H-Dot Mediated Nanotherapeutics Mitigate Systemic Toxicity of Platinum-Based Anticancer Drugs.

Platinum-based anticancer agents have revolutionized oncological treatments globally. However, their therapeutic efficacy is often accompanied by systemic toxicity. Carboplatin, recognized for its relatively lower toxicity profile than cisplatin, still presents off-target toxicities, including dose-dependent cardiotoxicity, neurotoxicity, and myelosuppression. In this study, we demonstrate a delivery strategy of carboplatin to mitigate its off-target toxicity by leveraging the potential of zwitterionic nanocarrier, H-dot. The designed carboplatin/H-dot complex (Car/H-dot) exhibits rapid drug release kinetics and notable accumulation in proximity to tumor sites, indicative of amplified tumor targeting precision. Intriguingly, the Car/H-dot shows remarkable efficacy in eliminating tumors across insulinoma animal models. Encouragingly, concerns linked to carboplatin-induced cardiotoxicity are effectively alleviated by adopting the Car/H-dot nanotherapeutic approach. This pioneering investigation not only underscores the viability of H-dot as an organic nanocarrier for platinum drugs but also emphasizes its pivotal role in ameliorating associated toxicities. Thus, this study heralds a promising advancement in refining the therapeutic landscape of platinum-based chemotherapy.

Inflammation alters iron distribution in bone and spleen in mice.

Anemia of inflammation (or inflammation-associated anemia) decreases the quality of life in billions of patients suffering from various inflammatory diseases, such as infection, autoimmune diseases, and cancer, associated with a prolonged state of immune activation. While proper utilization of iron, a nutrient metal essential for erythropoiesis, is important for the prevention of anemia, the alteration of body iron homeostasis upon inflammation, which can contribute to the development of anemia, is not completely understood. Thus, we sought to examine temporal and spatial changes in the distribution of iron and iron-associated molecules during inflammation in mice. To induce inflammation, C57BL/6J mice were injected with turpentine oil weekly for 3 weeks, which resulted in anemia, decreased protein expression of ferroportin, a cellular iron exporter, in the spleen, duodenum, and liver, and increased iron stores in the duodenum and spleen. Tracer kinetic studies after oral administration of 59Fe revealed that more iron was found in the spleen and less in the femur bone in turpentine oil-injected mice compared to the saline-injected mice, indicating tissue-specific abnormalities in iron distribution during inflammation. However, there was no difference in the utilization of iron for red blood cell production after turpentine oil injection; instead, serum hemopexin level and lactate dehydrogenase activity were increased, suggesting increased red blood cell destruction upon inflammation. Our findings provide an improved understanding of temporal and spatial changes in the distribution and utilization of iron during inflammation.

Application of Allometric Scaling to Nanochelator Pharmacokinetics.

Deferoxamine (DFO) is an effective FDA-approved iron chelator; however, its use is considerably limited by off-target toxicities and an extremely cumbersome dose regimen involving daily infusions. The recent development of a deferoxamine-based nanochelator (DFO-NP) with selective renal excretion has shown promise in ameliorating iron overload and associated physiological complications in rodent models with a substantially improved safety profile. While the dose- and administration route-dependent pharmacokinetics (PK) of DFO-NPs have been recently characterized, the optimized PK model was not validated, and the prior studies did not directly address the clinical translatability of DFO-NPs into humans. In the present work, these gaps were addressed by applying allometric scaling of DFO-NP PK in rats to predict those in mice and humans. First, this approach predicted serum concentration-time profiles of DFO-NPs, which were similar to those experimentally measured in mice, validating the nonlinear disposition and absorption models for DFO-NPs across the species. Subsequently, we explored the utility of allometric scaling by predicting the PK profile of DFO-NPs in humans under clinically relevant dosing schemes. These in silico efforts demonstrated that the novel nanochelator is expected to improve the PK of DFO when compared to standard infusion regimens of native DFO. Moreover, reasonable formulation strategies were identified and discussed for both early clinical development and more sophisticated formulation development.

Early adaptive responses in the skeletal muscle of young mice with hereditary hemochromatosis.

BACKGROUND: Hereditary hemochromatosis (HH) is characterized by iron overload that can cause multiple organ dysfunction primarily due to uncontrolled iron-mediated oxidative stress. Although HH leads to muscular weakness, disorder, and fatigue, the mechanism by which HH affects skeletal muscle physiology is largely unknown. METHODS: Using Hfe knockout mice (6-7 months old), a well-defined mouse model of HH, we examined iron status in the skeletal muscle, as well as other organs. As mitochondria are key organelle for muscular function, this study also explored how molecular markers for mitochondrial function and related systems are regulated in the HH skeletal muscle using western blots. RESULTS: Although iron overload was evident at the systemic level, only mild iron overload was observed in the skeletal muscle of HH. Of note, mitochondrial electron transport chain complex I was upregulated in the HH skeletal muscle, which was accompanied by enhanced autophagy. However, these molecular changes were not associated with oxidative stress, suggesting altered mitochondrial metabolism in the muscle in response to iron overload. CONCLUSIONS: These early adaptive responses may be important for supporting mitochondrial health before fully developing skeletal muscle dysfunction in HH. More studies are needed to determine the role of autophagy in the HH-related muscle mitochondrial dysfunction.

Mechanism-Based Pharmacokinetic Modeling of Absorption and Disposition of a Deferoxamine-Based Nanochelator in Rats.

Deferoxamine (DFO) is an effective FDA-approved iron chelator. However, its use is considerably limited by off-target toxicities and an extremely cumbersome dose regimen with daily infusions. The recent development of a deferoxamine-based nanochelator (DFO-NP) with selective renal excretion has shown promise in ameliorating animal models of iron overload with a substantially improved safety profile. To further the preclinical development of this promising nanochelator and to inform on the feasibility of clinical development, it is necessary to fully characterize the dose and administration-route-dependent pharmacokinetics and to develop predictive pharmacokinetic (PK) models describing absorption and disposition. Herein, we have evaluated the absorption, distribution, and elimination of DFO-NPs after intravenous and subcutaneous (SC) injection at therapeutically relevant doses in Sprague Dawley rats. We also characterized compartment-based model structures and identified model-based parameters to quantitatively describe the PK of DFO-NPs. Our modeling efforts confirmed that disposition could be described using a three-compartment mamillary model with elimination and saturable reabsorption both occurring from the third compartment. We also determined that absorption was nonlinear and best described by parallel saturable and first-order processes. Finally, we characterized a novel pathway for saturable SC absorption of an ultrasmall organic nanoparticle directly into the systemic circulation, which offers a novel strategy for improving drug exposure for nanotherapeutics.

Comparative Analysis of Various Weight Loss Success Criteria Models After Bariatric Metabolic Surgery in Korean Morbid Obese Patients.

Purpose: To identify weight loss prediction models by validating previous models using weight loss success criteria. Materials and Methods: Patients with morbid obesity from 4 hospitals were retrospectively analyzed between Jan 2019 and 2022. Preoperative demographics, postoperative data, and 1-year follow-up weight loss outcomes were compared between 2 groups who underwent laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB). Additionally, the predictive factors for the success of excess weight loss (EWL) (>50%) and total weight loss (TWL) (>25%) were analyzed. Results: Of the 162 patients, 137 were enrolled during the study period, 75 underwent LSG, and 62 underwent LRYGB. The >50% EWL and >25% TWL 1 year after surgery were 61.3% and 43.1%, respectively. Diabetes mellitus medication use was reduced in 94.8% of patients with type 2 diabetes mellitus. Male sex and body mass index (BMI) were independent risk factors for successful weight loss (SWL) or >50% EWL (odds ratio [OR] for BMI 0.830, 95% confidence interval [CI] 0.764-0.902), whereas achieving >25% TWL was not affected by sex or BMI (OR for BMI 1.010, 95% CI 0.957-1.065). External validation of the prediction models showed an acceptable range of accuracy (adjusted R2 66.5-71.3%). Conclusion: LSG and LRYGB are feasible and effective bariatric procedures for SWL in Korean patients with morbid obesity. The TWL model was a more appropriate criterion than EWL, and weight loss prediction models may help assess the 1-year outcomes of bariatric surgery.

Biliopancreatic Limb Length as a Potential Key Factor in Superior Glycemic Outcomes After Roux-en-Y Gastric Bypass in Patients With Type 2 Diabetes: A Meta-Analysis.

BACKGROUND: Optimal length of biliopancreatic (BP) and Roux limb in Roux-en-Y gastric bypass (RYGB) for improved glycemic control are not known. PURPOSE: To investigate how the lengths of the BP and Roux limbs in RYGB differentially affect postoperative glycemic outcomes in patients with type 2 diabetes. DATA SOURCES: We conducted a systematic literature search using the PubMed, Embase, and the Cochrane Library databases. STUDY SELECTION: We included studies that reported glycemic outcomes after RYGB and lengths of the BP and Roux limbs. DATA EXTRACTION: A total of 28 articles were included for data extraction. Glycemic outcomes after RYGB were assessed on the basis of two definitions: remission and improvement. DATA SYNTHESIS: We categorized the included studies into four groups according to the BP and Roux limb lengths. The type 2 diabetes remission/improvement rates were as follows: long BP-long Roux group 0.80 (95% CI 0.70-0.90)/0.81 (0.73-0.89), long BP-short Roux group 0.76 (0.66-0.87)/0.82 (0.75-0.89), short BP-long Roux group 0.57 (0.36-0.78)/0.64 (0.53-0.75), and short BP-short Roux group 0.62 (0.43-0.80)/0.53 (0.45-0.61). Meta-regression analysis also showed that a longer BP limb resulted in higher postoperative type 2 diabetes remission and improvement rates, whereas a longer Roux limb did not. There was no significant difference or heterogeneity in baseline characteristics, including diabetes-related variables, among the four groups. LIMITATIONS: Not all included studies were randomized controlled trials. CONCLUSIONS: Longer BP limb length led to higher rates of type 2 diabetes remission and improvement by 1 year after RYGB in comparisons with the longer Roux limb length.

Circulating hemopexin modulates anthracycline cardiac toxicity in patients and in mice.

Anthracyclines such as doxorubicin (Dox) are effective chemotherapies, but their use is limited by cardiac toxicity. We hypothesized that plasma proteomics in women with breast cancer could identify new mechanisms of anthracycline cardiac toxicity. We measured changes in 1317 proteins in anthracycline-treated patients (n = 30) and replicated key findings in a second cohort (n = 31). An increase in the heme-binding protein hemopexin (Hpx) 3 months after anthracycline initiation was associated with cardiac toxicity by echocardiography. To assess the functional role of Hpx, we administered Hpx to wild-type (WT) mice treated with Dox and observed improved cardiac function. Conversely, Hpx-/- mice demonstrated increased Dox cardiac toxicity compared to WT mice. Initial mechanistic studies indicate that Hpx is likely transported to the heart by circulating monocytes/macrophages and that Hpx may mitigate Dox-induced ferroptosis to confer cardioprotection. Together, these observations suggest that Hpx induction represents a compensatory response during Dox treatment.

Pharmacokinetics and tissue distribution of deferoxamine-based nanochelator in rats.

Aim: To characterize the pharmacokinetics of deferoxamine-conjugated nanoparticles (DFO-NPs), a novel nanochelator for removing excess iron. Materials & methods: The pharmacokinetics of DFO-NPs were evaluated in Sprague-Dawley rats at three doses (3.3, 10 and 30 µmol/kg) after intravenous and subcutaneous administration. Results: DFO-NPs exhibited a biphasic concentration-time profile after intravenous administration with a short terminal half-life (2.0-3.2 h), dose-dependent clearance (0.111-0.179 l/h/kg), minimal tissue distribution and exclusive renal excretion with a possible saturable reabsorption mechanism. DFO-NPs after subcutaneous administration exhibited absorption-rate-limited kinetics with a prolonged half-life (5.7-10.1 h) and favorable bioavailability (47-107%). Conclusion: DFO-NPs exhibit nonlinear pharmacokinetics with increasing dose, and subcutaneous administration substantially improves drug exposure, thereby making it a clinically viable administration route for iron chelation.

Iron is an essential metal nutrient, but excess iron produces toxic effects that damage multiple organs including the heart, liver and pancreas. Deferoxamine (DFO) is a US FDA-approved drug for treating iron overload, but its use is limited by serious adverse effects and an inconvenient daily dose scheme. The recent development of a DFO-based nanomedicine (DFO-NP) has shown promise in treating iron overload in animals and was safer in animals. Before this new drug can be given to humans, how it is absorbed into the body, processed in the body and removed from the body when given in different amounts and dose routes must be determined. In this study, we tested the absorption, distribution and removal of DFO-NPs after intravenous and subcutaneous injection in rats. This study showed that DFO-NPs behave differently when changing the dose and that subcutaneous injection makes the drug stay in the body longer without ill effect, which means it could be given to patients this way.

A small molecule redistributes iron in ferroportin-deficient mice and patient-derived primary macrophages.

Deficiencies of the transmembrane iron-transporting protein ferroportin (FPN1) cause the iron misdistribution that underlies ferroportin disease, anemia of inflammation, and several other human diseases and conditions. A small molecule natural product, hinokitiol, was recently shown to serve as a surrogate transmembrane iron transporter that can restore hemoglobinization in zebrafish deficient in other iron transporting proteins and can increase gut iron absorption in FPN1-deficient flatiron mice. However, whether hinokitiol can restore normal iron physiology in FPN1-deficient animals or primary cells from patients and the mechanisms underlying such targeted activities remain unknown. Here, we show that hinokitiol redistributes iron from the liver to red blood cells in flatiron mice, thereby increasing hemoglobin and hematocrit. Mechanistic studies confirm that hinokitiol functions as a surrogate transmembrane iron transporter to release iron trapped within liver macrophages, that hinokitiol-Fe complexes transfer iron to transferrin, and that the resulting transferrin-Fe complexes drive red blood cell maturation in a transferrin-receptor-dependent manner. We also show in FPN1-deficient primary macrophages derived from patients with ferroportin disease that hinokitiol moves labile iron from inside to outside cells and decreases intracellular ferritin levels. The mobilization of nonlabile iron is accompanied by reductions in intracellular ferritin, consistent with the activation of regulated ferritin proteolysis. These findings collectively provide foundational support for the translation of small molecule iron transporters into therapies for human diseases caused by iron misdistribution.

Can We Reboot the Role of Intraperitoneal Chemotherapy in the Treatment for Gastric Cancer with Peritoneal Carcinomatosis?: A Retrospective Cohort Study Regarding Minimally Invasive Surgery Conjoined with Intraperitoneal plus Systemic Chemotherapy.

Background: Peritoneal carcinomatosis (PC) is the most common form of metastasis in gastric cancer (GC) and is related with a poor prognosis. Several treatment modalities including systemic chemotherapy and intraperitoneal chemotherapy have been studied and adopted in treatment of GC patients with PC. Nevertheless, few studies have reported the comparison of the oncologic outcomes between minimally invasive surgery (MIS) with intraperitoneal (IP) chemotherapy and conventional chemotherapy for GC with PC. Methods: We retrospectively reviewed the clinical records of 74 patients who had been diagnosed as GC with PC via either intra-abdominal exploration or abdominopelvic computed tomography between January 2011 and April 2021. After performing propensity score-matching for this retrospective data, we compared the outcomes of 26 patients who underwent MIS followed by IP combined systemic chemotherapy (MIS-IP group) and 26 patients who underwent systemic chemotherapy only (SC-only group). Results: The 2-year progression free survival rate of the MIS-IP group was significantly higher than the SC-only groups (36.4% and 10.5%, respectively; p = 0.010). In multivariate analysis to detect relevant factors on PFS, IP chemotherapy (HR 0.213; p < 0.001), Eastern Cooperative Oncology Group performance status (HR 3.689; p = 0.002), and the amount of ascites (p = 0.011) were significant prognostic factors. Conclusions: This study demonstrated the therapeutic potential of MIS conjoined IP plus systemic chemotherapy for GC patients with PC. MIS conjoined by IP plus systemic chemotherapy can be adopted as a treatment option to reboot the role of IP chemotherapy in GC patients with PC.

Iron Promotes Cardiac Doxorubicin Retention and Toxicity Through Downregulation of the Mitochondrial Exporter ABCB8.

In several cancers, the efflux and resistance against doxorubicin (DOX), an effective anticancer drug, are associated with cellular iron deficiency and overexpression of the mitochondrial exporter ABCB8. Conversely, decreased ABCB8 expression and disrupted iron homeostasis in the heart have been implicated in DOX-associated cardiotoxicity. While studies have demonstrated that altered iron status can modulate the susceptibility to DOX cardiotoxicity, the exact molecular mechanisms have not been clearly understood. Here, we hypothesized that iron stores influence cardiac ABCB8 expression and consequently cardiac retention and toxicity of DOX. First, we found that ABCB8 deficiency in cardiomyocytes decreased DOX efflux, increased DOX-induced toxicity, and decreased cell viability. Conversely, intracellular DOX retention and toxicity were ameliorated by ABCB8 overexpression. To determine if altered cardiac iron status modifies ABCB8 expression, we treated cardiomyocytes with high iron or iron chelators. Western blot and qPCR analyses revealed that ABCB8 levels were decreased in iron overload and increased in iron deficiency. Subsequently, DOX retention and toxicity were increased in cardiomyocytes with iron overload, whereas iron deficiency ameliorated these effects. Next, we validated our results using a mouse model of hereditary hemochromatosis (HH), a genetic iron overload disorder. HH mice exhibited decreased ABCB8 expression and increased DOX retention and toxicity. These changes were abolished by the treatment of HH mice with a low-iron diet. Finally, cardiac-specific overexpression of ABCB8 in HH mice prevented cardiac DOX accumulation and abrogated DOX-induced cardiotoxicity without altering iron overload in the heart. Together, our results demonstrate that ABCB8 mediates DOX efflux and that iron regulates DOX retention and toxicity by altering cardiac ABCB8 expression. Our study identifies a novel role of iron in DOX-induced cardiotoxicity and suggests potential therapeutic intervention for DOX and anthracycline-based cancer pharmacology.

Long-Term Survival Outcomes of Elderly Patients Treated With S-1 or Capecitabine Plus Oxaliplatin for Stage II or III Gastric Cancer: A Multicenter Cohort Study.

Purpose: Tegafur/gimeracil/oteracil (S-1) and capecitabine plus oxaliplatin (CAPOX) are standard adjuvant chemotherapies (ACs) administered after gastrectomy to patients with stage II or III gastric cancer. However, the efficacy of AC in elderly patients remains unclear. The objective of this retrospective multicenter cohort study was to compare the efficacies of S-1 and CAPOX AC in patients aged ≥70 years. Materials and Methods: Nine hundred eighty-three patients who were treated with AC using S-1 (768 patients) or CAPOX (215 patients) were enrolled in this study. Each patient underwent AC after curative gastrectomy for stage II or III gastric cancer at one of 27 hospitals in the Republic of Korea between January 2012 and December 2013. Relapse-free survival (RFS) and overall survival (OS) were analyzed according to AC regimen and age group. Results: Of the 983 patients, 254 (25.8%) were elderly. This group had a similar RFS (P=0.099) but significantly poorer OS (p=0.003) compared with the non-elderly group. Subgroup analysis of the non-elderly group revealed no AC-associated differences in survival. Subgroup analysis of the elderly group revealed significantly better survival in the S-1 group than in the CAPOX group (RFS, P<0.001; OS, P<0.001). Multivariate analysis revealed that the CAPOX regimen was an independent poor prognostic factor for RFS (hazard ratio [HR], 1.891; 95% confidence interval [CI], 1.072-3.333; P=0.028) and OS (HR, 2.970; 95% CI, 1.550-5.692; P=0.001). Conclusions: This multicenter observational cohort study found significant differences in RFS and OS between S-1 and CAPOX AC among patients with gastric cancer aged ≥70 years.

Reversal of genetic brain iron accumulation by N,N'-bis(2-mercaptoethyl)isophthalamide, a lipophilic metal chelator, in mice.

N,N'-bis(2-mercaptoethyl)isophthalamide (NBMI) is a novel lipophilic metal chelator and antioxidant used in mercury poisoning. Recent studies have suggested that NBMI may also bind to other metals such as lead and iron. Since NBMI can enter the brain, we evaluated if NBMI removes excess iron from the iron-loaded brain and ameliorates iron-induced oxidative stress. First, NBMI exhibited preferential binding to ferrous (Fe2+) iron with a negligible binding affinity to ferric (Fe3+) iron, indicating a selective chelation of labile iron. Second, NBMI protected SH-SY5Y human neuroblastoma cells from the cytotoxic effects of high iron. NBMI also decreased cellular labile iron and lessened the production of iron-induced reactive oxygen species in these cells. Deferiprone (DFP), a commonly used oral iron chelator, failed to prevent iron-induced cytotoxicity or labile iron accumulation. Next, we validated the efficacy of NBMI in Hfe H67D mutant mice, a mouse model of brain iron accumulation (BIA). Oral gavage of NBMI for 6 weeks decreased iron accumulation in the brain as well as liver, whereas DFP showed iron chelation only in the liver, but not in the brain. Notably, depletion of brain copper and anemia were observed in BIA mice treated with DFP, but not with NBMI, suggesting a superior safety profile of NBMI over DFP for long-term use. Collectively, our study demonstrates that NBMI provides a neuroprotective effect against BIA and has therapeutic potential for neurodegenerative diseases associated with BIA.

Injectable Thermosensitive Hydrogels for a Sustained Release of Iron Nanochelators.

Deferoxamine (DFO) is an FDA-approved iron-chelating agent which shows good therapeutic efficacy, however, its short blood half-life presents challenges such as the need for repeated injections or continuous infusions. Considering the lifelong need of chelating agents for iron overload patients, a sustained-release formulation that can reduce the number of chelator administrations is essential. Here, injectable hydrogel formulations prepared by integrating crosslinked hyaluronic acid into Pluronic F127 for an extended release of DFO nanochelators are reported. The subcutaneously injected hydrogel shows a thermosensitive sol-gel transition at physiological body temperature and provides a prolonged release of renal clearable nanochelators over 2 weeks, resulting in a half-life 47-fold longer than that of the nanochelator alone. In addition, no chronic toxicity of the nanochelator-loaded hydrogel is confirmed by biochemical and histological analyses. This injectable hydrogel formulation with DFO nanochelators has the potential to be a promising formulation for the treatment of iron overload disorders.

Impact of the Deep Neuromuscular Block on Oncologic Quality of Laparoscopic Surgery in Obese Gastric Cancer Patients: A Randomized Clinical Trial.

BACKGROUND: Obesity can hinder laparoscopic procedures and impede oncological safety during laparoscopic cancer surgery. Deep neuromuscular block (NMB) reportedly improves laparoscopic surgical conditions, but its oncological benefits are unclear. We aimed to evaluate whether deep NMB improves the oncologic quality of laparoscopic cancer surgery in obese patients. STUDY DESIGN: We conducted a double-blinded, parallel-group, randomized, phase 3 trial at 9 institutions in Korea. Clinical stage I and II gastric cancer patients with a BMI at or above 25 kg m -2 were eligible and randomized 1:1 ratio to the deep or moderate NMB groups, with continuous infusion of rocuronium (0.5-1.0 and 0.1-0.5 mg kg -1 h -1, respectively). The primary endpoint was the number of retrieved lymph nodes (LNs). The secondary endpoints included the surgeon's surgical rating score (SRS) and interrupted events. RESULTS: Between August 2017 and July 2020, 196 patients were enrolled. Fifteen patients were excluded, and 181 patients were finally included in the study. There was no significant difference in the number of retrieved LNs between the deep (N = 88) and moderate NMB groups (N = 93; 44.6 ± 17.5 vs 41.5 ± 16.9, p = 0.239). However, deep NMB enabled retrieving more LNs in patients with a BMI at or above 28 kg/m2 than moderate NMB (49.2 ± 18.6 vs 39.2 ± 13.3, p = 0.026). Interrupted events during surgery were lower in the deep NMB group than in the moderate NMB group (21.6% vs 36.6%; p = 0.034). The SRS was not influenced by NMB depth. CONCLUSION: Deep NMB provides potential oncologic benefits by retrieving more LNs in patients with BMI at or above 28 kg/m2 during laparoscopic gastrectomy.

Survival impact of compliance in extra-perigastric lymphadenectomy for gastric cancer: 20 years of real-world data from a single institution.

BACKGROUND: Compliance in lymphadenectomy was first introduced as part of quality control in a Dutch clinical trial. Although a few studies have investigated compliance, no studies have evaluated the survival impact at individual lymph node stations. METHODS: In total, 2,932 patients who underwent radical gastrectomy between 1996 and 2014 at the Korea University Guro Hospital in Seoul, South Korea were retrospectively reviewed. We compared survival outcomes among the compliance, noncompliance, and metastatic groups. RESULTS: The highest compliance among extra-perigastric stations was recorded for #8a (86.6%), followed by #7 (76.6%) and #9 (68.3%). Stations #11 and #12 showed low compliance rates of 28.9% and 31.0%, respectively. Compliance at #7, #8a, and #9 was related to better 5-year relapse-free survival rates (74.5%, 72.8%, and 71.3%, respectively) than noncompliance (61.9% [hazard ratio, 1.72; 95% confidence interval, 1.40-2.11], 61.0% [hazard ratio, 1.6; 95% confidence interval 1.26-2.04], 65.3% [hazard ratio, 1.25; 95% confidence interval 1.04-1.51], respectively). At #11 and #12, there were no significant differences in relapse-free survival between compliance (69.1% and 70.2%, respectively) and noncompliance (67.4% [hazard ratio, 0.85; 95% confidence interval 0.53-1.36], 65.1% [hazard ratio, 1.13; 95% confidence interval 0.71-1.81], respectively). In multivariable analysis, stations #7 and #8 alone showed an increased hazard ratio of relapse-free survival in the noncompliance group relative to the compliance group. CONCLUSION: We showed a survival benefit of compliance during lymphadenectomy for gastric cancer. Although further prospective trials to validate our results are warranted, compliance could be adopted in real-world practice to achieve better survival among patients with gastric cancer.

Comparative risk of anemia and related micronutrient deficiencies after Roux-en-Y gastric bypass and sleeve gastrectomy in patients with obesity: An updated meta-analysis of randomized controlled trials.

Although Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are the most prevalent bariatric surgical procedures, high-level evidence is scarce regarding the assessment of postoperative nutritional risk in RYGB versus SG. Therefore, we performed a systematic review and meta-analysis to compare the risk of anemia and related micronutrient deficiencies after RYGB and SG. We analyzed 10 randomized controlled trials that compared RYGB and SG with reported incidence of postoperative anemia and/or anemia-related micronutrient deficiencies (iron, vitamin B12 , or folate). There were no significant differences in the risk of postoperative anemia (moderate level of evidence), iron deficiency (high level of evidence), or folate deficiency (moderate level of evidence). Patients undergoing RYGB had a higher risk of postoperative vitamin B12 deficiency than those undergoing SG (relative risk, 1.86; 95% confidence interval, 1.15-3.02; p = 0.012; high level of evidence). Our findings imply that patients undergoing RYGB require more stringent vitamin B12 supplementation and surveillance than those undergoing SG. Additionally, our results may aid patients with high concern for anemia and related micronutrient deficiencies in making informed decisions regarding surgical methods based on nutritional risk.

Mitochondrial iron metabolism and neurodegenerative diseases.

Iron is a key element for mitochondrial function and homeostasis, which is also crucial for maintaining the neuronal system, but too much iron promotes oxidative stress. A large body of evidence has indicated that abnormal iron accumulation in the brain is associated with various neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, Parkinson's disease, and Friedreich's ataxia. However, it is still unclear how irregular iron status contributes to the development of neuronal disorders. Hence, the current review provides an update on the causal effects of iron overload in the development and progression of neurodegenerative diseases and discusses important roles of mitochondrial iron homeostasis in these disease conditions. Furthermore, this review discusses potential therapeutic targets for the treatments of iron overload-linked neurodegenerative diseases.

Subacute oral toxicity and bacterial mutagenicity of a mixture of Puerariae radix and Hizikia fusiforme extracts.

The study aims to identify the safety profile of a mixed extract (KGC-02-PS) from two traditional medicinal herbs, Puerariae radix and Hizikia fusiforme. In a subacute oral toxicity study, KGC-02-PS was administered orally for 28 days by gavage to Sprague Dawley rats (both sexes) at a daily dose of 0, 500, 1000, and 2000 mg/kg body weight. Bodyweight, food consumption, and clinical signs were monitored during the experimental period. After administering the final dose, this study conducted hematology, serum biochemistry, and pathological evaluations. In addition, the study performed a bacterial reverse mutation test with varying concentrations of KGC-02-PS (312.5 µg - 5,000 µg/plate) following OECD guideline No. 471, before testing five bacterial strains (Salmonella typhimurium TA98, TA100, TA1535, TA1537, and Escherichia coli WP2) in the presence or absence of metabolic activation. The preclinical evaluation of KGC-02-PS's subacute oral toxicity yielded no associated toxicological effects or any changes in clinical signs, body weight, and food consumption. Moreover, examining KGC-02-PS's hematological and serum biochemical characteristics and pathology yielded no toxicological changes in terms of organ weight measurements and gross or histopathological findings. KGC-02-PS neither increased the number of revertant colonies in all bacterial strains used in the bacterial reverse mutation test, nor did it induce genotoxicity related to bacterial reverse mutations under the study's conditions. Also, KGC-02-PS's no-observed-adverse-effect level was greater than 2000 mg/kg.