TME) and induce antitumor responses, thereby inhibiting postoperative tumor recurrence.

Patient-derived xenograft model in colorectal cancer basic and translational research.

Colorectal cancer (CRC) is one of the most popular malignancies globally, with 930 000 deaths in 2020. The evaluation of CRC-related pathogenesis and the discovery of potential therapeutic targets will be meaningful and helpful for improving CRC treatment. With huge efforts made in past decades, the systematic treatment regimens have been applied to improve the prognosis of CRC patients. However, the sensitivity of CRC to chemotherapy and targeted therapy is different from person to person, which is an important cause of treatment failure. The emergence of patient-derived xenograft (PDX) models shows great potential to alleviate the straits. PDX models possess similar genetic and pathological characteristics as the features of primary tumors. Moreover, PDX has the ability to mimic the tumor microenvironment of the original tumor. Thus, the PDX model is an important tool to screen precise drugs for individualized treatment, seek predictive biomarkers for prognosis supervision, and evaluate the unknown mechanism in basic research. This paper reviews the recent advances in constructed methods and applications of the CRC PDX model, aiming to provide new knowledge for CRC basic research and therapeutics.

Levetiracetam induces severe psychiatric symptoms in people with epilepsy

Background: Drug-induced psychiatric symptoms are an important cause of treatment failure. Worldwide, levetiracetam has been widely used to treat epilepsy; however, associated psychobehavioral abnormalities have been observed . This study aimed to characterize levetiracetam-induced severe psychiatric symptoms and to propose preventive and therapeutic measures. Methods: In this retrospective cluster sampling study, psychiatric symptoms of patients who had taken levetiracetam for at least 1 month were analyzed. Results: 111(7.8%) of the 1,412 included patients exhibited severe psychiatric symptoms. Hallucinations, delusions, aggressive behavior, and agitation were the most common manifestations . Some patients also showed suicidal and self-harm behaviors. These symptoms were mainly controlled by reducing the dose of levetiracetam, stopping the drug, or adding antipsychotic drugs to the treatment regimen. Conclusion: The severe psychiatric symptoms caused by levetiracetam require special attention.

A Phase II Clinical Trial of "Off-the-Shelf" NK Cells with Allogeneic Stem Cell Transplantation to Decrease Disease Relapse in Patients with High-Risk Myeloid Malignancies

Background Acute myeloid leukemia, myelodysplastic syndrome, and TKI resistant CML continue to be among the most aggressive forms of blood cancer. Allogeneic hematopoietic stem cell transplantation (alloSCT) remains one of the most effective treatments available. Much of the benefit of AlloSCT is due to the immune-mediated graft-versus-leukemia effect to prevent relapse. Nevertheless, disease relapse remains the most important cause of treatment failure after alloSCT. A potential solution to reduce the risk of relapse may be found in Natural Killer (NK) cells, which have a demonstrable ability to eliminate leukemic and virally infected cells. However, naturally produced NK cells seen in patients early post-transplant are functionally impaired. A potential solution would be to provide donor-derived, expanded and activated NK cells in the peri-transplant setting. Natural killer cells are a unique class of lymphocytes, with cytotoxic, and immunoregulatory function which can mediate potent anti-leukemia effects. NK cells are regulated by Killer-cell Immunoglobulin-like Receptors (KIR) receptor-ligand interactions and mediate cytotoxicity. Alloreactive NK cells have been reported to enhance engraftment, reduce GVHD and prevent relapse of leukemia post transplant. This study will utilize NK cells from third party donors as adjuvant treatment to eradicate leukemia and prevent disease relapse after transplantation. Study Design and Methods Our clinical trial is registered as NCT05115630. Inclusion criteria includes age 18 to 65 years old, weighing at least 42 kg, with High risk AML, MDS, or TKI-resistant/intolerant CML who have either an HLA matched related donor, HLA matched unrelated donor, a haploidentical related donor, or a one antigen mismatched unrelated donor. HLA matching includes HLA A, B, C, and DR-B1. Exclusion criteria include patients who are HIV positive or has active hepatitis B or C, uncontrolled infections, liver cirrhosis, CNS involvement within 3 months prior to the transplant, or positive pregnancy test in a woman with child bearing potential. We will also exclude any patient with inability to comply with medical therapy or follow-up, patient with a known history of allergic reactions to any constituents of the product, including a known history of allergic reactions to cellular products or DMSO, other malignancy/cancer diagnosis <2 years ago. We will also exclude any patient requiring systemic corticosteroids with prednisone dose >10 mg or equivalent or who has KDS-1001 Donor specific antibodies (dsa) >5000 MFI units, or has KDS-1001 Donor anti-C1q positive. Statistical considerations and exploratory endpoints This is a single-arm Phase II trial of 3rd party natural killer (NK) cells at a fixed dose added to an allogeneic stem cell transplant for AML/MDS/CML. The goal is to reduce the risk of relapse of the malignancy post transplant, and to improve relapse free survival. The primary endpoint is the adverse event Failure = [graft failure, grade 3-4 GVHD, relapse or non-relapse death within 100 days post-transplant]. The stopping rule for time-to-failure (defined as graft failure, gr 3-4 GHVD, or non-relapse death) will be implemented to avoid waiting 100 days (3 months) to evaluate each patient to perform safety monitoring. The design will be based on T with 3 months follow-up, applying the design of Thall et al. Possibly right-censored values of T for patients treated in the trial will be monitored continuously throughout the trial. The accrual rate is expected to be approximately 2 patients per month, with each patient's follow-up continued until all patients have been followed for 3 months from their date of first NK cell administration. The distributions of time to failure and RFS time will be estimated using the method of Kaplan and Meier. Exploratory analyses with immunophenotyping for NK cell chimerism and persistence will be done as feasible. Immune reconstitution studies or additional future research may be performed.

Particle beam radiation therapy for head and neck rhabdomyosarcoma in adults

Rhabdomyosarcoma (RMS) is rare in adults, with a significantly worse prognosis than its pediatric counterpart. Radiotherapy (RT) plays a significant role in treating head and neck RMS (HNRMS), but the outcomes of conventional RT are limited by the complex anatomy and unfavorable pathology subtypes of the adult H&N RMS. Here, we aim to report the effectiveness and safety of carbon-ion beam RT (CIRT), either alone or in combination with proton radiotherapy (PRT) in the management of adult HNRMS. Fifteen adult patients with HNRMS were enrolled on a prospective registry protocol between 06/2015 and 12/2019. Eight patients presented with parameningeal tumors, and eight had unfavorable pathology subtypes [alveolar =7, not otherwise specified (NOS) =1]. Eleven patients had gross tumors before the start of RT (volume range, 46.1-137.6 cm3). Two patients failed the earlier RT. All except for one patient received multi-drug chemotherapy. The median absolute dose of particle beam RT was 70.0 Gy [relative biological effectiveness (RBE)]. With a median follow-up of 21 months, local or distant recurrence occurred in three and four patients, respectively, and two added patients had both local and distant failure. One patient died of distant metastasis (DM), and another died of an unrelated condition. The 1- and 2-year overall survival (OS), local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and progression-free survival (PFS) rates were 87.5% and 70.0%, 92.3% and 67.1%, 72.2% and 54.2%, and 65.0% and 24.4%, respectively, for the entire cohort. Both patients who failed earlier RT and received salvage CIRT developed DM but were alive at last follow-up. No acute toxicity of ≥ grade 3 or late toxicity of ≥ grade 2 was observed. CIRT, either used alone or in combination with PRT, is not only feasible and safe but also useful in local disease control for HNRMS. DM is the most important cause of treatment failure; thus, more effective systemic treatment is needed to improve the prognosis of HNRMS further.

Inhibition Mechanism of PinX1 Gene on Cancer Stem Cells of Nasopharyngeal Carcinoma.

The recurrence and long-term metastasis of these tumors are important causes of treatment failure and death. On the other hand, PinX1 is a nucleolar protein found in recent years that can interact with telomere/telomerase simultaneously, and it is highly conserved in human and yeast. Some studies have shown that the PinX1 gene can inhibit the tumor stem cells of NPC. Therefore, the mechanism of inhibition of the PinX1 gene on the tumor stem cells of NPC has been studied in this paper. In this paper, CNE2 cells of NPC were used as experimental materials, CD133 as a marker, PinX1 overexpression plasmids and their corresponding empty plasmids were respectively transfected in CD133+ cells, PinX1 siRNA and their corresponding NC siRNA were respectively transfected in CD133- cells for control experiments. In this study, we found that the telomerase activity of the CD133 - + NC group was 1.001 ± 0.086, the CD133 - + pinx1sirna group was 0.974 ± 0.046, CD133+ + vector group was 0.928 ± 0.102, CD133+ + over PinX1 group was 0.703 ± 0.086. Therefore, the PinX1 gene can inhibit NPC stem cells by inhibiting telomerase activity.

Non-persistence to antihypertensive drug therapy in Lithuania

PurposePoor persistence to antihypertensive therapy is an important cause of treatment failure. Investigating persistence is especially important in countries with a high cardiovascular mortality, like Lithuania. The aim of this study was to describe the antihypertensive treatment at initiation, to determine the percentage of patients not being persistent with antihypertensive treatment after 1 year and to explore factors associated with non-persistence.MethodsIn this cohort study, data on dispensed prescription medicines from the Lithuanian National Health Insurance Fund (NHIF) were used. All adult patients with a diagnosis of hypertension having first antihypertensive dispensed in 2018 were included. Descriptive statistics was used to determine the number of patients started with monotherapy and combination therapy. Treatment choice by Anatomical Therapeutic Chemical (ATC) and number of active pharmaceutical ingredient (API) was described. Non-persistence was assessed using the anniversary method. Multivariate logistic regression was used to explore factors associated with non-persistence.ResultsA total of 72,088 patients were included into the study, 56% started on monotherapy treatment, with 49% being dispensed an angiotensin converting enzyme inhibitor, and 44% started on combination therapy. Overall, 57% of patients were non-persistent after 1 year. Patients’ gender and prescriber qualification showed no association with non-persistence. Younger patients, patients from rural area, patients started with monotherapy, and patients with no medication change had higher odds to become non-persistent.ConclusionsThe majority of patients were initiated with treatment following hypertension management guidelines, but it is of concern that over half of the patients were non-persistent to antihypertensive therapy in the first year.

Effect of redo varicocelectomy on semen parameters and pregnancy outcome: An original report and meta‐analysis

Recurrence following varicocelectomy is an important cause of treatment failure and persistence of subnormal semen parameters. This original study was combined with a systemic review and meta-analysis aiming to evaluate the efficacy of redo varicocelectomy on male fertility potential and pregnancy outcome. The retrospective study included 32 patients who underwent microsurgical subinguinal varicocelectomy for patients with recurrent varicocele. Changes in semen parameters and hormone profiles before and after surgery were compared. The literature review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and included seven articles in addition to our original report. Results of the original study revealed statistically significant improvements in sperm concentration, progressive motility, total motile sperm count and normal morphology following redo varicocelectomy. The meta-analysis results echoed those reported in our original study and depicted significant improvements in sperm concentration (mean difference [MD]=+20.281 million/ml, p< 0.001), total motility (MD=+9.659%, p= 0.001), total motile sperm count (MD=+23.258 million sperm, p< 0.001) and normal morphology (MD=+4.460%, p< 0.001). Overall pregnancy outcome was reported in seven studies with a rate of 34.6%. No significant changes were noted in any of the collected hormone results both in this original report and in the meta-analysis. In conclusion, redo varicocelectomy has a beneficial role on male fertility potential and can be offered for men with recurrent varicocele as directed by their individual clinical condition.

P-216 Serum levels of HMGB1 might have a predictive role for neoadjuvant radiotherapy combined with chemotherapy in rectal cancer patients

The standard treatment for locally advanced rectal cancer (LARC), is neoadjuvant concurrent chemoradiation (nCCRT), after which total mesorectal excision is performed. The degree of response to combined therapy varies in patients. Tumor repopulation during radiotherapy is an important cause of treatment failure. High mobility group box 1 (HMGB1) is a nuclear protein released during the course of radiotherapy. It is essential for normal cellular function but also regulates the proliferation and migration of tumor cells.

A Circ-0007022/miR-338-3p/Neuropilin-1 Axis Reduces the Radiosensitivity of Esophageal Squamous Cell Carcinoma by Activating Epithelial-To-Mesenchymal Transition and PI3K/AKT Pathway.

Radiotherapy resistance is an important cause of treatment failure in esophageal squamous cell carcinoma (ESCC). Circular RNAs have attracted a lot of attention in cancer research, but their role in ESCC radiosensitivity has not been elucidated yet. Here, we aimed to evaluated the functional impacts of circ-0007022 on ESCC radiosensitivity. In this study, a stable radiotherapy-resistant cell line was established and verified by a series of functional experiments. Subsequently, high-throughput sequencing revealed that circ-0007022 was significantly overexpressed in the radiotherapy-resistant cell line and this conclusion was verified in ESCC patients’ tumor tissues by real-time quantitative PCR. Moreover, loss-of-function and overexpression experiments in vitro and in vivo revealed that, after irradiation, the abilities of proliferation and migration in circ-0007022-overexpressing stable transgenic strain were significantly higher than that in circ-0007022-knockdown stable transgenic strain. Additionally, RNA Immunoprecipitation, RNA pull-down, luciferase reporter assays, and fluorescence in situ hybridization experiments demonstrated the mechanism of how circ-0007022 could sponge miR-338-3p and upregulate downstream target of miR-338-3p, neuropilin-1 (NRP1). Moreover, NRP1 led to poor prognosis for ESCC patients receiving radiotherapy, and NRP1 knock-down enhanced radiosensitivity of ESCC cells. Furthermore, circ-0007022 overexpression activated Epithelial-to-mesenchymal transition and PI3K/Akt pathway, and NRP1 knock-down could reversed this phenomenon. Finally, Akt Inhibitor reversed circ-0007022s role in radiotherapy in ESCC cells. Taken together, the circ-0007022/miR-338-3p/NRP1 axis enhances the radiation resistance of ESCC cells via regulating EMT and PI3K/Akt pathway. The new circRNA circ-0007022 is thus expected to be a therapeutic target for ESCC patients.

Engineering ROS-Responsive Bioscaffolds for Disrupting Myeloid Cell-Driven Immunosuppressive Niche to Enhance PD-L1 Blockade-Based Postablative Immunotherapy.

The existence of inadequate ablation remains an important cause of treatment failure for loco‐regional ablation therapies. Here, using a preclinical model, it is reported that inadequate microwave ablation (iMWA) induces immunosuppressive niche predominated by myeloid cells. The gene signature of ablated tumor presented by transcriptome analyses is highly correlated with immune checkpoint blocking (ICB) resistance. Thus, an in situ scaffold with synergistic delivery of IPI549 and anti‐programmed death‐ligand 1 blocking antibody (aPDL1) for postablative cancer immunotherapy is designed and engineered, in which IPI549 capable of targeting myeloid cells could disrupt the immunosuppressive niche and subsequently improve ICB‐mediated antitumor immune response. Based on five mouse cancer models, it is demonstrated that this biomaterial system (aPDL1&IPI549@Gel) could mimic a “hot” tumor‐immunity niche to inhibit tumor progression and metastasis, and protect cured mice against tumor rechallenge. This work enables a new standard‐of‐care paradigm for the immunotherapy of myeloid cells‐mediated “cold” tumors after loco‐regional inadequate practices.