Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells.

Selective targeting of cancer stem cells (CSCs) offers promise for a new generation of therapeutics. However, assays for both human CSCs and normal stem cells that are amenable to robust biological screens are limited. Using a discovery platform that reveals differences between neoplastic and normal human pluripotent stem cells (hPSC), we identify small molecules from libraries of known compounds that induce differentiation to overcome neoplastic self-renewal. Surprisingly, thioridazine, an antipsychotic drug, selectively targets the neoplastic cells, and impairs human somatic CSCs capable of in vivo leukemic disease initiation while having no effect on normal blood SCs. The drug antagonizes dopamine receptors that are expressed on CSCs and on breast cancer cells as well. These results suggest that dopamine receptors may serve as a biomarker for diverse malignancies, demonstrate the utility of using neoplastic hPSCs for identifying CSC-targeting drugs, and provide support for the use of differentiation as a therapeutic strategy.

Novel targets of ß-TrCP cooperatively accelerate carbohydrate and fatty acid consumption.

Cellular energy is primarily produced from glucose and fat through glycolysis and fatty acid oxidation (FAO) followed by the tricarboxylic acid cycle in mitochondria; energy homeostasis is carefully maintained via numerous feedback pathways. In this report, we uncovered a new master regulator of carbohydrate and lipid metabolism. When ubiquitin E3 ligase ß-TrCP2 was inducibly knocked out in ß-TrCP1 knockout adult mice, the resulting double knockout mice (DKO) lost fat mass rapidly. Biochemical analyses of the tissues and cells from ß-TrCP2 KO and DKO mice revealed that glycolysis, FAO, and lipolysis were dramatically upregulated. The absence of ß-TrCP2 increased the protein stability of metabolic rate-limiting enzymes including 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), adipose triglyceride lipase (ATGL), carnitine palmitoyltransferase 1A (CPT1A), and carnitine/acylcarnitine translocase (CACT). Our data suggest that ß-TrCP is a potential regulator for total energy homeostasis by simultaneously controlling glucose and fatty acid metabolism and that targeting ß-TrCP could be an effective strategy to treat obesity and other metabolic disorders.

Reconstruction of all hepatic arteries in right lobe grafts with 2 hepatic arteries and zero percent hepatic artery thrombosis.

Hepatic artery thrombosis (HAT) is a common cause of graft loss in living-donor liver transplantation, occurring in ~2.5%-8% of patients. Some right lobe grafts have 2 hepatic arteries (HAs), and the optimal reconstruction technique remains controversial. This study aimed to identify risk factors for HAT and to evaluate the efficacy of reconstructing 2 HAs in right lobe grafts. This retrospective, single-center study analyzed 1601 living-donor liver transplantation recipients with a right liver graft and divided them into 1 HA (n = 1524) and 2 HA (n = 77) groups. The reconstruction of all HAs was performed using a microscope with an interrupted suture. The primary outcome was any HAT event. Of the 1601 patients, 37.8% had a history of transcatheter arterial chemoembolization, and 130 underwent pretransplant hepatectomy. Extra-anatomical arterial reconstruction was performed in 38 cases (2.4%). HAT occurred in 1.2% of patients (20/1601) who underwent surgical revascularization. In the multivariate analysis, undergoing pretransplant hepatectomy ( p = 0.008), having a female donor ( p = 0.02), having a smaller graft-to-recipient weight ratio ( p = 0.002), and undergoing extra-anatomical reconstruction ( p = 0.001) were identified as risk factors for HAT. However, having 2 HA openings in right liver grafts was not a risk factor for HAT in our series. Kaplan-Meier survival analysis showed no significant difference in graft survival and patient survival rates between the 1 HA and 2 HA groups ( p = 0.09, p = 0.97). In our series, although the smaller HA in the 2 HA group should increase the risk of HAT, HAT did not occur in this group. Therefore, reconstructing both HAs when possible may be a reasonable approach in living-donor liver transplantation using a right liver graft with 2 HA openings.

Durvalumab with or without tremelimumab plus chemotherapy in HRR non-mutated, platinum-resistant ovarian cancer (KGOG 3045): A phase II umbrella trial.

AIM: We investigated the efficacy and safety of durvalumab (D) with or without tremelimumab (T) in addition to single-agent chemotherapy (CT) in patients with platinum-resistant recurrent ovarian cancer (PROC) lacking homologous recombination repair (HRR) gene mutations. PATIENTS AND METHODS: KGOG 3045 was an open-label, investigator-initiated phase II umbrella trial. Patients with PROC without HRR gene mutations who had received ≥2 prior lines of therapy were enrolled. Patients with high PD-L1 expression (TPS ≥25%) were assigned to arm A (D + CT), whereas those with low PD-L1 expression were assigned to arm B (D + T75 + CT). After completing arm B recruitment, patients were sequentially assigned to arms C (D + T300 + CT) and D (D + CT). RESULTS: Overall, 58 patients were enrolled (5, 18, 17, and 18 patients in arms A, B, C, and D, respectively). The objective response rates were 20.0, 33.3, 29.4, and 22.2%, respectively. Grade 3-4 treatment-related adverse events were observed in 20.0, 66.7, 47.1, and 66.7 of patients, respectively, but were effectively managed. Multivariable analysis demonstrated that adding T to D + CT improved progression-free survival (adjusted HR, 0.435; 95% CI, 0.229-0.824; P = 0.011). Favorable response to chemoimmunotherapy was associated with MUC16 mutation (P = 0.0214), high EPCAM expression (P = 0.020), high matrix remodeling gene signature score (P = 0.017), and low FOXP3 expression (P = 0.047). Patients showing favorable responses to D + T + CT exhibited significantly higher EPCAM expression levels (P = 0.008) and matrix remodeling gene signature scores (P = 0.031) than those receiving D + CT. CONCLUSIONS: Dual immunotherapy with chemotherapy showed acceptable response rates and tolerable safety in HRR non-mutated PROC, warranting continued clinical investigation.

Deep Learning Based Automatic Segmentation of the Thoracic Aorta from Chest Computed Tomography in Healthy Korean Adults.

OBJECTIVE: Segmenting the aorta into zones based on anatomical landmarks is a current trend to better understand interventions for aortic dissection or aneurysm. However, comprehensive reference values for aortic zones are lacking. The aim of this study was to establish reference values for aortic size using a fully automated deep learning based segmentation method. METHODS: This retrospective study included 704 healthy adults (mean age 50.6 ± 7.5 years; 407;57.8%] males) who underwent contrast enhanced chest computed tomography (CT) for health screening. A convolutional neural network (CNN) was trained and applied on 3D CT images for automatic segmentation of the aorta based on the Society for Vascular Surgery and Society of Thoracic Surgeons classification. The CNN generated masks were reviewed and corrected by expert cardiac radiologists. RESULTS: Aortic size was significantly larger in males than in females across all zones (zones 0 - 8, all p < .001). The aortic size in each zone increased with age, by approximately 1 mm per 10 years of age, e.g., 25.4, 26.7, 27.5, 28.8, and 29.8 mm at zone 2 in men in the age ranges of 30 - 39, 40 - 49, 50 - 59, 60 - 69, and ≥ 70 years, respectively (all p < .001). CONCLUSION: The deep learning algorithm provided reliable values for aortic size in each zone, with automatic masks comparable to manually corrected ones. Aortic size was larger in males and increased with age. These findings have clinical implications for the detection of aortic aneurysms and other aortic diseases.

Long-Term Follow-Up of Interstitial Lung Abnormality: Implication in Follow-Up Strategy and Risk Thresholds.

Rationale: The optimal follow-up computed tomography (CT) interval for detecting the progression of interstitial lung abnormality (ILA) is unknown. Objectives: To identify optimal follow-up strategies and extent thresholds on CT relevant to outcomes. Methods: This retrospective study included self-referred screening participants aged 50 years or older, including nonsmokers, who had imaging findings relevant to ILA on chest CT scans. Consecutive CT scans were evaluated to determine the dates of the initial CT showing ILA and the CT showing progression. Deep learning-based ILA quantification was performed. Cox regression was used to identify risk factors for the time to ILA progression and progression to usual interstitial pneumonia (UIP). Measurements and Main Results: Of the 305 participants with a median follow-up duration of 11.3 years (interquartile range, 8.4-14.3 yr), 239 (78.4%) had ILA on at least one CT scan. In participants with serial follow-up CT studies, ILA progression was observed in 80.5% (161 of 200), and progression to UIP was observed in 17.3% (31 of 179), with median times to progression of 3.2 years (95% confidence interval [CI], 3.0-3.4 yr) and 11.8 years (95% CI, 10.8-13.0 yr), respectively. The extent of fibrosis on CT was an independent risk factor for ILA progression (hazard ratio, 1.12 [95% CI, 1.02-1.23]) and progression to UIP (hazard ratio, 1.39 [95% CI, 1.07-1.80]). Risk groups based on honeycombing and extent of fibrosis (1% in the whole lung or 5% per lung zone) showed significant differences in 10-year overall survival (P = 0.02). Conclusions: For individuals with initially detected ILA, follow-up CT at 3-year intervals may be appropriate to monitor radiologic progression; however, those at high risk of adverse outcomes on the basis of the quantified extent of fibrotic ILA and the presence of honeycombing may benefit from shortening the interval for follow-up scans.

Randomized, two-arm, noncomparative phase 2 study of olaparib plus cediranib or durvalumab in HRR-mutated, platinum-resistant ovarian cancer: A substudy of KGOG 3045.

Choosing an optimal concomitant drug for combination with poly-ADP ribose polymerase (PARP) inhibitor based on patient-specific biomarker status may help increase to improve treatment efficacy in patients with ovarian cancer. However, the efficacy and safety of different PARP inhibitor-based combinations in patients with homologous recombination repair (HRR) mutations have not been evaluated in ovarian cancer. In this sub-study of Korean Gynecologic Oncology Group (KGOG) 3045, we compared the efficacy and safety of two olaparib-based combinations and biomarkers of patients with platinum-resistant ovarian cancer with HRR gene mutations. Patients were randomized to receive either olaparib (200 mg twice a day) + cediranib (30 mg daily) (Arm 1, n = 16) or olaparib (300 mg) + durvalumab (1,500 mg once every 4 weeks) (Arm 2, n = 14). The objective response rates for Arm 1 and Arm 2 were 50.0% and 42.9%, respectively. Most patients (83.3%) had BRCA mutations, which were similarly distributed between arms. Grade 3 or 4 treatment-related adverse events were observed in 37.5% and 35.7% of the patients, respectively, but all were managed properly. A high vascular endothelial growth factor signature was associated with favorable outcomes in Arm 1, whereas immune markers (PD-L1 expression [CPS ≥10], CD8, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio) were associated with favorable outcomes in Arm 2. The activation of homologous recombination pathway upon disease progression was associated with poor response to subsequent therapy. Based on comprehensive biomarker profiling, including immunohistochemistry, whole-exome and RNA sequencing and whole blood-based analyses, we identified biomarkers that could help inform which of the two combination strategies is appropriate given a patient's biomarker status. Our findings have the potential to improve treatment outcome for patients with ovarian cancer in the PARP inhibitor era.

Comparison of outcomes of EUS-guided ablation and surveillance only for pancreatic cystic lesions: a propensity score-matching study (with videos).

BACKGROUND AND AIMS: EUS-guided ethanol ablation is a recently introduced treatment approach for pancreatic cystic lesions (PCLs), including branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs). However, the utility of this procedure is limited because of its relatively low efficacy in treating PCLs. METHODS: We retrospectively reviewed patients with PCLs, including those with enlarging suspected BD-IPMNs or those with PCLs measuring >3 cm, who were suboptimal candidates for surgery and had been managed using EUS-guided rapid ethanol lavage (EUS-REL; immediate ethanol lavage performed 4 times, 2015-2022) or surveillance only (SO; 2007- 2022). Propensity score matching (PSM) was performed to minimize bias. The primary outcome was the cumulative incidence rate of BD-IPMN progression. Secondary outcomes were the efficacy and safety of EUS-REL, surgical resection rate (SR), overall survival (OS), and disease-specific survival (DSS) in both groups. RESULTS: Overall, 169 and 610 patients were included in the EUS-REL and SO groups, respectively. PSM created 159 matched pairs. The radiologic complete resolution rate after EUS-REL was 74%. Procedure-related pancreatitis in the EUS-REL group was 13.0% (n = 22; 19 mild and 3 moderate grade); no severe adverse events were reported. The 10-year cumulative incidence rate of BD-IPMN progression was significantly lower in the EUS-REL group than in the SO group (1.6% vs 21.2%; hazard ratio, 12.35; P = .003). EUS-REL showed a lower tendency of SR compared with that associated with SO. The rates of 10-year OS and 10-year DSS were comparable in both groups. CONCLUSIONS: EUS-REL was associated with a significantly lower 10-year cumulative incidence rate of BD-IPMN progression and a lower tendency of SR, whereas its 10-year OS and DSS rates were similar to those of SO for PCLs. EUS-REL may be a viable alternative to SO for managing patients with enlarging suspected BD-IPMNs or those with PCLs >3 cm who are suboptimal candidates for surgery.

Protective Effects of Hemp (Cannabis sativa) Root Extracts against Insulin-Deficient Diabetes Mellitus In Mice.

The pharmacological potential of industrial hemp (Cannabis sativa) has been widely studied. However, the majority of studies have focused on cannabidiol, isolated from the inflorescence and leaf of the plant. In the present study, we evaluated the anti-diabetic potential of hemp root water (HWE) and ethanol extracts (HEE) in streptozotocin (STZ)-induced insulin-deficient diabetic mice. The administration of HWE and HEE ameliorated hyperglycemia and improved glucose homeostasis and islet function in STZ-treated mice (p < 0.05). HWE and HEE suppressed ß-cell apoptosis and cytokine-induced inflammatory signaling in the pancreas (p < 0.05). Moreover, HWE and HEE normalized insulin-signaling defects in skeletal muscles and apoptotic response in the liver and kidney induced by STZ (p < 0.05). Gas chromatography-mass spectrometry analysis of HWE and HEE showed possible active compounds which might be responsible for the observed anti-diabetic potential. These findings indicate the possible mechanisms by which hemp root extracts protect mice against insulin-deficient diabetes, and support the need for further studies geared towards the application of hemp root as a novel bioactive material.

Noncirrhotic Portal Hypertension after Trastuzumab Emtansine in HER2-positive Breast Cancer as Determined by Deep Learning-measured Spleen Volume at CT.

Background Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for use in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Case reports have suggested an association between T-DM1 and portal hypertension. Purpose To evaluate the association of T-DM1 therapy with spleen volume changes and portal hypertension on CT scans and clinical findings compared with lapatinib and capecitabine therapy. Materials and Methods Patients with HER2-positive breast cancer who were administered at least two cycles of T-DM1 or lapatinib and capecitabine (controls) in a tertiary institution from 2001 to 2020 and who underwent CT before initial treatment and at least once during treatment were retrospectively enrolled. Spleen volume changes and the signs of portal hypertension (gastroesophageal varix [GEV], spontaneous portosystemic shunt [SPSS], and ascites) were evaluated at contrast-enhanced CT. Patients were followed until treatment ended or for 2 years after the start of treatment. Spleen volume changes were measured with a deep learning algorithm and evaluated by using a linear mixed model. The incidences of splenomegaly and portal hypertension were compared between the T-DM1 and control groups by using a χ2 test or Fisher exact test. Results The T-DM1 group included 111 patients (mean age, 54 years ± 11 [SD]; 111 women) and the control group included 122 patients (mean age, 50 years ± 9; 121 women). Spleen volume progressively increased with T-DM1 therapy but was constant in the control group (104% ± 5 vs -1% ± 6 at the 33rd treatment cycle, respectively; P < .001). Incidences of splenomegaly (46% [51 of 111] vs 3% [four of 122] of patients; P < .001), GEV (11% [12 of 111] vs 1% [one of 122] of patients; P < .001), and SPSS (27% [30 of 111] vs 1% [one of 122] of patients; P < .001) were higher in the T-DM1 group than in the control group. Conclusion Trastuzumab emtansine therapy was associated with noncirrhotic portal hypertension at CT, with higher incidences of splenomegaly, gastroesophageal varix, and spontaneous portosystemic shunt than those with lapatinib and capecitabine therapy. © RSNA, 2022 Online supplemental material is available for this article.

Extrahepatic carcinogenicity of oral nucleos(t)ide analogues in chronic hepatitis B carriers: A 35,000-Korean outcome study.

Evidence on the carcinogenicity of oral nucleos(t)ide analogues (NAs) is inconclusive and lacks data on the effects by chemical structure of the NAs in patients with chronic hepatitis B (CHB). We aimed to provide definitive results on this issue using a large set of CHB patients and data on all major NA drugs. The study population consisted of 10,331 patients with CHB receiving primary NA treatment for more than 6 months, and 24,836 untreated controls followed for at least as long as the treated patients. Using the inverse-probability-of-treatment-weighted (IPTW) method, the cumulative incidence of extrahepatic cancers was compared in the treated and untreated patients and across the cyclopentane, L-nucleoside and acyclic phosphonate categories of NAs. Analyses of individual cancers as sub-endpoints were also performed. The cumulative incidence of overall extrahepatic malignancies did not differ between the two groups in the IPTW cohort (hazard ratio [HR] 1.002; 95% confidence interval [CI] [0.859-1.169]). Similar statistical trends were observed in analyses across the three NA chemical subsets and controls. Per-cancer analyses indicated that NA treatment was significantly associated with increased risks of colorectal/anal cancers (HRs [95% CI], 1.538 [1.175-2.013]) and lymphoma (1.784 [1.196-2.662]). Conversely, breast cancer (HRs [95% CI], 0.669 [0.462-0.967]) and prostate cancer (0.521 [0.329-0.825]) were less prevalent in the NA-treated group. In conclusion, prolonged NA treatment presents carcinogenic risks for colorectal/anal and lymphoid tissues in CHB patients, although it does not affect most extrahepatic organs. The protective effect of NAs on breast and prostate cancers should be confirmed.

Predictive Performance of Current Nodal Staging Systems in Various Categories of Pancreatic Cancer.

BACKGROUND: Nodal staging systems (NSS) for pancreatic ductal adenocarcinoma (PDAC) classify patients on the basis of number of metastatic lymph nodes (MLN), metastatic/retrieved lymph node ratio (LNR), and log odds of positive LN (LODDS). The relative prognostic performance of these NSS, however, remains unclear. PATIENTS AND METHODS: We identified 2584 patients who underwent surgery for PDAC between 2010 and 2019. Subgroups of each staging system were classified using K-adaptive partitioning method and assessed by comparing time-dependent areas under the curve (AUC) 5 years after surgery. RESULTS: Patients were subgrouped by MLN (0, 1-3, ≥ 4), LNR (0, 0-0.23, > 0.23), and LODDS (< - 3.5, - 3.5 to - 0.970, > - 0.97). All three NSS were independent prognostic factors for overall survival (OS) and recurrence-free survival (RFS). The AUCs for OS were comparable for the MLN (0.622), LNR (0.609), and LODDS (0.596) systems. Subgroup evaluation based on 12 retrieved lymph nodes (RLN), R1 resection, and extent of resection showed that the AUCs of the MLN and LNR NSS were comparable for OS and RFS regardless of the number of RLNs, R1 resection, and extent of resection. By contrast, the AUCs of the LODDS NSS were lower. CONCLUSION: The NSS based on the number of MLN is the best prognostic indicator, with prognostic performance comparable to the other NSS and greater convenience for practical use. This NSS was applicable regardless of the numbers of RLN, R1 resection, and extent of resection.

Measuring patient acuity and nursing care needs in South Korea: application of a new patient classification system.

BACKGROUND: An accurate and reliable patient classification system (PCS) can help inform decisions regarding adequate assignments for nurse staffing. This study aimed to evaluate the criterion validity of the Asan Patient Classification System (APCS), a new tertiary hospital-specific PCS, by comparing its rating and total scores with those of KPCS-1 and KPCS-GW for measuring patient activity and nursing needs. METHODS: We performed a retrospective analysis of the medical records of 50,314 inpatients admitted to the general wards of a tertiary teaching hospital in Seoul, South Korea in March, June, September, and December 2019. Spearman's correlation and Kappa statistics according to quartiles were calculated to examine the criterion validity of the APCS compared with the KPCS-1 and KPCS-GW. RESULTS: The average patient classification score was 28.3 points for APCS, 25.7 points for KPCS-1, and 21.6 points for KPCS-GW. The kappa value between APCS and KPCS-1 was 0.91 (95% CI:0.9072, 0.9119) and that between APCS and KPCS-GW was 0.88 (95% CI:0.8757, 0.8810). Additionally, Spearman's correlation coefficients among APCS, KPCS-1, and KPCS-GW showed a very strong correlation. However, 10.8% of the participants' results were inconsistent, and KPCS-1 tended to classify patients into groups with lower nursing needs compared to APCS. CONCLUSION: This study showed that electronic health record-generated APCS can provide useful information on patients' severity and nursing activities to measure workload estimation. Additional research is needed to develop and implement a real-world EHR-based PCS system to accommodate for direct and indirect nursing care while considering diverse population and dynamic healthcare system.

Dilation-Responsive Microshape Programing Prevents Vascular Graft Stenosis.

Shape memory materials have been successfully applied to minimally invasive implantation of medical devices. However, organ-movement-specific shape programing at a microscale level has never been demonstrated despite significant unmet needs. As vein-to-artery grafting induces vein dilation and stenosis, a polymeric self-enclosable external support (SES) is designed to wrap the vascular out-wall. Its micropores are programmed to increase sizes and interconnections upon dilation. Vessel dilation promotes venous maturation, but overdilation induces stenosis by disturbed blood flow. Therefore, the unique elastic shape-fixity of SES provides a foundation to enable a stable microscale shape transition by maintaining the vein dilation. The shape transition of micropore architecture upon dilation induces beneficial inflammation, thereby regenerating vasa vasorum and directing smooth muscle cell migration toward adventitia with the consequent muscle reinforcement of veins. This game-changer approach prevents the stenosis of vein-to-artery grafting by rescuing ischemic disorders and promoting arterial properties of veins.

Dual versus monotherapy with bronchodilators in GOLD group B COPD patients according to baseline FEV1 level: a patient-level pooled analysis of phase-3 randomized clinical trials.

BACKGROUND: Which patients should receive dual therapy as initial treatment for chronic obstructive pulmonary disease (COPD) is only loosely defined. We evaluated if a lower forced expiratory volume in 1 s (FEV1) identifies a population more likely to benefit from dual therapy than monotherapy among group B COPD patients in whom Global initiative for Chronic Obstructive Pulmonary Disease (GOLD) recommends monotherapy as initial treatment. METHODS: This was a patient-level pooled analysis of phase-3 randomized controlled trials involving dual bronchodilators. Study patients were classified into two groups based on the FEV1 of 50% of the predicted value (GOLD I/II versus GOLD III/IV). We evaluated the efficacy of dual versus monotherapy (long-acting beta-2 agonist [LABA] or long-acting muscarinic antagonist [LAMA]) between these two groups in the following outcomes: changes in trough FEV1, the St. George's Respiratory Questionnaire (SGRQ) score, the proportion of SGRQ responders, time to first exacerbation, and risk of adverse events. RESULTS: A total of 14,449 group B patients from 12 studies were divided into GOLD III/IV (n = 8043) or GOLD I/II group (n = 6406). In the GOLD III/IV group, dual therapy was significantly more effective in improving FEV1, reducing SGRQ scores, and achieving a higher proportion of SGRQ responders compared with either LABA or LAMA. Dual therapy also showed a significantly longer time to first exacerbation compared with LABA in the GOLD III/IV group. In contrast, in the GOLD I/II group, the benefits of dual therapy over monotherapy were less consistent. Although dual therapy resulted in significantly higher FEV1 than either LABA or LAMA, it did not show significant differences in the SGRQ score and proportion of SGRQ responders as compared with LABA. The time to first exacerbation was also not significantly different between dual therapy and either LABA or LAMA in the GOLD I/II group. CONCLUSIONS: Dual therapy demonstrated benefits over monotherapy more consistently in patients with lower FEV1 than those with higher FEV1.

An increase in inflammation and islet dysfunction is a feature of prediabetes.

AIMS: Type 2 diabetes (T2D) is a global health problem that will be diagnosed in almost 300 million people by 2025 according to the World Health Organization. Before being diagnosed with T2D, individuals may have glucose levels above normal but below the diabetic range. This condition is known as prediabetes. Studies showed that people with prediabetes had an increase in several pro-inflammatory cytokines in their serum and in their fasting glucose levels. The answer remains unclear when inflammation begins in the pancreas and islets, and what is the extent of this inflammation. METHODS: Subjects with haemoglobin A1c levels from 5.7% to 6.4% were classified as pre-diabetic. Sections of pancreas and isolated islets from normal donors and donors with prediabetes were tested for markers of inflammation and glucose-stimulated insulin secretion (GSIS). RESULTS: Gene and protein expression of the inflammatory markers resistin, interleukin-1 beta, tumour necrosis factor-alpha, interleukin-6, and monocyte chemoattractant protein-1 increased in donors with prediabetes compared to normal donors. GSIS response was significantly decreased in pre-diabetic islets compared to normal islets. Donors with prediabetes also had decreased expression of CD163+ cells but not CD68+ cells. CONCLUSIONS: Based on our findings, inflammation and islet dysfunction may be more significant than originally thought in people with prediabetes. Rather than being in a normal state before diabetes occurs, it appears that subjects are already in an early diabetic condition resembling more closely T2D.

Preoperative nutritional risk index and postoperative one-year skeletal muscle loss can predict the prognosis of patients with gastric adenocarcinoma: a registry-based study.

BACKGROUND: Patients with gastric cancer have an increased nutritional risk and experience a significant skeletal muscle loss after surgery. We aimed to determine whether muscle loss during the first postoperative year and preoperative nutritional status are indicators for predicting prognosis. METHODS: From a gastric cancer registry, a total of 958 patients who received curative gastrectomy followed by chemotherapy for stage 2 and 3 gastric cancer and survived longer than 1 year were investigated. Clinical and laboratory data were collected. Skeletal muscle index (SMI) was assessed based on the muscle area at the L3 level on abdominal computed tomography. RESULTS: Preoperative nutritional risk index (NRI) and postoperative decrement of SMI (dSMI) were significantly associated with overall survival (hazards ratio: 0.976 [95% CI: 0.962-0.991] and 1.060 [95% CI: 1.035-1.085], respectively) in a multivariate Cox regression analysis. Recurrence, tumor stage, comorbidity index were also significant prognostic indicators. Kaplan-Meier analyses exhibited that patients with higher NRI had a significantly longer survival than those with lower NRI (5-year overall survival: 75.8% vs. 63.0%, P <  0.001). In addition, a significantly better prognosis was observed in a patient group with less decrease of SMI (5-year overall survival: 75.7% vs. 66.2%, P = 0.009). A logistic regression analysis demonstrated that the performance of preoperative NRI and dSMI in mortality prediction was quite significant (AUC: 0.63, P <  0.001) and the combination of clinical factors enhanced the predictive accuracy to the AUC of 0.90 (P <  0.001). This prognostic relevance of NRI and dSMI was maintained in patients experiencing tumor recurrence and highlighted in those with stage 3 gastric adenocarcinoma. CONCLUSIONS: Preoperative NRI is a predictor of overall survival in stage 2 or 3 gastric cancer patients and skeletal muscle loss during the first postoperative year was significantly associated with the prognosis regardless of relapse in stage 3 tumors. These factors could be valuable adjuncts for accurate prediction of prognosis in gastric cancer patients.

Anti-Atherogenic Effect of Stem Cell Nanovesicles Targeting Disturbed Flow Sites.

Atherosclerosis development leads to irreversible cascades, highlighting the unmet need for improved methods of early diagnosis and prevention. Disturbed flow formation is one of the earliest atherogenic events, resulting in increased endothelial permeability and subsequent monocyte recruitment. Here, a mesenchymal stem cell (MSC)-derived nanovesicle (NV) that can target disturbed flow sites with the peptide GSPREYTSYMPH (PREY) (PMSC-NVs) is presented which is selected through phage display screening of a hundred million peptides. The PMSC-NVs are effectively produced from human MSCs (hMSCs) using plasmid DNA designed to functionalize the cell membrane with PREY. The potent anti-inflammatory and pro-endothelial recovery effects are confirmed, similar to those of hMSCs, employing mouse and porcine partial carotid artery ligation models as well as a microfluidic disturbed flow model with human carotid artery-derived endothelial cells. This nanoscale platform is expected to contribute to the development of new theragnostic strategies for preventing the progression of atherosclerosis.

Clinical outcomes of contemporary drug-eluting stents in patients with and without diabetes mellitus: Multigroup propensity-score analysis using data from stent-specific, multicenter, prospective registries.

BACKGROUND: Whether the diabetic status differentially affects the clinical outcomes with different drug-eluting stents (DES) has been controversial. METHODS AND RESULTS: From stent-specific, prospective DES registries, we evaluated 17,184 patients (11,428 in non-diabetics and 5,756 in diabetics) who received several contemporary DES: 3570 sirolimus-eluting stents (SES), 5,023 cobalt-chromium everolimus-eluting stents (CoCr-EES), 2,985 platinum-chromium EES (PtCr-EES), 2,913 Resolute zotarolimus-eluting stents (Re-ZES), and 2,693 biodegradable-polymer biolimus-eluting stents (BP-BES). The primary outcome was patient-oriented composite endpoint (POCE, a composite of all-cause death, any myocardial infarction, and any revascularization) at 3-year follow-up and target-vessel failure (a composite of cardiac death, target-vessel myocardial infarction, and target-vessel revascularization) at 3 years was also evaluated. In non-diabetics, the rates of POCE were not significantly different (CoCr-EES 14.3%, PtCr-EES 13.0%, Re-ZES 14.3%, BP-BES 13.4%, and SES 14.6%; overall p = .39). In diabetics, similar results were revealed (CoCr-EES 18.4%, PtCr-EES 20.3%, Re-ZES 17.3%, BP-BES 17.7%, and SES 17.8%; overall p = .44). In multiple treatment propensity-score weighting analysis, regardless of the diabetic status, the hazard ratios for POCE between-individual comparison were similar. Target-vessel failure (a composite of cardiac death, target-vessel myocardial infarction, and target-vessel revascularization) was also comparable except the higher ratio of Re-ZES than PtCr-EES (hazard ratio 1.25, 1.26, 95% confidence interval 1.00-1.55, p = .048) in patients without diabetes. CONCLUSIONS: In this clinical-practice registry study, regardless the diabetic status, the 3-year rates of the primary outcome were similar among different types of DES, suggesting no differential clinical response between contemporary DES in patients with or without diabetes.

3D Bioprinted Osteogenic Tissue Models for In Vitro Drug Screening.

Metabolic bone disease affects hundreds of millions of people worldwide, and as a result, in vitro models of bone tissue have become essential tools to help analyze bone pathogenesis, develop drug screening, and test potential therapeutic strategies. Drugs that either promote or impair bone formation are in high demand for the treatment of metabolic bone diseases. These drugs work by targeting numerous signaling pathways responsible for regulating osteogenesis such as Hedgehog, Wnt/ß-catenin, and PI3K-AKT. In this study, differentiated bone marrow-derived mesenchymal stem cell (BM-MSC) scaffold-free 3D bioprinted constructs and 2D monolayer cultures were utilized to screen four drugs predicted to either promote (Icariin and Purmorphamine) or impair osteogenesis (PD98059 and U0126). Osteogenic differentiation capacity was analyzed over a four week culture period by evaluating mineralization, alkaline phosphatase (ALP) activity, and osteogenesis related gene expression. Responses to drug treatment were observed in both 3D differentiated constructs and 2D monolayer cultures. After four weeks in culture, 3D differentiated constructs and 2D monolayer cultures treated with Icariin or Purmorphamine showed increased mineralization, ALP activity, and the gene expression of bone formation markers (BGLAP, SSP1, and COL1A1), signaling molecules (MAPK1, WNT1, and AKT1), and transcription factors (RUNX2 and GLI1) that regulate osteogenic differentiation relative to untreated. 3D differentiated constructs and 2D monolayer cultures treated with PD98059 or U0126 showed decreased mineralization, ALP activity, and the expression of the aforementioned genes BGLAP, SPP1, COL1A1, MAPK1, AKT1, RUNX2, and GLI1 relative to untreated. Differences in ALP activity and osteogenesis related gene expression relative to untreated cells cultured in a 2D monolayer were greater in 3D constructs compared to 2D monolayer cultures. These findings suggest that our bioprinted bone model system offers a more sensitive, biologically relevant drug screening platform than traditional 2D monolayer in vitro testing platforms.