Investigation the mechanism of iron overload-induced colonic inflammation following ferric citrate exposure.

Iron overload occurs due to excessive iron intake compared to the body's demand, leading to iron deposition and impairment of multiple organ functions. Our previous study demonstrated that chronic oral administration of ferric citrate (FC) caused colonic inflammatory injury. However, the precise mechanism underlying this inflammatory response remains unclear. The current study aims to investigate the mechanism by which iron overload induced by FC exposure leads to colonic inflammation. To accomplish this, mice were orally exposed to three different concentrations of FC (71 mg/kg/bw (L), 143 mg/kg/bw (M) and 286 mg/kg/bw (H)) for continuous 16 weeks, with the control group receiving ultrapure water (C). Exposure to FC caused disturbances in the excretory system, altered colonic flora alpha diversity, and enriched pathogenic bacteria, such as Mucispirillum, Helicobacter, Desulfovibrio, and Shigella. These changes led to structural disorders of the colonic flora and an inflammatory response phenotype characterized by inflammatory cells infiltration, atrophy of intestinal glands, and irregular thickening of the intestinal wall. Mechanistic studies revealed that FC-exposure activated the NF-κB signaling pathway by up-regulating TLR4, MyD88, and NF-κB mRNA levels and protein expression. This activation resulted in increased production of pro-inflammatory cytokines, further contributing to the colonic inflammation. Additionally, in vitro experiments in SW480 cells confirmed the activation of NF-κB signaling pathway by FC exposure, consistent with the in vivo findings. The significance of this study lies in its elucidation of the mechanism by which iron overload caused by FC exposure leads to colonic inflammation. By identifying the role of pathogenic bacteria and the NF-κB signaling pathway, this study could potentially offer a crucial theoretical foundation for the research on iron overload, as well as provide valuable insights for clinical iron supplementation.

Does previous transurethral resection of the prostate negatively influence subsequent robotic-assisted radical prostatectomy in men diagnosed with prostate cancer? A systematic review and meta-analysis.

It is not uncommon to incidentally discover prostate cancer during the transurethral resection of the prostate (TURP) for the treatment of benign prostatic hyperplasia and necessitate a subsequent robotic-assisted radical prostatectomy (RARP). The study aims to evaluate whether TURP have negative influence on subsequent RARP. Through a literature search using MEDLINE, EMBASE and the Cochrane Library, 10 studies with 683 patients who underwent RARP after previous TURP and 4039 patients who underwent RARP only were identified for the purposes of the meta-analysis. Compared to standard RARP, RARP after TURP was related to longer operative time (WMD: 29.1 min, 95% CI: 13.3-44.8, P < 0.001), more blood loss (WMD: 49.3 ml, 95% CI: 8.8-89.7, P = 0.02), longer time to catheter removal (WMD: 0.93 days, 95% CI: 0.41-1.44, P < 0.001), higher rates of overall (RR: 1.45, 95% CI: 1.08-1.95, P = 0.01) and major complications (RR: 3.67, 95% Cl: 1.63-8.24, P = 0.002), frequently demand for bladder neck reconstruction (RR: 5.46, 95% CI: 3.15-9.47, P < 0.001) and lower succeed in nerve sparing (RR: 0.73, 95% CI: 0.62-0.87, P < 0.001). In terms of quality of life, there are worse recovery of urinary continence (RR of incontinence rate: RR: 1.24, 95% CI: 1.02-1.52, P = 0.03) and potency (RR: 0.8, 95% CI: 0.73-0.89, P < 0.001) at 1 year in RARP with previous TURP. In addition, the RARP with previous TURP had greater percentage positive margins (RR: 1.24, 95% CI: 1.02-1.52, P = 0.03), while there is no difference in length of stay and biochemical recurrence rate at 1 year. RARP is feasible but challenging after TURP. It significantly increases the difficulty of operation and compromises surgical, functional and oncological outcomes. It is important for urologists and patients to be aware of the negative impact of TURP on subsequent RARP and establish treatment strategies to lessen the adverse effects.

Ferric citrate-induced colonic mucosal damage associated with oxidative stress, inflammation responses, apoptosis, and the changes of gut microbial composition.

Ferric citrate (FC) has been used as an iron fortifier and nutritional supplement, which is reported to induce colitis in rats, however the underlying mechanism remains to be elucidated. We performed a 16-week study of FC in male healthy C57BL/6 mice (nine-month-old) with oral administration of Ctr (0.9 % NaCl), 1.25 % FC (71 mg/kg/bw), 2.5 % FC (143 mg/kg/bw) and 5 % FC (286 mg/kg/bw). FC-exposure resulted in colon iron accumulation, histological alteration and reduce antioxidant enzyme activities, such as glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and total antioxidant capacity (T-AOC), together with enhanced lipid peroxidation level, including malondialdehyde (MDA) level and 4-Hydroxynonenal (4-HNE) protein expression. Exposure to FC was associated with upregulated levels of the interleukin (IL)- 6, IL-1ß, IL-18, IL-8 and tumor necrosis factor α (TNF-α), while down-regulated levels of IL-4 and IL-10. Exposure to FC was positively associated with the mRNA and protein expressions of cysteine-aspartic proteases (Caspase)- 9, Caspase-3, Bcl-2-associated X protein (Bax), while negatively associated with B-cell lymphoma 2 (Bcl2) in mitochondrial apoptosis signaling pathway. FC-exposure changed the diversity and composition of gut microbes. Additionally, the serum lipopolysaccharide (LPS) contents increased in FC-exposed groups when compared with the control group, while the expression of colonic tight junction proteins (TJPs), such as Claudin-1 and Occludin were decreased. These findings indicate that the colonic mucosal injury induced by FC-exposure are associated with oxidative stress generation, inflammation response and cell apoptosis, as well as the changes in gut microbes diversity and composition.

Polysaccharide from Salviae miltiorrhizae Radix et Rhizoma Attenuates the Progress of Obesity-Induced Non-Alcoholic Fatty Liver Disease through Modulating Intestinal Microbiota-Related Gut-Liver Axis.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide, thus treatments for it have attracted lots of interest. In this study, the Salviae miltiorrhizae Radix et Rhizoma (SMRR) polysaccharide was isolated by hot water extraction and ethanol precipitation, and then purified by DEAE anion exchange chromatography and gel filtration. With a high-fat-diet-induced obesity/NAFLD mouse model, we found that consumption of the SMRR polysaccharide could remarkably reverse obesity and its related progress of NAFLD, including attenuated hepatocellular steatosis, hepatic fibrosis and inflammation. In addition, we also reveal the potential mechanism behind these is that the SMRR polysaccharide could regulate the gut-liver axis by modulating the homeostasis of gut microbiota and thereby improving intestinal function.

TRIM67 Deficiency Exacerbates Hypothalamic Inflammation and Fat Accumulation in Obese Mice.

Obesity has achieved the appearance of a global epidemic and is a serious cause for concern. The hypothalamus, as the central regulator of energy homeostasis, plays a critical role in regulating food intake and energy expenditure. In this study, we show that TRIM67 in the hypothalamus was responsive to body-energy homeostasis whilst a deficiency of TRIM67 exacerbated metabolic disorders in high-fat-diet-induced obese mice. We found exacerbated neuroinflammation and apoptosis in the hypothalamus of obese TRIM67 KO mice. We also found reduced BDNF in the hypothalamus, which affected the fat sympathetic nervous system innervation and contributed to lipid accumulation in adipose tissue under high-fat-diet exposure. In this study, we reveal potential implications between TRIM67 and the hypothalamic function responding to energy overuptake as well as a consideration for the therapeutic diagnosis of obesity.

Traditional uses, phytochemistry, pharmacology, toxicity and quality control of medicinal genus Aralia: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Aralia, which belongs to Araliaceae family, is mainly distributed in Asia, such as China, Japan and South Korea. It has a long medicinal history and is widely used in the treatment of various diseases, such as hepatitis, rheumatoid arthritis, bruises, lumps and carbuncles. AIM OF THE STUDY: The purpose of this review is to systematically evaluate the traditional uses, phytochemistry, pharmacology, toxicity and quality control of main medicinal plants of Aralia, discusses the application of ethnic medicine, modern scientific research and the relationship between them, and put forward some suggestions to promote the further development and utilization of Aralia. MATERIALS AND METHODS: The relevant information on Aralia was collected through electronic databases (PubMed, Web of Science, Science Direct, Springer, CNKI and Wanfang), Chinese herbal classics, Ph.D. and M.Sc. dissertations, Chinese Pharmacopoeia. Plant names were verified by "The Plant List" (http://www.theplantlist.org). The literature cited in this review can be traced back to 1878 to 2021. RESULTS: More than 290 chemical constituents have been isolated from the genus Aralia, including triterpenoid saponins, terpenoids, organic acids, flavonoids, polyacetylenes, phenylpropanoids and other constituents. Pharmacological studies have shown that the extracts and compounds of Aralia have a wide range of pharmacological activities, including anti-inflammation, analgesic, anti-tumor, liver protection, protection of cardiovascular and nervous system, regulating substance metabolism, antibacterial, antiviral and antioxidation. CONCLUSIONS: The genus Aralia is not only an excellent traditional herbal medicine, but also a source of bioactive molecules with good application prospects. However, the structure-activity relationship, in vivo activity and action mechanism of its bioactive components need to be further studied. In addition, more toxicological and quality control studies are essential to evaluate the efficacy and safety of Aralia as medicine.

Expert consensus of Chinese Association for the Study of Pain on the application of ozone therapy in pain medicine.

This consensus was compiled by first-line clinical experts in the field of pain medicine and was organized by the Chinese Association for the Study of Pain. To reach this consensus, we consulted a wide range of opinions and conducted in-depth discussions on the mechanism, indications, contraindications, operational specifications and adverse reactions of ozone iatrotechnique in the treatment of pain disorders. We also referred to related previous preclinical and clinical studies published in recent years worldwide. The purpose of this consensus is to standardize the rational application of ozone iatrotechnique in pain treatment, to improve its efficacy and safety and to reduce and prevent adverse reactions and complications in this process.

Effects of Low-melting-point Fractions of Cocoa Butter on Rice Bran Wax-corn Oil Mixtures: Thermal, Crystallization and Rheological Properties.

The fatty acid compositions, polymorphism, solid fat content (SFC), thermal properties, microstructure and rheological properties of fat blends of rice bran wax and corn oil (RWC) with low-melting-point fractions of cocoa butter (LFCB) in the range of 20-50% were investigated. With the raising content of LFCB, the hardness, SFC, storage modulus (G') and loss modulus (G'') of blend samples increased. The unsaturated fatty acids of blend samples with different LFCB proportion were in the range of 60.42% to 71.25%. Two kinds of polymorphism were observed in blend samples, which were ß'-Form and ß-Form. During the crystallization process, the rice bran wax was first crystallized, and then induced a part of LFCB formed ß'-Form crystals and another LFCB formed the ß-Form crystals. The results show that the addition of LFCB could improve the plasticity of fat blends and reduce the difference in properties between them and commercial shortening.

Impact of microsatellite status on negative lymph node count and prognostic relevance after curative gastrectomy.

BACKGROUND AND OBJECTIVES: The impact of microsatellite instability-high (MSI-H) phenotype on lymph node yield after lymphadenectomy has never been discussed in gastric cancer (GC). In this study, we aimed to assess the association of microsatellite status with negative lymph node count (NLNC) as well as its prognostic value. METHODS: We retrospectively analyzed 1491 GC patients and divided them into two groups: MSI-HGC (n = 141 [9.5%]) and microsatellite stability (MSSGC ) (n = 1350 [90.5%]). The NLNC and survival data were compared between the two groups. The log odds of positive lymph nodes (LNs) to negative LNs and the target lymph node examined threshold (TLNT) were calculated in both groups. RESULTS: A statistically significant difference was found in median NLNC (26 vs. 23, p < .001) between MSI-HGC and MSSGC patients. MSI status was an independent factor for NLNC (p < .001). NLNC showed positive prognostic value for cases with metastatic lymph node (LN+ ) in both MSI-HGC and MSSGC groups. The TLNT(90%) for MSI-HGC and MSSGC were 33 and 26, respectively. CONCLUSIONS: MSI-HGC was associated with higher NLNC in GC patients and this was independent of the presence of LN+ . However, more LNs are needed during pathological examination to capture LN+ cases in MSI-HGC.

Paeoniflorin inhibits the macrophage-related rosacea-like inflammatory reaction through the suppressor of cytokine signaling 3-apoptosis signal-regulating kinase 1-p38 pathway.

ABSTRACT: Rosacea is a facial chronic inflammatory skin disease with immune and vascular system dysfunction. Paeoniflorin (PF) is a traditional Chinese medicine with anti-inflammatory properties. However, its effects on rosacea remain unknown. Here, we investigated the mechanisms through which PF inhibits the macrophage-related rosacea-like inflammatory response. Immunohistochemical methods were used to detect differences in the inflammatory response and degree of macrophage infiltration in granulomatous rosacea lesions and their peripheral areas. Cell Counting Kit-8 was used to determine the cytotoxicity of PF towards RAW 264.7 cells. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to measure the influence of PF on mRNA and protein expression levels of suppressor of cytokine signaling 3 (SOCS3), apoptosis signal-regulating kinase 1 (ASK1)-p38, Toll-like receptor 2, and cathelicidin antimicrobial peptide ( or LL37) in the lipopolysaccharide (LPS)-induced macrophage-related rosacea-like inflammatory response of RAW 264.7 cells. Inflammatory cell infiltration was more pronounced in granulomatous rosacea lesions than in peripheral areas. LL37 expression increased significantly, and the infiltration of a large number of CD68+ macrophages was observed in the lesions. PF promoted SOCS3 expression in RAW 264.7 cells and inhibited the LPS-induced increase in toll-like receptor 2 and LL37 expression through the ASK1-p38 cascade, thereby alleviating the macrophage-related rosacea-like inflammatory response. These changes could be abrogated by SOCS3 siRNA in vitro.In conclusion, the pathogenesis of rosacea involves abnormal macrophage infiltration within the lesions. PF inhibits the macrophage-related rosacea-like inflammatory response through the SOCS3-ASK1-p38 pathway, demonstrating its potential application as a novel drug for rosacea therapy.

Protective Effect of Vitamin E on Cadmium-Induced Renal Oxidative Damage and Apoptosis in Rats.

Cadmium (Cd), a widely distributed heavy metal, is extremely toxic to the kidney. Vitamin E (VE) is an important antioxidant in the body. It is known that VE exerts a protective effect on renal oxidative damage caused by Cd, but the effect and mechanism of VE on apoptosis are not fully understood. Thus, we conducted this study to explore the protective effect of VE on Cd-induced renal apoptosis and to elucidate its potential mechanism. Thirty-two 9-week-old male Sprague-Dawley rats were randomly divided into four groups, namely control, VE (100 mg/kg VE), Cd (5 mg/kg CdCl2), and VE + Cd (100 mg/kg VE + 5 mg/kg CdCl2), and received intragastric administration of Cd and/or VE for 4 weeks. The results showed that Cd exposure significantly reduced the weight of the body and kidney, elevated the accumulation of Cd in the kidney as well as the levels of BUN and Scr in serum, caused renal histological alterations, decreased the GSH and T-AOC contents and antioxidant enzyme (SOD, CAT, GSH-PX) activities, and increased renal MDA content. And the increased number of TUNEL-positive cells by Cd was accompanied by upregulated mRNA and protein expressions of apoptotic regulatory molecules (Bax, Caspase-3, GRP94, GRP78, Caspase-8) and downregulated Bcl-2 expressions. However, the combined treatment of Cd and VE could restore the above parameters to be close to those in the control rats. In conclusion, VE supplement could alleviate Cd-induced rat renal damage and oxidative stress through enhancing the antioxidant defense system and inhibiting apoptosis of renal cells.

The Effect of Cooling Rate on the Microstructure and Macroscopic Properties of Rice Bran Wax Oleogels.

The main purpose of this paper is to study the microstructure and macroscopic characteristics of rice bran wax (RBW) oleogels at a cooling rate of 1°C/min and 10°C/min by polarized light microscopy, X-ray diffraction, differential scanning calorimetry, texture analyzer, and micro rheometer. The oleogels of soybean oil were prepared by RBW in concentrations of 5%, 7.5%, 10%, 15% and 20% (wt/wt). The results of this study indicated that the concentration of RBW and cooling rates were affected by the crystal size and spatial distribution of these crystals. For the same RBW concentration, oleogels contained smaller crystals when cooled at 10°C/min compared to 1°C/min. And the oleogels obtained at a rate of 10°C/min exhibited a tighter crystal network, lower melting point, harder texture, and energy storage modulus. These results demonstrated the impact of cooling rate on the rheological behavior, nucleation, and crystallization process.

Iron Overload Resulting from the Chronic Oral Administration of Ferric Citrate Impairs Intestinal Immune and Barrier in Mice.

Ferric citrate (FC) is an iron-containing phosphate binder used as a food additive for iron supplementation. To explore the potential effect of ferric citrate on intestinal epithelial function, in the present study, we administered the mice orally for 16 weeks with different doses of iron citrate (2.5 mg/day (1.25%), 5 mg/day (2.5%), and 10 mg/day (5.0%)). We found that the iron levels of serum and tissue significantly increased, which caused the body to be in an iron overload state; meanwhile, the villus height, the ratio of villus height to crypt depth, and the number of intraepithelial lymphocytes and goblet cells in jejunum all decreased. Iron overload upregulated the pro-inflammatory cytokines (IL-1ß, IL-2, IL-6, TNF-ɑ), while downregulated the anti-inflammatory cytokines (IL-4, IL-10) and sIgA. Moreover, iron overload increased serum D-lactate (D-LA) levels and decreased tight junction proteins (claudin-1, occludin, and ZO-1), MUC-2, and TFF3. In addition, iron overload upregulated the content of MDA and protein carbonyl, while downregulated the activity and content of T-AOC, GSH-PX, SOD, CAT, and GSH. To sum up, the present results showed that long-term oral administration of FC resulted in iron overload, which consequently impaired intestinal immune and barrier function in mice. Meanwhile, the effect on intestinal damage may be highly related to the increase of oxidative stress in the jejunum.

Neoadjuvant FLOT versus SOX phase II randomized clinical trial for patients with locally advanced gastric cancer.

Neoadjuvant chemotherapy with docetaxel, oxaliplatin, fluorouracil, and leucovorin (FLOT regimen) has shown promising results in terms of pathological response and survival rate in patients with locally advanced resectable gastric cancer (LAGC). However, tegafur gimeracil oteracil potassium capsule (S-1) plus oxaliplatin (SOX regimen) is the preferred chemotherapy regimen in Eastern countries. Here, we conduct an open label, two-arm, phase II randomized interventional clinical trial (Dragon III; ClinicalTrials.gov: NCT03636893) to evaluate the safety and efficacy of both regimens. Patients with LAGC are randomly assigned to receive either 4 cycles of the neoadjuvant FLOT regimen (40 patients) or 3 cycles of the SOX regimen (34 patients) before gastrectomy. The primary endpoint is the comparison of complete (TRG1a) or subtotal (TRG1b) tumor regression grading in the primary tumor. There are no significant differences in adverse effects or postoperative morbidity and mortality between the two groups. No significant differences in the proportion of tumor regression grading between the FLOT group and the SOX group are found. Complete or subtotal TRG is 20.0% in the FLOT group versus 32.4% in the SOX group. Therefore, our study does not find statistically significant differences between neoadjuvant FLOT and SOX regimens for the primary outcomes reported here in locally advanced gastric cancer.

AMPK activation by ozone therapy inhibits tissue factor-triggered intestinal ischemia and ameliorates chemotherapeutic enteritis.

Chemotherapeutic enteritis is a major dose-limiting adverse reaction to chemotherapy, with few effective drugs in clinic. Intestinal ischemic injury plays prominent role in chemotherapeutic enteritis clinically. However, mechanism is not clear. In this article, irinotecan (CPT-11) was used to establish chemotherapeutic enteritis mice model. Western blotting, gelatin zymography, immunohistochemistry (IHC), Laser Doppler flowmetry (LDF) were used to detect the pathogenesis of ischemia-hypoxia injury. CPT-11 increased levels of tissue factor (TF) both in the blood and in intestines, and decreased the intestinal blood flow in mice. Interestingly, the elevation of TF in the blood displayed "double-peak," which was consistent with the intestinal mucosal "double-strike" injury trend. Intestinal microthrombus and mixed thrombus formation were detectable in chemotherapeutic enteritis. Furthermore, ozone therapy relieved chemotherapeutic enteritis in mice. Ozone inhibited TF expression induced by CPT-11 via activating AMPK/SOCS3, and effectively ameliorated the intestinal mucosal injury in mice. Moreover, ozone autotransfusion therapy effectively attenuated chemotherapeutic enteritis and the blood hypercoagulability in patients. For the first time, we proposed that TF-induced thrombotic intestinal ischemic injury is a core trigger pathological mechanism of chemotherapeutic enteritis, and provided a new treatment strategy, ozone therapy, to suppress TF expression and treat chemotherapeutic enteritis.

Soy isoflavones improve the oxidative stress induced hypothalamic inflammation and apoptosis in high fat diet-induced obese male mice through PGC1-alpha pathway.

Obesity is a common metabolic disorder that increases the risk of many diseases, such as type II diabetes, hypertension, cardiovascular disease. Hypothalamus plays a very important role in the progression of obesity, and many studies reveal that hypothalamic injures are implicated in obesity processes. Here, we describe that the consumption of soy isoflavones, with a structural similarity to that of estradiol, could mitigate obesity through improving the hypothalamic inflammation and apoptosis, which are induced by oxidative stress. Also, our in vitro studies demonstrate that daidzein and genistein, common ingredients of soy isoflavones, could protect hypothalamic N42 cells against palmitic acid induced oxidative stress and apoptosis. Moreover, the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC1-alpha), which plays a role in oxidative defense, is increased after soy isoflavone treatment in vivo and in vitro, suggesting an improved effect of soy isoflavones on hypothalamic antioxidant defense is mediated by PGC-1α. Our study reveals a potential mechanism of soy isoflavones regulating oxidative stress induced hypothalamic inflammation and cellular apoptosis, which will be important for obesity treatment.

Zeaxanthin in Soybean Oil: Impact of Oxidative Stability, Degradation Pattern, and Product Analysis.

In this study, the antioxidant capacity and oxidative stability of zeaxanthin with different concentrations in soybean oil were evaluated. The oxidative or isomerization products of zeaxanthin were monitored during oxidation for 12 h at 110 °C. It was found that the ability to scavenge the free radicals (DPPH, FRAP, and ABTS) was dependent upon the concentration of zeaxanthin. However, antioxidation of zeaxanthin was observed when the concentration was less than 50 µg/g. When the concentration exceeded 50 µg/g, zeaxanthin acted as a pro-oxidant. There were three kinds of non-volatile products of zeaxanthin that were detected: (a) Z-violaxanthin, (b) 9-Z-zeaxanthin, and (c) 13-Z-zeaxanthin, and it was found that the content of 13-Z-zeaxanthin formed by isomerization was the highest. In addition, the linear ketone (6-methyl-3,5-heptadien-2-one) and cyclic volatile products (3-hydroxy-ß-cyclocitral, 3-hydroxy-5,6-epoxy-7,8-dihydro-ß-ionone, and 3-hydroxy-ß-ionone) formed by in situ oxidative cleavage were identified.

Study protocol of a multicenter phase III randomized controlled trial investigating the efficiency of the combination of neoadjuvant chemotherapy (NAC) and neoadjuvant laparoscopic intraperitoneal hyperthermic chemotherapy (NLHIPEC) followed by R0 gastrectomy with intraoperative HIPEC for advanced gastric cancer (AGC): dragon II trial.

BACKGROUND: Even though treatment modalities such as adjuvant systemic radio-chemotherapy and neoadjuvant chemotherapy (NAC) have individually have improved overall survival (OS) and progression-free survival (PFS) rates in advanced Gastric Cancer (AGC), the peritoneum still presides as a common site of treatment failure and disease recurrence. The role of hyperthermic intraperitoneal chemotherapy (HIPEC) has been acknowledged as prophylaxis for peritoneal carcinomatosis (PC) in AGC patients and in this study, we aim at investigating the safety and efficacy of the combination of neoadjuvant laparoscopic HIPEC (NLHIPEC) with NAC in the neoadjuvant phase followed by surgery of curative intent with intraoperative HIPEC followed by adjuvant chemotherapy (AC). METHODS: In this multicenter Phase III randomized controlled trial, 326 patients will be randomly separated into 2 groups into a 1:1 ratio after laparoscopic exploration. The experiment arm will receive the proposed comprehensive Dragon II regimen while the control group will undergo standard R0 D2 followed by 8 cycles of AC with oxaliplatin with S-1 (SOX) regimen. The Dragon II regimen comprises of 1 cycle of NLHIPEC for 60mins at 43 ± 0.5 °C with 80 mg/m2 of Paclitaxel followed by 3 cycles of NAC with SOX regimen and after assessment, standard R0 D2 gastrectomy with intraoperative HIPEC followed by 5 cycles of SOX regimen chemotherapy. The end-points for the study are 5 year PFS, 5 year OS, peritoneal metastasis rate (PMR) and morbidity rate. DISCUSSION: This study is one of the first to combine NLHIPEC with NAC in the preoperative phase which is speculated to provide local management of occult peritoneal carcinomatosis or peritoneal free cancer cells while NAC will promote tumor downsizing and down-staging. The addition of the intraoperative HIPEC is speculated to manage dissemination due to surgical trauma. Where the roles of intraoperative HIPEC and NAC have individually been investigated, this study provides innovative insight on a more comprehensive approach to management of AGC at high risk of peritoneal recurrence. It is expected that the combination of NLHIPEC with NAC and HIPEC will increase PFS by 15% and decrease PMR after gastrectomy of curative intent. TRIAL REGISTRATION: World Health Organization Clinical Trials - International Registry Platform (WHO-ICTRP) with Registration ID ChiCTR1900024552, Registered Prospectively on the 16th July, 2019.

Cluster of Vacuolated Spinous Keratinocytes: A Clue to Cornoid Lamellation and a Case of Porokeratosis Disseminata.

Cornoid lamella is a definitive diagnostic feature of porokeratosis, a disorder of keratinization that has various different clinical presentations. A tiered column of parakeratosis and a diminished granular layer with dyskeratotic keratinocytes at the column base are all useful and known features of cornoid lamellation. We have found a cluster of vacuolated spinous cells to be a reliable fourth feature of cornoid lamellation and a feature when present alone to be a reliable sign of impending cornoid lamellation on deeper sections. Furthermore, we present a novel clinical phenotype of disseminated papular porokeratosis with effective clinical response to combination of phototherapy, oral and topical retinoids, and topical vitamin D derivative, which too contained all 4 features of cornoid lamellation.

Iron overload resulting from the chronic oral administration of ferric citrate induces parkinsonism phenotypes in middle-aged mice.

Iron homeostasis is critical for maintaining normal brain physiological functions, and its mis-regulation can cause neurotoxicity and play a part in the development of many neurodegenerative disorders. The high incidence of iron deficiency makes iron supplementation a trend, and ferric citrate is a commonly used iron supplement. In this study, we found that the chronic oral administration of ferric citrate (2.5 mg/day and 10 mg/day) for 16 weeks selectively induced iron accumulation in the corpus striatum (CPu), substantia nigra (SN) and hippocampus, which typically caused parkinsonism phenotypes in middle-aged mice. Histopathological analysis showed that apoptosis- and oxidative stress-mediated neurodegeneration and dopaminergic neuronal loss occurred in the brain, and behavioral tests showed that defects in the locomotor and cognitive functions of these mice developed. Our research provides a new perspective for ferric citrate as a food additive or in clinical applications and suggests a new potential approach to develop animal models for Parkinson's disease (PD).