Reason For Treatment Failure Research Articles

ZHX2 inhibits thyroid cancer metastasis through transcriptional inhibition of S100A14

BackgroundThyroid cancer is the most common malignant endocrine tumour, and metastasis has become the main reason for treatment failure. However, the underlying molecular mechanism of thyroid cancer metastasis remains poorly understood. We investigated the role of the tumour suppressor zinc fingers and homeoboxes 2 (ZHX2) in the metastasis of thyroid cancer.MethodsTo study the role of ZHX2 in thyroid cancer metastasis, we evaluated the EMT process using cell migration, wound healing and lung metastatic tumour formation in vitro and in vivo models.ResultsZHX2 expression was significantly decreased in thyroid cancer tissues, which correlated with poor prognosis of thyroid cancer patients. ZHX2 knockdown significantly promoted the migration of thyroid cancer cells. Mechanistically, ZHX2 associated with the S100 calcium binding protein A14 (S100A14) promoter to decrease the transcription of S100A14. Moreover, S100A14 was highly expressed in human thyroid cancer samples, and its expression negatively correlated with ZHX2 expression.ConclusionsInhibition of S100A14 attenuated the ZHX2 knockdown-induced enhanced metastasis of thyroid cancer cells both in vitro and in vivo. The evidence presented here suggests that ZHX2 inhibits the progression of thyroid cancer by blocking S100A14-mediated metastasis.

Targeting Breast Cancer and Their Stem Cell Population through AMPK Activation: Novel Insights.

Despite some significant advancements, breast cancer has become the most prevalent cancer in the world. One of the main reasons for failure in treatment and metastasis has been attributed to the presence of cancer initiating cells—cancer stem cells. Consequently, research is now being focussed on targeting cancer cells along with their stem cell population. Non-oncology drugs are gaining increasing attention for their potent anticancer activities. Metformin, a drug commonly used to treat type 2 diabetes, is the best example in this regard. It exerts its therapeutic action by activating 5′ adenosine monophosphate-activated protein kinase (AMPK). Activated AMPK subsequently phosphorylates and targets several cellular pathways involved in cell growth and proliferation and the maintenance of stem-like properties of cancer stem cells. Therefore, AMPK is emerging as a target of choice for developing effective anticancer drugs. Vanadium compounds are well-known PTP inhibitors and AMPK activators. They find extensive applications in treatment of diabetes and obesity via PTP1B inhibition and AMPK-mediated inhibition of adipogenesis. However, their role in targeting cancer stem cells has not been explored yet. This review is an attempt to establish the applications of insulin mimetic vanadium compounds for the treatment of breast cancer by AMPK activation and PTP1B inhibition pathways.

Transcriptional analysis and target genes discovery of Pseudomonas aeruginosa biofilm developed ex vivo chronic wound model

Bacterial biofilms formation is one of the major reasons for treatment failure in chronic wound infections. Therefore, diagnostic biomarkers remain the best option for prevention and treatment of chronic wound infections by biofilms. Herein, Pseudomonas aeruginosa PAO1 was used to mimic biofilm development in porcine skin explants wells as ex vivo wound model. The microscopic imaging showed that PAO1 in porcine skin explants wells formed micro-colonies at 24 h, developed mushroom-like structure at 48 h, and at 72 h mushroom-like structure disappeared, remaining a thin bacterial lawn. RNA-seq data analysis revealed that the expression levels of genes involved in the type II hxc secretion system were significantly higher in biofilms than in planktonic cells, especially the expression of lapA encoding alkaline phosphatase. However, the expression levels of genes associated with denitrification pathway were markedly decreased in biofilms, especially the transcription of nirS encoding nitrite reductase to produce nitric oxide (NO). Therefore, their expressions and products were further detected using RT-qPCR and biochemical assays, respectively. The results found that the expression of lapA and alkaline phosphatase activity were induced, but the expression of nirS and intracellular NO were reduced at the whole biofilms cycle. The study indicates that LapA and NO would play an important role for P. aeruginosa biofilm formation in chronic wound infections. LapA would serve as potential target to monitor chronic wound infections by P. aeruginosa biofilms. Inducing NO would be used to treat chronic wound infections due to P. aeruginosa biofilms.

Assessing Antibiotic Tolerance of Staphylococcus aureus Derived Directly from Patients by the Replica Plating Tolerance Isolation System (REPTIS).

Antibiotic-tolerant Staphylococcus aureus poses a great challenge to clinicians as well as to microbiological laboratories and is one reason for treatment failure. Antibiotic-tolerant strains survive transient antibiotic exposure despite being fully susceptible in vitro. Thus, fast and reliable methods to detect tolerance in the routine microbiology laboratory are urgently required. We therefore evaluated the feasibility of the replica plating tolerance isolation system (REPTIS) to detect antibiotic tolerance in Staphylococcus aureus isolates derived directly from patients suffering from different types of infections and investigated possible connections to clinical presentations and patient characteristics. One hundred twenty-five S. aureus isolates were included. Replica plating of the original resistance testing plate was used to assess regrowth in the zones of inhibition, indicating antibiotic tolerance. Bacterial regrowth was assessed after 24 and 48 h of incubation, and an overall regrowth score (ORS) was assigned. Regrowth scores were compared to the clinical presentation. Bacterial regrowth was high for most antibiotics targeting protein synthesis and relatively low for antibiotics targeting other cellular functions such as DNA replication, transcription, and cell wall synthesis, with the exception of rifampin. Isolates with a blaZ penicillinase had lower regrowth in penicillin and ampicillin. Low ORSs were more prevalent among isolates recovered from patients with immunosuppression or methicillin-resistant S. aureus (MRSA) isolates. In conclusion, REPTIS is useful to detect antibiotic tolerance in clinical microbiological routine diagnostics. Further studies should evaluate the impact of rapid detection of antibiotic tolerance as a clinical decision-making tool for tailored antibiotic treatments.

Management dilemmas in Nocardia brain infection.

Brain nocardiosis is a rare but severe infection mostly occurring among immunocompromised patients. In this review, we present recent data on this infection and address some of the common clinical dilemmas encountered in patients with brain nocardiosis. Strategies used to approach a patient with suspected brain nocardiosis include the 'conservative strategy' (without early neurosurgery) and the 'neurosurgical strategy' (with early aspiration or excision of brain abscess[es]). The advantages and disadvantages of both strategies are summarised. Our opinion is that the use of the 'conservative strategy' should be limited to well-selected patients presenting with an easily accessible extra-neurological lesion(s) and have brain abscesses at low risk of treatment failure. In terms of antimicrobial therapy, we summarise the data supporting the use of a multidrug regimen in patients with brain nocardiosis.Last, we list possible reasons for treatment failure in patients with brain nocardiosis and suggest interventions to overcome them. Literature is scarce regarding brain nocardiosis, as a consequence of the rarity of this disease. A multidisciplinary and individualised management is required to optimise the outcome of patients with brain nocardiosis.

Molecular detection of genotypic clarithromycin‐resistant strains and its effect on the eradication rate of concomitant therapy in Helicobacter pylori infection

Antimicrobial eradication rates for Helicobacter pylori have been decreasing and the reason for treatment failure was found to be resistance to one or more of the antibiotics. Clarithromycin resistance to H pylori was associated with point mutations in the 23S rRNA gene and the PCR-RFLP method can detect these point mutations. The aim of this study was to determine the molecular detection of genotypic clarithromycin-resistant strains and its effect on the eradication rate of concomitant therapy in H pylori infection. The presence of H pylori DNA was confirmed by amplifying the UreC gene by polymerase chain reaction (PCR) and point mutations on 23S rRNA (A2142G and A2143G) were detected by PCR-RFLP. A total of 98 H pylori-infected patients were involved and among them, genotypic clarithromycin-sensitive strain was 93.9% and clarithromycin-resistant strain was 6.1%. All patients were found to have the A2143G point mutation but A2142G was not detected. Successful eradication rate of concomitant therapy was found to be 89.8% and unsuccessful rate was 10.2%. Among patients with the clarithromycin-resistant gene, only 16.7% had successful eradication and 83.3% had unsuccessful eradication. There was a statistically significant association between failure rate of concomitant therapy and detection of clarithromycin-resistant genes (P < 0.01). The presence of A2143G point mutation in the clarithromycin-resistant strain has a negative effect on the eradication rate of H pylori infection.

Integrated functional and spatial profiling of tumour immune responses induced by immunotherapy: the iPROFILER platform.

BackgroundCancer immunotherapy elicits functional activation and changes in immune cell distribution in cancer. Tumour heterogeneity is a reason for treatment failure but is difficult to capture in experimental settings. This proof-of-principle study describes the integrated functional and digital spatial profiling platform iPROFILER to capture in-situ immune activation patterns with high precision.Materials and methodsiPROFILER combines an algorithm-based image analysis approach for spatial profiling with functional analyses of patient-derived tumour fragments (PDTFs). This study utilized a folate receptor 1 (FOLR1)xCD3 bispecific antibody in dual-affinity re-targeting (DART) format as a tool for inducing T-cell responses in patient tumour samples, and an in-depth investigation of the immune perturbations induced in the tumour microenvironment was performed.ResultsEx-vivo DART stimulation induces upregulation of multiple activation markers in CD4+ and CD8+ T-cell populations and secretion of pro-inflammatory cytokines in FOLR1-positive tumour specimens. This response was reduced or absent in tissue samples that did not express FOLR1. Immunological responses were driven by a strong induction of interferon gamma (IFNγ) and IFNγ-induced chemokines suggestive of activation of cytotoxic or Th1-like T cells. Ex-vivo DART treatment led to a numerical increase in effector T cells and an upregulation of immune activation markers in the tumour microenvironment as captured by digital image analysis. Analysis of immune activation in tumour and stromal regions further supported the potential of the platform to measure local differences in cell-type-specific activation patterns.ConclusionsiPROFILER effectively combines functional and spatial readouts to investigate immune responses ex vivo in human tumour samples.

Preventive HIPEC in combination with perioperative FLOT versus FLOT alone for resectable diffuse type gastric and gastroesophageal junction type II/III adenocarcinoma: The phase III “PREVENT” trial of the AIO /CAOGI /ACO.

TPS4149 Background: The main reason for treatment failure after curative surgical resection of gastric cancer is intra-abdominal spread, with 40- 50% peritoneal seeding as primary localization of recurrence. Peritoneal relapse is seen in 60-70% of tumors of diffuse type, compared to only 20-30% of intestinal type. Hyperthermic IntraPEritoneal Chemoperfusion (HIPEC) is an increasingly used therapy method for patients with peritoneal metastases. The preventive use of HIPEC could represent an elegant approach for patients (pts) before macroscopic peritoneal seeding, since patients with operable disease are fit and may have potential risk of microscopic involvement, thus having a theoretical chance of cure with HIPEC even without the need for cytoreduction. No results from a PCRT from the Western hemisphere have yet been published. Methods: This is a multicenter, randomized, controlled, open-label study including a total of 200 pts with localized and locally advanced diffuse and mixed type (Laurens`s classification) adenocarcinoma of the stomach and Type II/III GEJ (i.e. ≥cT3 any N or any T N positive). All enrolled pts will have received 3-6 pre-operative cycles of biweekly FLOT (Docetaxel 50 mg/m²; Oxaliplatin 85 mg/m²; Leucovorin 200 mg/m²; 5-FU 2600 mg/m², q2wk). Pts will be randomized 1:1 to receive surgery only and postoperative FLOT (Arm A- Control arm) or surgery + intraoperative HIPEC (cisplatin 75mg/m2 solution administered at a temperature of 42°C for 90 minutes) and postoperative FLOT (Arm B- experimental arm). Surgery is carried out as gastrectomy or transhiatal extended gastrectomy. Primary endpoint is PFS/DFS, major secondary endpoints are OS, R0 resection rate, perioperative morbidity/mortality including VAS pain score and quality of life as assessed by EORTC QLQ C30 questionnaire. The trial starts with a safety run-in phase. After 20 patients had curatively intended resection in Arm B, an interim safety analysis is performed assessing feasibility, safety, and tolerability in Arm B. First patient was randomized on 18JAN2021. Currently one patient is recruited. EudraCT: 2017-003832-35; ClinicalTrials.gov ID: NCT04447352. Clinical trial information: NCT04447352.

Flea infestation: a snapshot on the common products and the reasons for treatment failure

The reasons why flea infestations remain frequent in companion animals despite the considerable number of anti-flea products is of interest. Successful flea control relies mainly on the use of effective anti-flea products and pet owners adhering to treatment recommendations. When flea infestations continue to persist despite the application of a potent anti-flea product, lack of efficacy may be suspected. In this article, the basics of flea biology and impact of flea infestation on the host are summarised. In addition, the factors that can result in ineffective treatment and control of flea infestation are discussed. Better understanding of the possible reasons can help to inform clinical practice and avoid treatment failures.

Use of Nanoparticles in Delivery of Nucleic Acids for Melanoma Treatment.

Melanoma accounts for 4% of all skin cancer malignancies, with only 14% of diagnosed patients surviving for more than 5 years after diagnosis. Until now, there is no clear understanding of the detailed molecular contributors of melanoma pathogenesis. Accordingly, more research is needed to understand melanoma development and prognosis.All the treatment approaches that are currently applied have several significant limitations that prevent effective use in melanoma. One major limitation in the treatment of cancer is the acquisition of multidrug resistance (MDR). The MDR results in significant treatment failure and poor clinical outcomes in several cancers, including skin cancer. Treatment of melanoma is especially retarded by MDR. Despite the current advances in targeted and immune-mediated therapy, treatment arms of melanoma are severely limited and stand as a significant clinical challenge. Further, the poor pharmacokinetic profile of currently used chemotherapeutic agents is another reason for treatment failure. Therefore, more research is needed to develop novel drugs and carrier tools for more effective and targeted treatment.Nucleic acid therapy is based on nucleic acids or chemical compounds that are closely related, such as antisense oligonucleotides, aptamers, and small-interfering RNAs that are usually used in situations when a specific gene implicated in a disorder is deemed a therapeutically beneficial target for inhibition. However, the proper application for nucleic acid therapies is hampered by the development of an effective delivery system that can maintain their stability in the systemic circulation and enhance their uptake by the target cells. In this chapter, the prognosis of the different types of melanoma along with the currently used medications is highlighted, and the different types of nucleic acids along with the currently available nanoparticle systems for delivering these nucleic acids into melanoma cells are discussed. We also discuss recently conducted research on the use of different types of nanoparticles for nucleic acid delivery into melanoma cells and highlight the most significant outcomes.

Tratamento da epilepsia em cães – revisão

Epilepsy is relatively common in dogs and is characterized by recurring seizures. In order to treat such cases effectively, the veterinarian must first clarify the etiology of the reported episodic events, investigate the cause of the seizures, carry out a detailed clinical evaluation of the patient from the start of the treatment, decide on the drug to be used, monitor the patient appropriately, and ensure that the dog’s owners understand and collaborate with the treatment. Reasons for treatment failures include the prescription of drugs unsuitable for use in dogs or the use of low doses. This article reviews factors related to the use of phenobarbital, potassium bromide and levetiracetam – drugs available in Brazil for which there is stronger evidence of safety and effectiveness in the treatment of canine epilepsy.

A long-term study of sinoscopic treatment of equine paranasal sinus disease: 155 cases (2012-2019).

There is little objective information concerning the intra- and post-operative complications or the long-term outcome of sinoscopic treatment of equine sinus disorders. To document the long-term outcome, including intra-operative complications, reasons for treatment failure and other complications, in horses undergoing standing sinoscopic treatment of sinus disorders. Retrospective clinical study. Records of sinus disease cases presented to The University of Edinburgh Veterinary School between January 2012 and July 2019 were reviewed. Follow-up information was obtained from clinical records and a telephone questionnaire. Long-term follow up for 155 cases treated sinoscopically showed that 108/155 (69.7%) fully responded to their initial treatment. Concurrent intranasal lesions were identified in 37.4% of cases. Sinusotomy was later required in 10 cases to improve surgical access or sinonasal drainage. Reasons for failure to fully respond to the initial treatment (n=47) included: intra-sinus bone sequestra (n=9), inspissated exudate (n=6) or insects (n=2); similar material and/or infected conchal bullae in the middle meatus (n=7); persistent oro-maxillary fistulae (n=4), misdiagnosed dental apical infections (n=4); impaired sinonasal drainage (n=4), progressive ethmoid haematoma regrowth (n=3) and undiagnosed causes (n=5). Further treatment of 43 of these cases (67% as outpatients) showed 34/43 cases fully responding to their second treatment. Only 4/155 cases (2.6%) required sinonasal fenestration. In the long term, 149/155 cases (96.1%) showed full and 2/155 cases (1.3%) showed partial improvement. Sinoscopy portal wound infection occurred in nine cases. The length of time between treatment and obtaining follow-up information in some cases. Advances in knowledge and techniques over the duration of the study. Sinoscopic treatment is a minimally-invasive technique causing minimal morbidity and was successful in 96.1% of cases. Meticulous care should be taken to ensure that bony sequestrae and inspissated exudate are fully removed from the sinuses and nasal cavity during sinoscopic treatments.

Assessing the prognostic value of stemness-related genes in breast cancer patients

Breast cancer (BC) is currently one of the deadliest tumors worldwide. Cancer stem cells (CSCs) are a small group of tumor cells with self-renewal and differentiation abilities and high treatment resistance. One of the reasons for treatment failures is the inability to completely eliminate tumor stem cells. By using the edgeR package, we identified stemness-related differentially expressed genes in GSE69280. Via Lasso-penalized Cox regression analysis and univariate Cox regression analysis, survival genes were screened out to construct a prognostic model. Via nomograms and ROC curves, we verified the accuracy of the prognostic model. We selected 4 genes (PSMB9, CXCL13, NPR3, and CDKN2C) to establish a prognostic model from TCGA data and a validation model from GSE24450 data. We found that the low-risk score group had better OS than the high-risk score group, whether using TCGA or GSE24450 data. A prognostic model including four stemness-related genes was constructed in our study to determine targets of breast cancer stem cells (BCSCs) and improve the treatment effect.

Effect of monoclonal antibody drug therapy on mucosal biomarkers in airway disease: A systematic review.

Monoclonal antibody therapies have a growing role in treating refractory airway disease. The review aimed to summarize the response of respiratory mucosa to monoclonal antibody treatments in inflammatory airway conditions. We conducted a systematic review including risk of bias assessment. MEDLINE, EMBASE and PubMed from 1 January 2000 to 16 November 2019 were searched. Eligible studies assessed the immunological and histological response of airway mucosa to monoclonal antibody therapy compared with baseline or a comparison group in patients with respiratory diseases (asthma, chronic rhinosinusitis and allergic rhinitis). Any prospective interventional studies, including randomized controlled trials (RCTs) and single-arm trials, were eligible. There were 4195 articles screened, and full-text analysis produced n=11 studies with extractable data. Nine were RCTs, and two were single-arm trials. These studies focused on asthma (n=9 articles), chronic rhinosinusitis (n=1) and allergic rhinitis (n=1). Five monoclonal antibody drugs were assessed (omalizumab, mepolizumab, dupilumab, benralizumab and tralokinumab). Risk of bias was low (n=6) or unclear (n=3) in the RCTs and moderate in the single-arm trials. Omalizumab reduced the mucosal concentration of its target, IgE. Dupilumab reduced the concentration of one of its targets, IL-13, but not IL-4. Omalizumab, mepolizumab and benralizumab reduced tissue eosinophil cell density. Dupilumab decreased mucosal eosinophil granule proteins. Tralokinumab did not affect airway mucosa. Knowledge of the expected biological response of monoclonal antibody therapy on biomarkers in disease tissue provides an important supplement to data about clinical outcomes. An understanding of the biological effect is essential to identify likely responders, reasons for treatment failure and necessary adjustments to monoclonal antibody treatment. Further investigation into the effect of monoclonal antibody therapy on disease mucosa and more precise endotyping are required to move closer to achieving personalized medicine.

The liver-first approach in treatment of rectal cancer patients with synchronous liver metastases

Objective: to evaluate feasibility and short-term results of the liver-first approach in our center.Materials and methods. Retrospective study of prospectively gathered group of patients who were treated in N. N. Blokhin National Medical Research Center of Oncology between 2017 and 2019. Patients with asymptomatic primary tumor located in rectum and rectosigmoid junction with synchronous resectable / borderline resectable metastasis in liver. 22 patients were planned to undergo the liver-first approach. Post-operative morbidity and mortality (Clavien–Dindo) as well as tumor regression grading (Dworak) were evaluated.Results. Of the 17 patients planned to undergo the liver-first strategy, the approach was completed in 15 (88,2 %) patients. The main reason for treatment failure was disease progression. Post-operative morbidity and mortality were 13,3 % and 0 %, respectively.Conclusions. Liver-first approach is justified in two cases: during waiting period after last day of chemoradiotherapy in patients with locally advanced (invasion depth T4a, positive circumferential resection margin, N+ status) mid-to-low rectal cancer and in patients with multiple borderline resectable bilobar liver damage.

Broccoli extract increases drug-mediated cytotoxicity towards cancer stem cells of head and neck squamous cell carcinoma

BackgroundHead and neck squamous cell carcinomas (HNSCC) are malignant neoplasms with poor prognosis. Treatment-resistant cancer stem cell (CSC) is one reason for treatment failure. Considerable attention has been focused on sulforaphane (SF), a phytochemical from broccoli possessing anticancer properties. We investigated whether SF could enhance the chemotherapeutic effects of cisplatin (CIS) and 5-fluorouracil (5-FU) against HNSCC–CSCs, and its mechanisms of action.MethodsCD44+/CD271+ FACS-isolated CSCs from SCC12 and SCC38 human cell lines were treated with SF alone or combined with CIS or 5-FU. Cell viability, colony- and sphere-forming ability, apoptosis, CSC-related gene and protein expression and in vivo tumour growth were assessed. Safety of SF was tested on non-cancerous stem cells and in vivo.ResultsSF reduced HNSCC–CSC viability in a time- and dose-dependent manner. Combining SF increased the cytotoxicity of CIS twofold and 5-FU tenfold, with no effects on non-cancerous stem cell viability and functions. SF-combined treatments inhibited CSC colony and sphere formation, and tumour progression in vivo. Potential mechanisms of action included the stimulation of caspase-dependent apoptotic pathway, inhibition of SHH pathway and decreased expression of SOX2 and OCT4.ConclusionsCombining SF allowed lower doses of CIS or 5-FU while enhancing these drug cytotoxicities against HNSCC–CSCs, with minimal effects on healthy cells.

A machine learning-based framework for Predicting Treatment Failure in tuberculosis: A case study of six countries

Tuberculosis is ranked as the 2nd deadliest disease in the world and is responsible for ten million deaths in 2017. Treatment failure is one of a main reason behind these deaths. Reasons of treatment failure are still unknown and the death rate due to TB is increasing. Machine learning and data analytics approaches are proved to be useful in healthcare domain in finding the associations among different attributes that can affect the outcome of any disease. Timely identification of reasons can save a patient's life. This study aims to find features that are strongly correlated with treatment failure using feature selection techniques. The validation of features is demonstrated using different classification algorithms. Moreover, this study provides a demographic based feature association of six highly burdened treatment failure countries. A verified real-life patient's dataset gathered from different countries including Azerbaijan, Belarus, Georgia, India, Moldova, and Romania is utilized to address the problem. Two types of experimentation are performed on combined dataset by achieving an average accuracy of 78% and an accuracy of 92% on Romania's data. Results shows the importance of features obtained through this study are highly influential in leading a patient towards treatment failure.

Outcomes Comparison of the Veterans’ Choice Program With the Veterans Affairs Health Care System for Hepatitis C Treatment

The US Department of Veterans Affairs (VA) has been stressed by the large number of veterans requiring direct-acting antiviral (DAA) medications for hepatitis C virus (HCV) treatment. The Veterans Choice Program provides VA patients more options to receive treatment. This study compared the experience of veterans who received HCV treatment through the Veterans Choice Program and those that received treatment at the VA Loma Linda Healthcare System (VALLHCS) in fiscal year (FY) 2016. A chart review was performed on all veterans referred by VALLHCS to Choice for HCV treatment during FY 2016, and matched to veterans who received treatment at VALLHCS. Data collected included Fibrosis-4 score (Fib-4), platelet count, days elapsed between time of referral and time of appointment (wait time), rate of sustained virologic response at 12 weeks (SVR12), reason for treatment failure, and cost effectiveness. One hundred veterans were referred to Choice; 71 were seen at least once by a Choice provider, and 61 completed a treatment course. Mean Fib-4 and platelet count was 1.9 and 228,000 for the Choice population and 3.4 and 158,000 for the VALLHCS population, respectively. There was no difference in SVR12 rate. Mean wait time was 42 days for Choice vs 29 days for VALLHCS (P < .001). Choice health care providers incurred a mean $8,561.40 in additional costs per veteran seen. While treatment success rates were similar between Choice and VALLHCS, the degree of liver fibrosis was more advanced in the VALLHCS population. The wait time for care was longer with Choice compared with a direct referral within the VA. While Choice offers a potential solution to providing care for veterans, the current program has unique problems that must be considered.

Abstract D118: Insulin receptor splicing regulation as a potential target for improved prostate cancer disparity outcomes

Abstract Prostate Cancer is the third most commonly diagnosed cancer in the US, with 174,650 new cases predicted in 2019. Rates of incidence and mortality are 2 to 3 times higher among men from African American (AA) descent. These statistics necessitate unconventional and out-of-the box treatment approach to impede this cancer, specifically in AA men that are most likely to succumb to the cancer. Alternative splicing (AS) is a process in which a pre-mRNA can be processed into different mature mRNAs with the aid of the splice regulatory machinery. AS contributes to structural transcript variation and proteome diversity and is tightly regulated during development and differentiation. It has been shown that deregulated splicing can give rise to protein isoforms that contribute to tumor initiation, progression and resistance to therapy. The insulin receptor gene (INSR) has uniquely evolved to undergo AS to produce two isoforms: the full-length INR-B and exon 11 skipped INR-A isoform. INR-B primarily mediates the metabolic effects of insulin, whereas INR-A triggers growth-promoting effects. This increased INR-A expression promotes the proliferation of the cells because it encodes for a receptor which has high affinity for both insulin and IGF2 growth hormones and it exploits the IGF pathway to accelerate the onset of tumor-cell hallmarks like proliferation and angiogenesis. Published work as well as preliminary data from our own lab suggest that there is a significantly increased expression of INR-A levels in prostate cancer. This atypical increased expression was further confirmed in multiple prostate cancer cell-lines. Our data further shows that this conversion of INR-B to INR-A takes place in the presence of stress conditions such as hypoxia. Furthermore, the INSR expression and splicing is particularly relevant in prostate cancer since Hif1a has been shown to be significantly elevated and associated with worse prognosis in prostate cancer. Hypoxic signaling has also been found to be a key driver of malignancy as well a reason for treatment failure. Strikingly, the INR-A isoform is expressed more often in prostate cancer samples from AA males than those from European descent (EA). Our goal is to understand the role of AS in cancer and to target the splicing pathway as a therapeutic intervention. To this end, we used a novel hypoxia-induced splicing system that recapitulates the IN-R splicing seen in tumors to identify splice regulatory proteins and their respective binding sites capable of regulating INSR splicing in prostate cancer. In collaboration with Ionis Pharmaceuticals we have shown that splice-switching oligonucleotides (SSOs) can target the splicing enhancer and repressor sequences we identified to interfere with INSR splicing and cancer cell behavior. We hypothesize that decreasing the expression of the A variant will lead to decreased tumor growth and increased susceptibility to current treatment regimens that will be particularly beneficial to AA men that express high levels of the INR-A isoform. Citation Format: Safiya Khurshid, Matias Montes, Frank Rigo, Dawn S Chandler. Insulin receptor splicing regulation as a potential target for improved prostate cancer disparity outcomes [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D118.

PCDHGA9 represses epithelial-mesenchymal transition and metastatic potential in gastric cancer cells by reducing \u03b2-catenin transcriptional activity

Gastric cancer (GC) has a high mortality rate, and metastasis is the main reason for treatment failure. It is important to study the mechanism of tumour invasion and metastasis based on the regulation of key genes. In a previous study comparing the expression differences between GES-1 and SGC-7901 cells, PCDHGA9 was selected for further research. In vitro and in vivo experiments showed that PCDHGA9 inhibited invasion and metastasis. A cluster analysis suggested that PCDHGA9 inhibited epithelial-mesenchymal transition (EMT) through the Wnt/β-catenin and TGF-β pathways. Laser confocal techniques and western blotting revealed that PCDHGA9 inhibited the nuclear translocation of β-catenin, regulated T cell factor (TCF)/ /lymphoid enhancer factor (LEF) transcriptional activity, directly impacted the signal transmission of the TGF-β/Smad2/3 pathway, strengthened the adhesion complex, weakened the effects of TGF-β, and blocked the activation of the Wnt pathway. In addition, PCDHGA9 expression was regulated by methylation, which was closely related to poor clinical prognosis. The aim of this study was to elucidate the molecular mechanism by which PCDHGA9 inhibits EMT and metastasis in GC to provide a new theoretical basis for identifying GC metastasis and a new target for improving the outcome of metastatic GC.