Stimulating macropinocytosis of peptide-drug conjugates through DNA-dependent protein kinase inhibition for treating KRAS-mutant cancer.

KRAS-mutant cancers, due to their protein targeting complexity, present significant therapeutic hurdles. The identification of the macropinocytic phenotype in these cancers has emerged as a promising alternative therapeutic target. Our study introduces MPD1, an macropinocytosis-targeting peptide-drug conjugates (PDC), which is developed to treat KRAS mutant cancers. This PDC is specifically designed to trigger a positive feedback loop through its caspase-3 cleavable characteristic. However, we observe that this loop is hindered by DNA-PK mediated DNA damage repair processes in cancer cells. To counter this impediment, we employ AZD7648, a DNA-PK inhibitor. Interestingly, the combined treatment of MPD1 and AZD7648 resulted in a 100% complete response rate in KRAS-mutant xenograft model. We focus on the synergic mechanism of it. We discover that AZD7648 specifically enhances macropinocytosis in KRAS-mutant cancer cells. Further analysis uncovers a significant correlation between the increase in macropinocytosis and PI3K signaling, driven by AMPK pathways. Also, AZD7648 reinforces the positive feedback loop, leading to escalated apoptosis and enhanced payload accumulation within tumors. AZD7648 possesses broad applications in augmenting nano-sized drug delivery and preventing DNA repair resistance. The promising efficacy and evident synergy underscore the potential of combining MPD1 with AZD7648 as a strategy for treating KRAS-mutant cancers.

Improvement in Testosterone Production by Acorus gramineus for the Alleviation of Andropause Symptoms.

Acorus gramineus has a number of beneficial effects, including protective effects against age-related disorders. In this study, the effects of A. gramineus on testosterone production and andropause symptoms were evaluated. We first treated TM3 mouse Leydig cells, responsible for testosterone production, with A. gramineus aqueous extract at different concentrations. In TM3 cells, the testosterone concentration increased in a concentration-dependent manner compared with those in the control. In addition, at 400 µg/mL extract, the mRNA expression level of the steroidogenic enzyme CYP11A1 was increased. Subsequently, 23-week-old Sprague-Dawley (SD) rats exhibiting an age-related reduction in serum testosterone (approximately 80% lower than that in 7-week-old SD rats) were administered A. gramineus aqueous extract for 8 weeks. Serum total testosterone and free testosterone levels were higher and serum estradiol, prostate-specific antigen levels, and total cholesterol levels were lower in the AG50 group (A. gramineus aqueous extract 50 mg/kg of body weight/day) than in the OLD (control group). The AG50 group also showed significant elevations in sperm count, grip strength, and mRNA expression of StAR, CYP11A1, 17ß-HSD, and CYP17A1 compared with those in the OLD group. In conclusion, A. gramineus aqueous extract facilitated steroidogenesis in Leydig cells, elevated testosterone levels, lowered serum estradiol and total cholesterol levels, and increased muscle strength and sperm count, thus alleviating the symptoms of andropause. These findings suggest that A. gramineus aqueous extract is a potentially effective therapeutic agent against various symptoms associated with andropause.

Efficacy of adjuvant mitomycin-C and triamcinolone-impregnated nasal packing for endoscopic dacryocystorhinostomy.

AIM: To compare the success rate and complications of adjuvant use of mitomycin C and triamcinolone-impregnated biodegradable nasal packing (TABP) in endoscopic dacryocystorhinostomy (DCR). And to evaluate the efficacy of combining intraoperative mitomycin C and TABP for endoscopic DCR. METHODS: A total of 198 eyes of 148 patients who underwent endoscopic DCR for acquired nasolacrimal duct obstruction were retrospectively analysed. The patients were randomly divided into three groups: Group A included patients treated without intraoperative mitomycin C but with TABP, Group B included patients treated without triamcinolone but with intraoperative mitomycin C and normal saline-impregnated nasal packing, and Group C included patients treated with intraoperative mitomycin C and TABP. RESULTS: The results revealed no significant difference in the overall success rates between Groups A (86.8%) and B (89.2%; P=0.377). However, Group C (97.5%) showed a significantly higher overall success rate than Groups A and B. The incidence of granulomas was significantly lower in group C (5%) than in Groups A (20.8%) and B (15.2%; P=0.009). Other complications, such as crust, synechiae, and revision surgery, did not differ significantly among the three groups. CONCLUSION: The combination of intraoperative mitomycin C and TABP effectively prevents granulomas and enhances surgical success rate. Additionally, there is no statistically significant difference observed between the use of mitomycin C or TABP alone.

Glioma subtype classification from histopathological images using in-domain and out-of-domain transfer learning: An experimental study.

We provide in this paper a comprehensive comparison of various transfer learning strategies and deep learning architectures for computer-aided classification of adult-type diffuse gliomas. We evaluate the generalizability of out-of-domain ImageNet representations for a target domain of histopathological images, and study the impact of in-domain adaptation using self-supervised and multi-task learning approaches for pretraining the models using the medium-to-large scale datasets of histopathological images. A semi-supervised learning approach is furthermore proposed, where the fine-tuned models are utilized to predict the labels of unannotated regions of the whole slide images (WSI). The models are subsequently retrained using the ground-truth labels and weak labels determined in the previous step, providing superior performance in comparison to standard in-domain transfer learning with balanced accuracy of 96.91% and F1-score 97.07%, and minimizing the pathologist's efforts for annotation. Finally, we provide a visualization tool working at WSI level which generates heatmaps that highlight tumor areas; thus, providing insights to pathologists concerning the most informative parts of the WSI.

Influence of Preoperative COVID-19 Vaccination on Outcomes After Coronary Artery Bypass Grafting-A Propensity Score-Matched Analysis.

BACKGROUND: Reports of intravascular thrombosis and cardiac complications have raised concerns about the safety of COVID-19 vaccinations, particularly in patients with high cardiovascular risk. Herein, we aimed to analyze the impact of preoperative COVID-19 vaccination on outcomes after coronary artery bypass grafting (CABG). METHODS AND RESULTS: Among 520 patients who underwent isolated CABG from 2020 to 2022, 481 patients (mean±SD age: 67±11 years, 86 women) whose COVID-19 vaccination status could be confirmed were included. A total of 249 patients who had not received any COVID-19 vaccine before CABG (never vaccinated group) and 214 patients who had completed primary vaccination (fully vaccinated group) were subjected to 1:1 propensity score matching, and 156 pairs of patients were matched. There was no significant difference in early mortality between the 2 groups after matching. After matching, overall survival (P=0.930) and major adverse cardiovascular and cerebrovascular event-free survival (P=0.636) did not differ between the 2 groups. One-year graft patency also did not differ significantly between the 2 groups; all patent grafts in 85/104 patients (82%) and 62/73 patients (85%) in the never vaccinated and fully vaccinated groups, respectively (P=0.685). Subgroup analysis showed equivalent overall and major adverse cardiovascular and cerebrovascular event-free survival among AstraZeneca and Pfizer vaccine recipients and between those with ≤30 days versus >30 days from vaccination to CABG. CONCLUSIONS: Despite the very high cardiovascular risk for patients undergoing CABG, COVID-19 vaccination did not affect major outcomes after CABG. Therefore, there is no reason for patients with coronary artery disease requiring CABG to avoid preoperative COVID-19 vaccination.

Enhancer of zeste homolog 2 (EZH2)-dependent sirtuin-3 determines sensitivity to glucose starvation in radioresistant head and neck cancer cells.

Sirtuin 3 (SIRT3) regulates mitochondrial function as a mitochondrial deacetylase during oxidative stress. However, the specific regulatory mechanism and function of SIRT3 in radioresistant cancer cells are unclear. In this study, we aim to investigate how SIRT3 determines the susceptibility to glucose deprivation and its regulation in p53-based radioresistant head and neck cancer cells. We observed mitochondrial function using two established isogenic radioresistant subclones (HN3R-A [p53 null] and HN3R-B [p53 R282W]) with intratumoral p53 heterogeneity. Cell counting analysis was performed to evaluate cell proliferation and cell death. The correlation between the regulation of SIRT3 and enhancer of zeste homolog 2 (EZH2) was confirmed by immunoblotting and chromatin immunoprecipitation assay. p53-deficient radioresistant cells (HN3R-A) expression reduced SIRT3 levels and increased sensitivity to glucose deprivation due to mitochondrial dysfunction compared to other cells. In these cells, activation of SIRT3 significantly prevented glucose deprivation-induced cell death, whereas the loss of SIRT3 increased the susceptibility to glucose deficiency. We discovered that radiation-induced EZH2 directly binds to the SIRT3 promoter and represses the expression. Conversely, inhibiting EZH2 increased the expression of SIRT3 through epigenetic changes. Our findings indicate that p53-deficient radioresistant cells with enhanced EZH2 exhibit increased sensitivity to glucose deprivation due to SIRT3 suppression. The regulation of SIRT3 by EZH2 plays a critical role in determining the cell response to glucose deficiency in radioresistant cancer cells. Therefore, EZH2-dependent SIRT3 could be used as a predictive biomarker to select treatment options for patients with radiation-resistance.

A study on the 10-year trend of surgeries performed for lumbar disc herniation and comparative analysis of prescribed opioid analgesics and hospitalization duration: 2010-2019 HIRA NPS Data.

BACKGROUND: This study, utilizing the claims data from the Health Insurance Review and Assessment Service of Korea, aimed to examine the 10-year (2010-2019) trends in various types of lumbar spine surgeries performed on patients diagnosed with lumbar herniated intervertebral disc (HIVD), and the current status of opioid prescriptions, as well as the duration of postoperative hospital stays based on the type of surgery performed. METHOD: This retrospective cross-sectional study examined patients with one or more national health insurance claims carrying a primary or secondary diagnosis of HIVD (ICD-10 codes: M511, M518, M519) over a 10-year period (2010-2019). From the patients undergoing lumbar spine surgery, we selected those who did not require reoperation within 30 days following the initial lumbar surgery. Our final study sample comprised patients who underwent only one type of surgery. RESULTS: Among the patients diagnosed with HIVD and subsequently undergoing lumbar surgery between 2010 and 2019, a slight downward trend was observed in those undergoing open discectomy (OD); however, OD persistently accounted for the highest proportion over the 10 years. Percutaneous endoscopic lumbar discectomy (PELD) demonstrated a consistent upward trend from 2016 to 2018. When inspecting trends, we noted a consistent escalation over the decade in the postoperative opioid prescription rates of strong opioids (50.7% in 2010 to 77.8% in 2019) and tramadol (50.9% in 2010 to 76.8% in 2019). Analyzing these trends by surgery type, spinal fusion exhibited a slightly higher rate of opioid prescriptions than other lumbar surgeries. Regarding the length of postoperative hospital stays, patients undergoing PELD recorded the shortest stay (7.04 ± 6.78 days), while spinal fusion necessitated the longest (20.14 ± 12.18 days). CONCLUSION: This study analyzed the trends in types of lumbar spine surgeries, opioid analgesic prescriptions, and length of hospital stays over 10 years (2010-2019) among patients with HIVD in Korea. Our data and findings provide valuable evidence that may prove beneficial for clinicians and researchers involved in HIVD-related practices.

The Impact of Sedation on Cardio-Cerebrovascular Adverse Events after Surveillance Esophagogastroduodenoscopy in Patients with Gastric Cancer: A Nationwide Population-Based Cohort Study.

Background/Aims: The impact of sedation on cardio-cerebrovascular (CCV) adverse events after esophagogastroduodenoscopy (EGD) in patients with gastric cancer (GC) is unclear. We investigated the incidence rate and impact of sedation on CCV adverse events after surveillance EGD in patients with GC. Methods: We performed a nationwide population-based cohort study using the Health Insurance Review and Assessment Service databases from January 1, 2018, to December 31, 2020. Using a propensity score-matched analysis, patients with GC were divided into two groups: sedative agent users and nonusers for surveillance EGD. We compared the occurrence of CCV adverse events within 14 days between the two groups. Results: Of the 103,463 patients with GC, newly diagnosed CCV adverse events occurred in 2.57% of patients within 14 days after surveillance EGD. Sedative agents were used in 41.3% of the patients during EGD. The incidence rates of CCV adverse events with and without sedation were 173.6/10,000 and 315.4/10,000, respectively. Between sedative agent users and nonusers based on propensity score matching (28,008 pairs), there were no significant differences in the occurrence of 14-day CCV, cardiac, cerebral, and other vascular adverse events (2.28% vs 2.22%, p=0.69; 1.44% vs 1.31%, p=0.23; 0.74% vs 0.84%, p=0.20; 0.10% vs 0.07%, p=0.25, respectively). Conclusions: Sedation during surveillance EGD was not associated with CCV adverse events in patients with GC. Therefore, the use of sedative agents may be considered in patients with GC during surveillance EGD without excessive concerns about CCV adverse events.

P16 expression and presence of lymphoid stroma are correlated with good prognosis in mucoepidermoid carcinoma of the head and neck.

BACKGROUND: Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. This study was designed to identify valuable prognosticator in MEC. METHODS: Histopathologic analysis, immunohistochemistry, and in situ hybridization were performed on 128 carcinomas diagnosed as MEC of the head and neck. RESULTS: Expression of p16 was found in 96 cases (76%) of MEC. Lymphoid stroma was identified in 63 cases (49%). There was a significant correlation between loss of p16 expression and absence of lymphoid stroma. Expression of p16 was significantly associated with better clinicopathologic features. Lymphoid stroma was significantly associated with lower histologic grade. Overall survival (OS) was significantly longer in cases expressing p16 (P = 0.00096) and lymphoid stroma cases (P = 0.0023). Multivariate analysis revealed loss of p16 expression as negative prognosticators for OS. CONCLUSION: Our data showed p16 expression and the presence of lymphoid stroma were significantly associated with good clinical outcomes. Testing for these factors could lead to better prognostication and treatment of patients with MEC.

Improved clinical outcomes following introduction of an attending intensivist for patients admitted to the cardiac surgical intensive care unit after valvular heart surgery: a single-center experience.

Background: Although numerous studies have documented the improved clinical outcomes of patients undergoing cardiac surgery following introduction of attending intensivist, most of these studies included heterogeneous patient populations. We aimed to investigate the impact of an attending intensivist on the clinical outcomes of patients admitted to the cardiac surgical intensive care unit (CSICU) following valvular heart surgery. Methods: Patients who underwent valvular heart surgery between January 2007 and December 2012 (control group, n=337) were propensity matched (1:1) between January 2013 and June 2017 (intensivist group, n=407). Results: During the propensity score matching analysis, 285 patients were extracted from each group. Patients in the intensivist group underwent mechanical ventilation for a significantly shorter time than those in the control group (21.8±69.8 vs. 39.2±115.3 hours, P=0.021). More patients were extubated within 6 hours in the intensivist group than in the control group (53.7% vs. 42.8%, P=0.015). The incidence of ventilator-associated pneumonia (1.4% vs. 4.9%, P=0.031), cardiac arrest due to cardiac tamponade associated with post-cardiotomy bleeding (0.4% vs. 3.9%, P=0.002), and acute kidney injury (2.8% vs. 7.7%, P=0.011) in the intensivist group was significantly lower than that in the control group. The 30-day mortality rate of the intensivist group was significantly lower than that of the control group (2.1% vs. 6.7%, P=0.015). Conclusions: Critical care provided in the CSICU staffed by an attending intensivist is associated with a lower 30-day mortality rate and reduced incidence of postoperative complications.

The clinical effectiveness of fused image of single-photon emission CT and facial CT for the evaluation of degenerative change of mandibular condylar head.

BACKGROUND: The primary objective of this study was to assess the clinical effectiveness of fused images obtained from single-photon emission computed tomography (SPECT) and facial computed tomography (CT) for evaluating degenerative changes in the mandibular condylar head. This assessment was accomplished by comparing the Technetium-99 m methylene diphosphonate (99mTc-MDP) uptake ratio with the results of clinical and radiographic findings. METHODS: The study included 17 patients (3 males and 14 females) with suspected osteoarthritis of the mandibular condyle, totaling 34 temporomandibular joints (TMJs). Based on clinical and radiographic examinations, the TMJs were categorized into four groups: normal (group N), internal derangement (group ID), osteoarthritis (group OA), and osteoarthritis sequelae (group OAseq). For each patient, bone SPECT and facial CT scans were registered and reconstructed to create fused SPECT/CT images. The 99mTc-MDP uptake levels in the TMJs were statistically compared among the four groups. RESULTS: The 99mTc-MDP uptake ratio showed a gradual increase in the order of the following: group N, group OAseq, group ID, and group OA. There was a significant difference observed among groups (p = 0.003), mainly driven by the disparity between group OA and both group N (p < 0.001) and group OAseq (p = 0.048). CONCLUSION: Fused SPECT/CT image can be an effective tool for evaluating degenerative changes in the mandibular condylar head. The technique demonstrated the ability to differentiate between normal TMJs and those with internal derangement, osteoarthritis, or osteoarthritis sequelae. This approach holds promise as a valuable method in clinical assessments of TMJ degeneration.

Frequent apocrine changes in pleomorphic adenoma with malignant transformation: a possible pre-malignant step in ductal carcinoma ex pleomorphic adenoma.

BACKGROUND: The most common type of carcinoma ex pleomorphic adenoma (CPA) is histologically equivalent to salivary duct carcinoma, which has an apocrine phenotype. Invasive CPA is often accompanied by non-invasive or in situ carcinoma, an observation that suggests the presence of precursor lesions. The aim of this study was to identify candidate precursor lesions of CPA within pleomorphic adenoma (PA). METHODS: Eleven resected cases of CPA with residual PA and 17 cases of PA with atypical changes were subjected to immunohistochemistry (IHC) for p53, human epidermal growth factor receptor 2 (HER2), androgen receptor (AR), pleomorphic adenoma gene 1, gross cystic disease fluid protein-15 (GCDFP-15), and anti-mitochondrial antibody. RESULTS: Invasive or in situ carcinoma cells in all CPAs were positive for AR, GCDFP-15, and HER2. Atypical foci in PAs corresponded to either apocrine or oncocytic changes on the basis of their reactivity to AR, GCDFP-15, and anti-mitochondrial antibody. Atypical cells in PAs surrounding CPAs had an apocrine phenotype without HER2 expression. CONCLUSIONS: Our study identified frequent apocrine changes in residual PAs in CPA cases, suggesting a possible precursor role of apocrine changes. We recommend the use of HER2 IHC in atypical PAs, and that clinicians take HER2 positivity into serious consideration.

Exosome-guided direct reprogramming of tumor-associated macrophages from protumorigenic to antitumorigenic to fight cancer.

Highly immunosuppressive tumor microenvironment containing various protumoral immune cells accelerates malignant transformation and treatment resistance. In particular, tumor-associated macrophages (TAMs), as the predominant infiltrated immune cells in a tumor, play a pivotal role in regulating the immunosuppressive tumor microenvironment. As a potential therapeutic strategy to counteract TAMs, here we explore an exosome-guided in situ direct reprogramming of tumor-supportive M2-polarized TAMs into tumor-attacking M1-type macrophages. Exosomes derived from M1-type macrophages (M1-Exo) promote a phenotypic switch from anti-inflammatory M2-like TAMs toward pro-inflammatory M1-type macrophages with high conversion efficiency. Reprogrammed M1 macrophages possessing protein-expression profiles similar to those of classically activated M1 macrophages display significantly increased phagocytic function and robust cross-presentation ability, potentiating antitumor immunity surrounding the tumor. Strikingly, these M1-Exo also lead to the conversion of human patient-derived TAMs into M1-like macrophages that highly express MHC class II, offering the clinical potential of autologous and allogeneic exosome-guided direct TAM reprogramming for arming macrophages to join the fight against cancer.

Elevated troponin I is associated with a worse long-term prognosis in patients undergoing beating-heart coronary surgery.

OBJECTIVES: The impacts of elevated troponin I levels after coronary artery bypass grafting (CABG) on long-term outcomes were investigated. METHODS: A total of 996 patients who underwent elective isolated CABG for stable or unstable angina were enrolled. Patients were divided into higher and lower groups based on 80th percentile postoperative peak troponin I (ppTnI) levels. The relationship between ppTnI and long-term clinical outcomes was analysed. RESULTS: The median ppTnI was 1.55 (2.74) ng/ml and was significantly higher in the conventional CABG subgroup than in the beating-heart CABG subgroup: 4.04 (4.71) vs 1.24 (1.99) ng/ml, P < 0.001. The 80th percentile of ppTnI was 3.3 ng/ml in the beating-heart CABG subgroup and 8.9 ng/ml in the conventional CABG subgroup. In the conventional CABG subgroup (n = 150), 10-year overall survival showed no significant difference between the higher (≥8.9 ng/ml) and lower (<8.9 ng/ml) ppTnI groups: 71% (10%) vs 76% (5%), P = 0.316. However, the beating-heart CABG subgroup (n = 846) showed significantly worse 10-year overall survival in the higher ppTnI group (≥3.3 ng/ml) than in the lower ppTnI group (<3.3 ng/ml): 64% (6%) vs 73% (3%), P = 0.010. In the beating-heart CABG subgroup, multivariable analysis showed that ppTnI exceeding the 80th percentile was a risk factor for overall death (hazard ratio: 1.505, 95% confidence interval: 1.019-2.225, P = 0.040). CONCLUSIONS: Higher ppTnI over the 80th percentile was associated with worse long-term survival in beating-heart CABG, but not in conventional CABG.

Accuracy of administrative claim data for gastric adenoma after endoscopic resection.

BACKGROUND/AIMS: Administrative databases provide valuable information for large-cohort studies. This study aimed to evaluate the diagnostic accuracy of an administrative database for resected gastric adenomas. METHODS: Data of patients who underwent endoscopic resection for benign gastric lesions were collected from three hospitals. Gastric adenoma cases were identified in the hospital database using International Classification of Diseases (ICD) 10-codes. The non-adenoma group included patients without gastric adenoma codes. The diagnostic accuracy for gastric adenoma was analyzed based on the pathological reports of the resected specimen. RESULTS: Among 5,095 endoscopic resections with codes for benign gastric lesions, 3,909 patients were included in the analysis. Among them, 2,831 and 1,078 patients were allocated to the adenoma and non-adenoma groups, respectively. Regarding the overall diagnosis of gastric adenoma with ICD-10 codes, the sensitivity, specificity, positive predictive value, and negative predictive value were 98.7%, 88.5%, 95.2%, and 96.8%, respectively. There were no significant differences in these parameters between the tertiary and secondary centers. CONCLUSION: Administrative codes of gastric adenoma, according to ICD-10 codes, showed good accuracy and can serve as a useful tool to study prognosis of these patients in real-world data studies in the future.

Risk Factors for Feeding Tube Dependency in Patients Undergoing Function Preservation Surgery for Advanced-Stage Laryngohypopharyngeal Cancer.

Dysphagia and feeding tube dependency commonly occur in patients with laryngeal or hypopharyngeal cancer (LHC) during and after treatment, often leading to poor functional outcomes. Therefore, we examined the factors related to feeding tube dependency among advanced-stage LHC patients undergoing curative surgery. This study included 69 consecutive patients who underwent conservative surgery for previously untreated, advanced-stage LHC (squamous cell carcinoma) between 2006 and 2016. Persistent feeding tube dependency was defined as 1 year or more after treatment completion. Binary logistic regression analysis was used to determine the factors associated with reactive prolonged and persistent feeding tube dependency. Cox proportional hazard regression analysis was used to determine the association between feeding tube dependency and survival. None of the study patients had a prophylactic feeding tube, but 15 (21.7%) patients had reactive feeding tube placement for 3 months or more. A total of 9 (13.0%) patients had persistent feeding tube dependency. Univariate analysis showed that age, tracheostomy, and common terminology criteria for adverse events (CTCAE) ≥ 3 were significantly associated with reactive prolonged and persistent feeding tube dependency (all P < 0.05). In the multivariate analysis, advanced age and CTCAE ≥ 3 remained the independent factors of reactive prolonged and persistent feeding tube dependency (all P < 0.05). Feeding tube dependency was not associated with overall survival or disease-free survival (P > 0.1). Feeding tube dependency might be related to clinical factors, such as age and severe adverse events, in the patients undergoing function-preserving surgery for advanced-stage LHC.

Sustained potentiation of bystander killing via PTEN-loss driven macropinocytosis targeted peptide-drug conjugate therapy in metastatic triple-negative breast cancer.

While conventional approaches for PTEN-loss cancers mainly focus on turning off growth promoting process through modulation of PI3K/AKT pathways, no effective therapeutic treatments that target PTEN-loss cancer cells have yielded results. Moreover, conventional targeted therapies, which are potent against only a subset of cancer cells with limited specificity, bring on temporary response. Here, we report the development of albumin-binding caspase-3 cleavable peptide-drug conjugate (PDC), which utilizes the enhanced albumin metabolism pathway in PTEN-loss cancer cells to enhance the intracellular delivery of chemotherapeutic payload that could exert a bystander killing effect. Albumin metabolism-mediated apoptosis triggered expression of caspase-3 allows the continuous activation of the PDC, accumulation of payloads, sustained upregulation of tumoral caspase-3, and intensified in-situ apoptosis. Importantly, PDC strategy exerts potent therapeutic efficacy against PTEN-loss metastatic triple-negative breast cancer, the highly aggressive and heterogenous nature of which remains a challenge conventional targeted therapies need to overcome. This study thus presents a conceptually novel approach to treat PTEN-loss cancer and creates new translational perspectives of exploiting PTEN-loss for providing an avenue to advance current targeted therapy.

Tristetraprolin regulates phagocytosis through interaction with CD47 in head and neck cancer.

CD47 is expressed in all human cancer cells, including head and neck cancer, and initiates a signaling cascade to inhibit macrophage phagocytosis. However, the mechanism underlying CD47 overexpression has not been elucidated in radioresistant head and neck cancer. The present study demonstrated that decreased Tristetraprolin (TTP) expression induced a sustained overexpression of CD47 using reverse transcription-quantitative PCR and western blotting, and that CD47 overexpression prevented phagocytosis using a phagocytosis assay in a radioresistant HN31R cell line. Subsequently, using TTP transfection, RNA interference, duel-luciferase assay and EMSA, it was revealed that TTP transfection enhanced phagocytosis through degradation of CD47 mRNA by directly binding to CD47 AREs within the CD47 3'UTR. Based on our previous study, methylation-specific PCR and western blotting revealed that DNMT1 was overexpressed in radioresistant HN31R cell line and TTP expression was decreased epigenetically by DMNT1 associated DNA methylation. Overall, these findings provided novel insight into the role of TTP as a biomarker of CD47-positive head and neck cancer patients.