Treatment Failure Research Articles

Crosslink among cyclin-dependent kinase 9, ATP binding cassette transporter G2 and Beclin 1 in colorectal cancer

Colorectal cancer (CRC) ranks third in the number of cancers mainly because of the inability to diagnose it at an early stage. The pathogenesis of CRC is complicated, which is the result of the complex interaction of multiple genetic and environmental factors. Currently, one of the main treatments for CRC is chemotherapy. But the primary cause of CRC treatment failure is drug resistance. The expression of cyclin-dependent kinase 9 (CDK9) was correlated with elevated autophagy levels in colon cancer, and high expression of CDK9 indicates a poor prognosis in CRC. The incidence of autophagy and the expressions of Beclin 1 and ATP binding cassette transporter G2 are different in left and right colon cancer, and autophagy may be involved in the occurrence of chemotherapy resistance. In this article, the roles of CDK9, ATP binding cassette transporter G2 and Beclin 1 in CRC were elucidated, emphasizing the linkages among them and providing potential therapeutic targets of CRC.

Do Pre-Treatment Biopsy Characteristics Predict Early Tumour Progression in Feline Diffuse Large B Cell Nasal Lymphoma Treated With Radiotherapy?

The standard of care treatment for localised feline nasal lymphoma (FeNL) is radiation therapy (RT). Early local or systemic failure occurs in 17%-45% of cats treated with RT with or without chemotherapy. The aim of this study was to determine if pre-treatment biopsy characteristics could predict early tumour progression in FeNL. Inclusion criteria consisted of histologically confirmed FeNL, available paraffin blocks of diagnostic quality, localised to the sinonasal cavity on staging pre-RT, treated with IMRT/IGRT (10 × 4.2 Gy) without chemotherapy and at least 1 year follow-up. All pre-RT biopsies were reviewed and evaluated with CD3, CD20, CD79a, pan-CK and Ki-67 immunohistochemistry and the mitotic activity index was determined. The primary endpoint was progression-free survival (PFS) at 1 year and hazard-ratios (HR) with confidence interval (CI) were calculated. Twenty-eight cats fit the inclusion criteria, and all had diffuse large B-cell lymphoma. Seventeen cats (61%) were progression free at 1 year. Of the 11 cats that progressed in the first year, two had local progression, two had both local and systemic progression and seven had systemic progression. The mitotic index (HR: 1.03, CI 0.9-1.19, p = 0.645), Ki-67 (HR: 1.00, CI 0.98-1.02, p = 0.845) and > 30% of tumour-infiltrating T cells (HR: 0.38, CI 0.09-1.56, p = 0.175) were not significantly associated with PFS. In this uniformly RT treated population of FeNL, none of the evaluated pre-RT histologic parameters could predict early treatment failure.

Design of a Magnetic Nanoplatform Based on CD26 Targeting and HSP90 Inhibition for Apoptosis and Ferroptosis-Mediated Elimination of Senescent Cells.

The accumulation of senescent cells, a hallmark of aging and age-related diseases, is also considered as a side effect of anticancer therapies, promoting drug resistance and leading to treatment failure. The use of senolytics, selective inducers of cell death in senescent cells, is a promising pharmacological antiaging and anticancer approach. However, more studies are needed to overcome the limitations of first-generation senolytics by the design of targeted senolytics and nanosenolytics and the validation of their usefulness in biological systems. In the present study, we have designed a nanoplatform composed of iron oxide nanoparticles functionalized with an antibody against a cell surface marker of senescent cells (CD26), and loaded with the senolytic drug HSP90 inhibitor 17-DMAG (MNP@CD26@17D). We have documented its action against oxidative stress-induced senescent human fibroblasts, WI-38 and BJ cells, and anticancer drug-induced senescent cutaneous squamous cell carcinoma A431 cells, demonstrating for the first time that CD26 is a valid marker of senescence in cancer cells. A dual response to MNP@CD26@17D stimulation in senescent cells was revealed, namely, apoptosis-based early response (2 h treatment) and ferroptosis-based late response (24 h treatment). MNP@CD26@17D-mediated ferroptosis might be executed by ferritinophagy as judged by elevated levels of the ferritinophagy marker NCOA4 and a decreased pool of ferritin. As 24 h treatment with MNP@CD26@17D did not induce hemolysis in human erythrocytes in vitro, this newly designed nanoplatform could be considered as an optimal multifunctional tool to target and eliminate senescent cells of skin origin, overcoming their apoptosis resistance.

Augmenting Adherence: Improving Medication Compliance and Patient Education in Anti-Retroviral Therapy through Graphical Representation.

Anti-Retroviral Therapy (ART) is a fundamental principle in the management of Human immunodeficiency virus (HIV) infection, significantly improving the quality of life for individuals living with the virus. However, the success of ART crucially depends on patient adherence to complex medication regimens that come with the therapy. Patients must meticulously adhere to their prescribed treatment plans to maintain viral suppression and prevent the progression of HIV. Medication adherence, a multifaceted challenge in healthcare, becomes particularly entangled within the realm of ART. Patients are often prescribed a combination of antiretroviral medications, each with unique dosing schedules and dietary requirements as instructed by the physician. For individuals with varying levels of health literacy, language proficiency, and cultural backgrounds, comprehending and adhering to these regimens can be overwhelming and challenging. Non-adherence to these medications can result in treatment failure, drug resistance, and compromised health outcomes that burden the healthcare systems. In that perspective, the role of pictograms as visual aids emerges as part and parcel of patient education and counseling within healthcare systems. Pictograms are graphical representations of concepts or actions designed to transcend linguistic and literacy barriers. When used in conjunction with ART, they simplify complex medication instructions, empower patients with knowledge, and improve adherence. Generally, the role of pictograms in supporting medication adherence and patient counseling in antiretroviral therapy is a powerful testament that serves a purpose in bridging communication and literacy gaps within the healthcare systems. By simplifying complex medication regimens, empowering patients with knowledge, and fostering adherence, pictograms contribute to better health outcomes and the overall success of ART. As healthcare providers and systems continue to harness the potential of pictograms, patient education and adherence in the management of HIV and other chronic conditions stand to be greatly enhanced.

Genetic coping mechanisms observed in Leishmania tropica, from the Middle East region, enhance the survival of the parasite after drug exposure.

Cutaneous leishmaniasis caused by L. tropica is common in the Middle East and treatment failure and drug resistance are known to occur. Several genetic mechanisms: aneuploidy, recombination and loss of heterozygosity, single nucleotide polymorphism (SNP) changes, copy number variation (CNV), and mutation of the H locus associated with drug resistance have been described. We studied SNP and CNV patterns in 22 isolates of L. tropica from Afghanistan, Iran and Syria in a geographic, phylogenetic and antimony exposure context. A high SNP frequency was observed in isolates from Syria on chromosome 23, including the H locus, linked to different ancestry at that chromosome segment. Among the isolates from Afghanistan and Iran, an elevated frequency of nonsynonymous SNPs was observed on several chromosomes. Changes in CNV patterns were seen in isolates exposed to drug pressure, especially for the ferric iron reductase gene. Expanded genes were categorised into five functional categories: translational elongation, mitochondrial transmembrane transport, positive regulation of cellular component organisation, response to stimulus and response to hypoxia. No CNV was identified at the H locus, the MAPK1 gene, the APQ1 gene, nor chromosomes 23, 31 or 36 regardless of previous antimonial exposure. In our study, Leishmania tropica had a jump in the nonsynonymous SNP rates at chromosome 23, including the H locus. CNV was observed among isolates exposed to antimonials, especially involving the gene encoding a ferric iron reductase. Several essential genetic coping mechanisms in the cell were enhanced when exposed to antimony, possibly for the survival of the parasite. Our work supports the perspective that Leishmania uses several mechanisms to adapt to environmental changes and drug exposure.

Boundary-work of primary care physicians using telemedicine technologies for communication.

Implementing telemedicine technologies (TT) for patient-physician communication leads to the emergence of new structures of boundaries. Hence, boundary work theory can provide a useful lens for examining how primary care physicians (PCPs) experience TT. The objective of this research was to examine the experiences of PCPs in using TT in their communication with patients. During 2023 in-depth interviews were conducted with 20 Israeli PCPs: family physicians and pediatricians. The concept of boundary work emerged as a focal point, with three forms of boundary work identified in the PCPs' descriptions of their TT experiences: collaborative, competitive, and configurational. Interviewees described improved collaboration with patients who find it difficult to get to the clinic and better service for administrative issues. However, they reported constant power struggles to maintain their authority. They expressed concern about treatment failure and suggested that healthcare organizations reconfigure TT so that it can be used to provide optimal care. They suggested that healthcare organizations should instruct physicians how to best manage TT consultations and regulate its usage. This article demonstrates that while implementing TT in primary care has many advantages, it uncovers boundary work for maintaining power and authority that both PCPs and healthcare organizations should take into account in practice as well as in policy.

Call for Papers: Infectious Diseases Research in the Global South: Treatments and Treatment Failures

Call for Papers: Infectious Diseases Research in the Global South: Treatments and Treatment Failures

Cutibacterium acnes periprosthetic joint infections.

Cutibacterium acnes (C. acnes; previously known as Propionibacterium acnes or P. acnes) periprosthetic hip and knee infections are under-reported. While culture contamination with C. acnes occurs, true infections are important to recognize and treat. We sought to describe the demographics and treatment outcomes of patients with C. acnes periprosthetic joint infections (PJIs) of the hip and knee. Patients with C. acnes PJI between January 2005 and December 2018 were retrospectively reviewed utilizing the institutional total joint registry. Patients with monomicrobial PJI and two or more positive cultures were considered to have true C. acnes PJI. Patients with polymicrobial infection or with only one positive culture were excluded. This resulted in 35 PJIs (21 hips and 14 knees); the patients' mean age was 63 years (35 to 84) and 15 (43%) were female. Mean follow-up was five years (1 to 14). The median time to positive culture was five days (IQR 5 to 6) and median synovial fluid cell count was 22,583 cells (IQR 15,200 to 53,231). The median ESR was 25 mm/hr (IQR 7 to 37), and CRP was 15 mg/l (IQR 3 to 29). Of the 35 PJIs, 18 (51%) were treated with chronic antibiotic suppression without surgical intervention, and the remainder were treated with two-stage exchange arthroplasty. The two-year survival free of any revision was 94%. Four patients failed treatment due to symptomatic infection, with three treated with two-stage exchange and one treated with irrigation and debridement with modular component exchange for a survival rate of 89% and 83% at two and five years, respectively. Laboratory evidence of C. acnes PJI in this cohort was typical compared to more conventional organisms. Cultures grew more quickly than previously thought in patients with C. acnes PJI. Treatment with two-stage exchange or chronic antibiotic suppression alone both had few treatment failures at mid-term follow-up.

Discovery of potent hypoxia-inducible factor-1α (HIF-1α) degraders by proteolysis targeting chimera (PROTAC)

Under hypoxic conditions in tumor cells, HIF-1α is unable to bind to VHL E3 ligase due to the blocked hydroxylation reaction, resulting in impaired degradation and intracellular accumulation. Mounting evidences show a close association between HIF-1α overexpression and drug resistance, treatment failure, and increased mortality. To address this, we innovatively introduced an E3 ligase ligand to the HIF-1α inhibitor IDF-11774 using the PROTACs strategy, aiming to reactivate the degradative pathway impeded under hypoxia, and thereby achieve the redegradation of HIF-1α protein. Western blotting analyses demonstrated that most of we synthesized compounds effectively degraded HIF-1α. Among these, compounds C3 and V2 exhibited excellent anti-proliferation activity on 231 cells with IC50 values of 48.98 μM and 7.54 μM, respectively. Both compounds induced protein degradation in a concentration-dependent manner, achieving degradation rates up to 80 %. Additionally, this degradation was inhibited by the proteasome inhibitor MG132. As a part of the ongoing effort to develop HIF-1 inhibitors, targeting the degradation of HIF-1α may offer an effective treatment against solid tumors.

Grade IV gastric ulceration, pyloric aplasia, and an ectopic duodenal papilla in a 13-year-old Quarter Horse gelding evaluated for recurrent colic.

The objective of this Case Report was to describe the clinical manifestation and postmortem findings of a horse evaluated for recurrent colic diagnosed with pyloric aplasia and an ectopic duodenal papilla. 13-year-old Quarter Horse gelding. The horse was presented to a referral center for signs of colic that were unresponsive to management on the farm. No abnormalities were noted on rectal palpation; however, upon passage of a nasogastric tube, 31 L of net gastric reflux was obtained. Gastroscopy noted grade IV squamous ulceration and moderate glandular ulceration, severe gastric dilatation, an abnormally positioned gastric outflow tract, and an ectopic duodenal papilla leaking bile-like fluid directly into the stomach. The horse was initially treated with gastroprotectants, promotility agents, and dietary modifications. Following treatment failure and repeated episodes of colic with increasing severity, the horse was euthanized and a necropsy performed. At necropsy, it was confirmed that the aboral aspect of the stomach formed a dilated pouch and continued directly into the proximal duodenum with no discernible pyloric sphincter. The area of the pylorus was delineated by a faint indentation. The ectopic duodenal papilla was traced to the liver. Congenital gastric abnormalities, even in adult horses, should be considered as differential diagnoses when investigating horses presenting with a history of chronic colic. Neither pyloric aplasia nor an ectopic duodenal papilla have been described in the equine literature, and this Case Report raises awareness of the presence of such malformations and their manifestations.

Social and health factors associated with unfavourable treatment outcomes in children and adolescents with drug-sensitive tuberculosis in Brazil: a national retrospective cohort study

Although tuberculosis (TB) poses a significant global health threat to children and adolescents, there is limited information on the factors associated with TB treatment outcomes in this group. This study investigated the social and health factors associated with unfavourable treatment outcomes in children and adolescents with TB in Brazil, a high TB burden country. We conducted a population-based national retrospective cohort study of children (0-9 years) and adolescents (10-17 years) with TB in Brazil notified to the national Sistema de Informação de Agravos de Notificação (Sinan) from Jan 1, 2001, to Dec 31, 2022. Unfavourable treatment outcomes were defined as loss to follow-up, treatment failure, and death. Logistic regression and multinomial models examined the association between social and health factors, unfavourable treatment outcomes overall, and loss to follow-up and death, respectively. A total of 88,270 children and adolescents with TB were included of whom 25,600 (30.6%) had healthcare worker-supervised directly observed therapy (DOT). Of these, 9303 (10.5%) individuals experienced unfavourable TB treatment outcomes. For children, HIV infection (adjusted Odds Ratio 2.4, 95% confidence interval 1.9-3.1) and did not receive DOT (2.3, 1.9-2.7) were associated with unfavourable treatment outcomes. For adolescents, alcohol use (1.6, 1.2-2.0), illicit drug use (4.2, 3.4-5.1), tobacco use (1.6, 1.3-2.1), HIV infection (2.7, 2.2-3.4), and not receiving DOT (2.6, 2.3-2.9) were associated with unfavourable TB treatment outcome. Receiving social protection through government cash transfers protected against death (0.5, 0.3-0.9). In Brazil, TB treatment success rates were comparable to WHO End TB Strategy targets (90%). Substance use, HIV infection, and the absence of supervised treatment were the main factors associated with unfavourable treatment outcomes. Strategies to improve equity of TB treatment outcomes in this vulnerable group, including integrated HIV-TB services, DOT in healthcare facilities or communities, and holistic, person-centred healthcare and social protection, should be evaluated. Department of Health and Social Care (DHSC), the Foreign, Commonwealth & Development Office (FCDO), the Medical Research Council (MRC) and Wellcome, UK.

Case Report and Literature Review of “Treatment Failure” of Aspergillus Infection Secondary to Influenza a Virus

Case Report and Literature Review of “Treatment Failure” of Aspergillus Infection Secondary to Influenza a Virus

Success Rates and Prognostic Factors in the Management of Keratoconus: A 10-Year Retrospective Cohort Study at Siriraj Hospital

Objective: To evaluate the success rates of different treatment modalities, identify prognostic factors associated with treatment outcomes and factors influencing disease progression in keratoconus patients. Materials and Methods: A retrospective cohort study of keratoconus patients at Siriraj Hospital during January 2013 to December 2023 was done. Patient characteristics, symptoms and signs related to keratoconus, outcomes of corneal topography, treatment modalities, and best-corrected visual acuity (BCVA) before and after treatment were recorded. Treatment outcome was defined as a “success” when the BCVA post-treatment was equal to or better than 6/12. Progression of keratoconus was based on the Belin ABCD progression criteria. Results: Total 119 patients (231 eyes) were analyzed. The mean age at diagnosis was 28.0 ± 9.5 years. Two hundred and sixteen eyes (93.5%) were clinical keratoconus. The overall success rate of all treatment modalities was 87.4%. Contact lenses were the most frequent treatment modality (147 eyes, 72.4%) with the highest success rate (90.5%). A worse initial BCVA, high keratometric reading and thinner cornea were risk factors for treatment failure in this group. Of 133 eyes disease progression could be evaluated (median follow-up time; 33 months) and 58 eyes(43.6%) met criteria for disease progression (median survival time; 8.8 years). No significant factors were found to be associated with disease progression. Conclusion: Success rate in keratoconus treatment at Siriraj Hospital was 87.4%. Contact lenses were most frequently applied 72.4%. Factors associated with treatment failure were found in this group but for disease progressionremained unclear due to limitations of the study.

Risk Factors of Complications After Uterine Artery Embolisation for Symptomatic Fibroids: A Case-Control Study.

We aim to clarify potential risk factors of complications after uterine artery embolisation (UAE). Complications after uterine artery embolisation (UAE) for symptomatic fibroids are rare, but failure of treatment occurs for approximately 13%-24% of patients at 10 years. We conducted a case-control study including all complications post UAE over 15 years in our specialised unit. All Grade 2 complications (or worse) for the Society of Interventional Radiology Standards of Practice Committee complications post UAE were considered. One thousand one hundred seventy-two UAE were performed. Complications were divided into two groups: early (< 1 month) or late (≥ 1 month) to differentiate complications from failure of procedure. Multinomial analysis was conducted to assess links between complications and potential risk factors. Sixty-nine (0.06%) complications were found: 24.6% hospitalisation for pain (n = 17/69), 30.4% for infection (n = 21/69) and 2.9% expulsion of fibroid (n = 2/69). Overall, 31 patients underwent a second procedure (45%). Intra-uterine device and multiple fibroids were strongly related to early complications (ORearly = 4.44, IC 95%: 1.5-13.3 and ORearly = 3.7, IC 95%: 1.2-11.3, respectively). The only factor that appeared to be associated with risk of early and late complications was the major fibroid's diameter (for an increased size of 25 mm, ORearly = 1.7, IC 95%: 1.1-2.6; ORlate = 1.5, IC 95%: 1.04-2.2). Our study enlightens about the potential risk factors of UAE's complications and differentiate their impact between early and late complications.

Associated factors with non[sbnd]operative management failure in bowel obstruction

BackgroundBowel obstruction caused by adhesion syndrome is a prevalent condition in emergency departments, presenting significant economic and morbidity challenges. While nonsurgical approaches succeed in 70–90% of cases, surgery becomes necessary for nonresponsive patients. This study aims to identify predictors of non-operative management failure in patients with bowel obstruction upon emergency room admission. MethodsA retrospective cross-sectional analytical study was conducted from 2015 to 2022 at Hospital Militar Central, focusing on patients with bowel obstruction secondary to adhesion syndrome. Comparative analysis of medical and surgical histories and admission laboratory values aimed to identify possibles factors associated with non-operative management failure and subsequent surgical intervention. ResultsAmong 354 patients with bowel obstruction, 130 met inclusion criteria, of whom 98 responded to non-operative treatment and 32 experienced treatment failure. Significant differences were found between groups, including age (p: 0.035), history of two or more abdominal surgeries (10.2% vs. 25%, p: 0.01), appendectomy (17% vs. 37%, p: 0.01), previous surgical intervention for bowel obstruction (22.5% vs. 9.38%, p: 0.008), and hospital stay duration (4.26 vs. 13.2 days, p: 0.001). In multivariate analysis using Poisson regression, age had a prevalence ratio (PR) of 1.01 [95% CI (1.00; 1.02), p < 0.04] for non-operative management failure, the history of peritonitis had a PR of 3.83 [95% CI (2.34; 6.26), p < 0.001], while each unit increase in lactate showed a PR increase of 1.24 [95% CI (0.99; 1.57), p 0.05]. ConclusionAge, history of peritonitis, and elevated lactate values upon emergency room admission are predictive factors for non-operative management failure in bowel obstruction in the population studied.

State of the art of real-life concentration monitoring of rifampicin and its implementation contextualized in resource-limited settings: the Tanzanian case.

The unique medical and socio-economic situation in each country affected by TB creates different epidemiological contexts, thus providing exploitable loopholes for the spread of the disease. Country-specific factors such as comorbidities, health insurance, social stigma or the rigidity of the health system complicate the management of TB and the overall outcome of each patient. First-line TB drugs are administered in a standardized manner, regardless of patient characteristics other than weight. This approach does not consider patient-specific conditions such as HIV infection, diabetes mellitus and malnutrition, which can affect the pharmacokinetics of TB drugs, their overall exposure and response to treatment. Therefore, the 'one-size-fits-all' approach is suboptimal for dealing with the underlying inter-subject variability in the pharmacokinetics of anti-TB drugs, further complicated by the recent increased dosing regimen of rifampicin strategies, calling for a patient-specific methodology. In this context, therapeutic drug monitoring (TDM), which allows personalized drug dosing based on blood drug concentrations, may be a legitimate solution to address treatment failure. This review focuses on rifampicin, a critical anti-TB drug, and examines its suitability for TDM and the socio-economic factors that may influence the implementation of TDM in clinical practice in resource-limited settings, illustrated by Tanzania, thereby contributing to the advancement of personalized TB treatment.

Combining ultrasound technology with targeted fucoidan/arginine-gelatin nanoparticles loaded with doxorubicin to enhance therapeutic efficacy and modulate bioeffects in drug-resistant triple-negative breast cancer.

Triple-negative breast cancer (TNBC) presents formidable challenges due to its aggressive nature and high recurrence rates, compounded by the involvement of epithelial-mesenchymal transition (EMT) in its progression and metastasis. Standard chemotherapy, which typically employs doxorubicin (DOX), remains a primary treatment approach. However, multidrug resistance (MDR) mechanisms, which include ATP-binding cassette transporters and EMT, contribute to treatment failures. Ultrasound has emerged as a promising modality among the various strategies explored to address MDR in TNBC. It serves as a diagnostic tool and holds therapeutic potential by inducing various biological effects depending on the exposure level. Targeted nanoparticles offer a means to enhance drug delivery efficiency. Our study aims to advance ultrasound technology combined with biocompatible nanoparticles using simplified preparation methods to improve treatment outcomes for drug-resistant TNBC. In particular, employing DOX-loaded fucoidan/arginine-gelatin nanoparticles facilitated the targeted delivery of chemotherapy drugs to tumors by effectively interacting with P-selectin, resulting in tumor growth inhibition. Furthermore, these nanoparticles mitigated MDR and EMT, particularly when combined with ultrasound treatment. This integrated approach of nanoparticle delivery with ultrasonography opens up a promising and innovative avenue for clinical cancer research.

CAR T-cell therapy for B-cell lymphomas: outcomes and resistance mechanisms.

Chimeric antigen receptor (CAR) T cells are an exciting curative intent approach to the treatment of non-Hodgkin lymphomas (NHLs). Several products have received FDA approval for 2nd or 3rd line indications, and studies are underway for their use earlier in the disease course. These CAR T cells are ex vivo manufactured autologous cell products that specifically target tumor antigens to optimize tumor specificity and minimize off-tumor side effects-in NHLs, this is typically achieved by targeting B-cell antigens. Engagement of the CAR and corresponding antigen is designed to result in T-cell activation and subsequent tumor clearance. While curative for many NHL patients, too many patients fail to respond to or relapse following CAR T-cell treatment, and salvage options post CAR T-cell therapy are limited. Treatment failures occur because of myriad resistance mechanisms including CAR T-cell dysfunction, generalized immune dysregulation, and intrinsic tumor resistance. Focusing on patients with NHL, we review the clinical outcomes of CAR T-cell therapy and the major resistance mechanisms that lead to poor outcomes. We also review the many innovative and encouraging strategies that are being developed to improve CAR T-cell therapy for NHL.

Artificial Intelligence Application for Anti-tumor Drug Synergy Prediction.

Currently, the main therapeutic methods for cancer include surgery, radiation therapy, and chemotherapy. However, chemotherapy still plays an important role in tumor therapy. Due to the variety of pathogenic factors, the development process of tumors is complex and regulated by many factors, and the treatment of a single drug is easy to cause the human body to produce a drug-resistant phenotype to specific drugs and eventually leads to treatment failure. In the process of clinical tumor treatment, the combination of multiple drugs can produce stronger anti-tumor effects by regulating multiple mechanisms and can reduce the problem of tumor drug resistance while reducing the toxic side effects of drugs. Therefore, it is still a great challenge to construct an efficient and accurate screening method that can systematically consider the synergistic anti- tumor effects of multiple drugs. However, anti-tumor drug synergy prediction is of importance in improving cancer treatment outcomes. However, identifying effective drug combinations remains a complex and challenging task. This review provides a comprehensive overview of cancer drug synergy therapy and the application of artificial intelligence (AI) techniques in cancer drug synergy prediction. In addition, we discuss the challenges and perspectives associated with deep learning approaches. In conclusion, the review of the AI techniques' application in cancer drug synergy prediction can further advance our understanding of cancer drug synergy and provide more effective treatment plans and reasonable drug use strategies for clinical guidance.

GEFT inhibits the GSDM-mediated proptosis signalling pathway, promoting the progression and drug resistance of rhabdomyosarcoma

The metastasis or recurrence of rhabdomyosarcoma (RMS) is the primary cause of tumour-related deaths. Patients with high-risk RMS have poor prognosis with a 5-year overall survival rate of 20–30%. The lack of specific drug-targeted therapy and chemotherapy resistance are the main reasons for treatment failure. Drugs or molecular target inhibitors can induce the pyroptosis of tumour cells or increase their sensitivity to chemotherapy, making pyroptosis an effective strategy for antitumour therapies. Pyroptosis is mediated by gasdermin (GSDM) family members. Here, we found that the expression of NLRP3, caspase-1, caspase-3, GSDMD and GSDME in RMS was remarkably lower than that in skeletal muscle tissues. Nigericin and dactinomycin in RMS cells achieved their regulatory effect on pyroptosis through the NLRP3/caspase-1/GSDMD pathway and caspase-3/GSDME pathway, respectively. Necrosulfonamide reversed the pyroptosis-related changes induced by nigericin, and siGSDME converted the dactinomycin-induced pyroptosis into apoptosis. Additionally, GEFT inhibited the GSDMD and GSDME pyroptosis pathways, thereby promoting the progression and drug resistance of RMS. Mouse xenograft and tumour analysis confirmed that nigericin and dactinomycin can effectively improve the therapeutic effect of RMS by activating the pyroptosis pathway. To the best of our knowledge, this study was the first to focus on pyroptosis in RMS. Overall, our investigation demonstrated that nigericin and dactinomycin play therapeutic roles in tumours by promoting RMS cell pyroptosis. Interference with GEFT and drug combination can exert a great inhibitory effect on tumours.