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International Journal of Nanomedicine 2024To explore the effect of calcium peroxide nanoparticles (CaO NPs) combined with programmed cell death protein 1 (PD-1) inhibitors in the treatment of liver cancer and...
PURPOSE
To explore the effect of calcium peroxide nanoparticles (CaO NPs) combined with programmed cell death protein 1 (PD-1) inhibitors in the treatment of liver cancer and its related mechanism.
METHODS
Hepa1-6 cells were cultured to construct the Hepa1-6 mouse liver cancer model. In vivo mechanism study, a unilateral tumor model was established. Eighteen tumor-bearing mice were randomly divided into the control group (intra-tumoral injection of PBS solution) and the experimental group (intra-tumoral injection of CaO NPs). A hypoxic probe, pH probe, and micro-CT were used to evaluate the effect of CaO NPs on improving hypoxia, neutralizing acidity, and inducing calcium overload within the tumor. To study the effect of CaO NPs combined with PD-1 inhibitors on proximal and distal tumors, the bilateral tumor model was established. Forty tumor-bearing mice were randomly divided into the control group (intra-tumoral/intra-peritoneal injection of PBS solution), CaO NPs group (intra-tumoral injection of CaO NPs), PD-1 group (intra-peritoneal injection of PD-1 inhibitor), and the combination group (intra-tumoral injection of CaO NPs and intra-peritoneal injection of PD-1 inhibitors). The administered side was recorded as the proximal tumor. Tumor volume and body weight were measured every 2 days after treatment. On day 8, serum and tumor samples were collected. The immune factors in serum (Interferon-γ (IFN-γ), Tumour necrosis factor-α (TNF-α), Interleukin-2 (IL-2), and Interleukin-10 (IL-10)) and tumor tissue (IFN-γ and TNF-α) were detected by ELISA. H&E staining was used to detect tumor necrosis. Immunohistochemical staining was used to detect the amount of CD4 and CD8 T cells within the tumor. By analyzing the tumor volume, pathological indexes, and immune-related indexes, the effects of CaO NPs combined with PD-1 inhibitors on proximal and distal tumors were evaluated, and they mediated immunomodulatory effects (including local and systemic immunity), and their effects on tumor burden were studied. In addition, a unilateral tumor model was established to study the effect of CaO NPs combined with PD-1 inhibitors on survival time.
RESULTS
The results of in vivo mechanism study showed that CaO NPs can improve hypoxia, neutralize acidity, and induce calcium overload within tumors. The results of the study on the effect of CaO NPs combined with PD-1 inhibitor on proximal and distal tumors showed that, compared with the other three groups, the bilateral tumor burden of the combination group was significantly reduced, the intra-tumoral infiltration of CD8 and CD4 T cells were significantly increased, the secretion of anti-tumor immune factors in tumor and serum was increased, and the secretion of pro-tumor immune factors was decreased. Mice in the combination group showed the longest survival compared with the other groups.
CONCLUSION
CaO NPs can improve hypoxia, neutralize acidity, and induce calcium overload within tumors, so as to reduce tumor burden and realize an immunosuppressive tumor transformation to a hot tumor, and play a synergistic role with PD-1 inhibitors in anti-liver cancer.
Topics: Mice; Animals; Carcinoma, Hepatocellular; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Calcium; CD8-Positive T-Lymphocytes; Tumor Necrosis Factor-alpha; Liver Neoplasms; Mice, Inbred Strains; Disease Models, Animal; Hypoxia; Immunologic Factors
PubMed: 38196507
DOI: 10.2147/IJN.S440387 -
Romanian Journal of Morphology and... 2023Currently, worldwide, the coronavirus disease 2019 (COVID-19) pandemic, which first appeared in Wuhan, China, in December 2019, is capsizing the medical system and...
Currently, worldwide, the coronavirus disease 2019 (COVID-19) pandemic, which first appeared in Wuhan, China, in December 2019, is capsizing the medical system and turning the attention of the entire healthcare system through the many aspects it presents, both from a pathophysiological and from a semiological view, insufficiently studied aspects. With a high rate of morbidity and mortality, the COVID-19 pandemic was initially observed as a pathology leading to a severe acute respiratory syndrome, but over time gastrointestinal and hepatic manifestations have been reported. The study includes an analysis of 21 patients in the stage of the clinical disease of COVID-19 or in the stage of recovery, hospitalized in the Departments of General Surgery II or Gastroenterology, Emergency Clinical County Hospital of Craiova, Romania, with predominantly digestive symptoms, with the clinical expression of infectious enterocolitis, although stool culture was negative for pathogenic bacteria. The evolution of patients was influenced by the appearance of peritonitis through colonic necrosis or remission of clinical symptoms under empirical therapy.
Topics: Humans; Abdomen, Acute; Pandemics; COVID-19; Liver Failure; Diarrhea; Enterocolitis
PubMed: 38184833
DOI: 10.47162/RJME.64.4.09 -
Clinical Nephrology. Case Studies 2023We present two atypical cases of calciphylaxis presenting with ocular ischemic pathology - both without the hallmark cutaneous manifestations - to raise awareness of...
PURPOSE
We present two atypical cases of calciphylaxis presenting with ocular ischemic pathology - both without the hallmark cutaneous manifestations - to raise awareness of this rare yet highly disabling condition.
OBSERVATIONS
We report two cases of ophthalmic calciphylaxis presenting as (1) anterior ischemic optic neuropathy (AION) and cilioretinal artery occlusion in a 76-year-old woman with pre-dialysis kidney failure, and (2) AION with contralateral central retinal artery occlusion (CRAO) in a 44-year-old man on hemodialysis.
CONCLUSION AND IMPORTANCE
These cases highlight the need for judicious clinical suspicion of calciphylaxis in patients with kidney failure, presenting with microvascular ischemic ophthalmic pathology such as AION or CRAO. Confirmation with temporal artery biopsy is essential to direct targeted individualized multi-disciplinary treatment of calciphylaxis and avoid unnecessary steroid exposure in cases masquerading as giant cell arteritis (GCA).
PubMed: 38169875
DOI: 10.5414/CNCS111088 -
Clinical Profile and Treatment Outcomes of Patients with Malaria Complicated by Acute Kidney Injury.Saudi Journal of Kidney Diseases and... Mar 2023As Odisha is an endemic region for malaria with many acute kidney injury (AKI) cases, this study evaluated the clinical profile and treatment outcomes of patients with... (Observational Study)
Observational Study
As Odisha is an endemic region for malaria with many acute kidney injury (AKI) cases, this study evaluated the clinical profile and treatment outcomes of patients with malaria complicated by AKI. This prospective observational study was conducted between December 2015 and September 2017. Detailed histories and clinical examinations were recorded. On admission, tests for routine hematology, plasma glucose, liver function, renal function, serum electrolytes, thick smears, thin smears, and malarial parasites were performed. Of the 958 AKI malarial patients admitted, 202 (82.6 % males) were included in the study, with a mean age of 38.37 years. In total, 86.14%, 3.46%, and 10.39% of patients had Plasmodium falciparum, Plasmodium vivax, and mixed malaria, respectively. Headache and decreased urination (83.66% each) were the most common symptoms after fever (100%). Anuria and oliguria were reported in 5.95% and 67.82% of patients, respectively, whereas 26.23% reported a urine output of >400 mL/24 h. All patients had raised serum creatinine and urea levels, and >60% had anemia, proteinuria, and/or hyponatremia. Multiple organ dysfunction syndrome was observed in 62.87% of patients. Acute tubular necrosis was seen in 60% of renal biopsy specimens (n = 15). Of the 75.75% of patients requiring dialysis, 82.12% and 17.88% of patients required hemodialysis and peritoneal dialysis, respectively, during which 11 patients died. AKI, a serious complication of P. falciparum or P. vivax malaria, is a life-threatening condition. Fever, anemia, oligo/anuria, hepatic involvement, cerebral malaria, high serum creatinine and urea, and disseminated intravascular coagulation were the main predictors of mortality in our study.
Topics: Male; Humans; Adult; Female; Anuria; Creatinine; Malaria; Malaria, Falciparum; Malaria, Vivax; Acute Kidney Injury; Treatment Outcome; Anemia; Urea
PubMed: 38146720
DOI: 10.4103/1319-2442.391889 -
Pleura and Peritoneum Dec 2023
PubMed: 38144216
DOI: 10.1515/pp-2023-0021 -
Journal of Personalized Medicine Nov 2023Isolated limb perfusion (ILP) involves the local administration of high doses of anticancer drugs into a limb affected by unresectable locally advanced tumors (with...
Do Tumor SURVIVIN and MDM2 Expression Levels Correlate with Treatment Response and Clinical Outcome in Isolated Limb Perfusion for In-Transit Cutaneous Melanoma Metastases?
Isolated limb perfusion (ILP) involves the local administration of high doses of anticancer drugs into a limb affected by unresectable locally advanced tumors (with special regard to in-transit melanoma metastases), minimizing systemic side effects. Tumor response to anticancer drugs may depend on the expression of apoptosis-related genes, such as SURVIVIN and MDM2. This retrospective cohort study investigated the association between tumor SURVIVIN and MDM2 expression levels and treatment response or clinical outcomes in patients undergoing ILP for in-transit melanoma metastases. The study cohort consisted of 62 patients with in-transit metastases who underwent ILP with tumor necrosis factor (TNF) and melphalan. Tissue samples were taken from the in-transit metastases, and RNA was extracted for gene expression analysis. Patients' response to treatment was assessed using clinical and radiological criteria two months after ILP, and disease response was classified as complete, partial, or stable/progressive disease. Disease-free survival (DFS) and overall survival (OS) were also analyzed. Expression of SURVIVIN and/or MDM2 was observed in 48% of patients; in these cases, complete response to ILP occurred in 40% of cases, with the overall response rate (complete + partial) being 85%. Patients with expression of MDM2 alone had a lower complete response rate (28%), while patients with expression of SURVIVIN alone had a higher complete response rate (50%). The combined expression of MDM2 and SURVIVIN resulted in a complete response rate of 30%. Patients without expression (of SURVIVIN or MDM2) had the highest complete response rate (58%). Survival analysis showed that high MDM2 expression was independently associated with a lower probability of a complete response to ILP. In addition, patients with MDM2 expression were three times more likely to have an incomplete response to ILP. This study highlights the importance of considering SURVIVIN and MDM2 expression in patients undergoing ILP for in-transit cutaneous melanoma metastases. High MDM2 expression was found to be an independent factor associated with a reduced likelihood of achieving a complete response to ILP, suggesting potential mechanisms of chemoresistance. These data support further research to explore the role of already available targeted therapies (i.e., MDM2 inhibitors) in improving tumor response to ILP in patients with in-transit melanoma metastases.
PubMed: 38138884
DOI: 10.3390/jpm13121657 -
Antioxidants (Basel, Switzerland) Nov 2023Peritoneal dialysis (PD) is a current replacement therapy for end-stage kidney diseases (ESKDs). However, long-term exposure to PD fluids may lead to damage of the...
Peritoneal dialysis (PD) is a current replacement therapy for end-stage kidney diseases (ESKDs). However, long-term exposure to PD fluids may lead to damage of the peritoneal membrane (PM) through mechanisms involving the activation of the inflammatory response and mesothelial-to-mesenchymal transition (MMT), leading to filtration failure. Peritoneal damage depends on a complex interaction among external stimuli, intrinsic properties of the PM, and subsequent activities of the local innate-adaptive immune system. Epigenetic drugs targeting bromodomain and extra-terminal domain (BET) proteins have shown beneficial effects on different experimental preclinical diseases, mainly by inhibiting proliferative and inflammatory responses. However the effect of BET inhibition on peritoneal damage has not been studied. To this aim, we have evaluated the effects of treatment with the BET inhibitor JQ1 in a mouse model of peritoneal damage induced by chlorhexidine gluconate (CHX). We found that JQ1 ameliorated the CHX-induced PM thickness and inflammatory cell infiltration. Moreover, JQ1 decreased gene overexpression of proinflammatory and profibrotic markers, together with an inhibition of the nuclear factor-κB (NF-κB) pathway. Additionally, JQ1 blocked the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and restored changes in the mRNA expression levels of NADPH oxidases (NOX1 and NOX4) and NRF2/target antioxidant response genes. To corroborate the in vivo findings, we evaluated the effects of the BET inhibitor JQ1 on PD patients' effluent-derived primary mesothelial cells and on the MeT-5A cell line. JQ1 inhibited tumor necrosis factor-α (TNF-α)-induced proinflammatory gene upregulation and restored MMT phenotype changes, together with the downmodulation of oxidative stress. Taken together, these results suggest that BET inhibitors may be a potential therapeutic option to ameliorate peritoneal damage.
PubMed: 38136175
DOI: 10.3390/antiox12122055 -
Immunobiology Jan 2024The lipopolysaccharide, a microbial toxin, is one of the major causative agents of sepsis. P-gp expression and its functions are altered during inflammation. LPS has...
Vitexin along with verapamil downregulates efflux pump P-glycoprotein in macrophages and potentiate M1 to M2 switching via TLR4-NF-κB-TNFR2 pathway in lipopolysaccharide treated mice.
The lipopolysaccharide, a microbial toxin, is one of the major causative agents of sepsis. P-gp expression and its functions are altered during inflammation. LPS has been known to impair the functions of P-gp, an efflux transporter. But the effect of LPS on P-gp expression in murine peritoneal macrophages is poorly understood. Molecular docking studies reveal that vitexin is a potent substrate and verapamil a potent inhibitor of P-gp. In the present experimental study, the curative potential of vitexin as a fruit component and verapamil treated as a control inhibitor of P-gp was examined in a murine LPS sepsis model. The effects of vitexin and verapamil on P-gp expression in macrophages correlating with changes in macrophage polarization and associated functional responses during LPS induced sepsis were studied. Peritoneal macrophages of LPS (10 mg/kg body weight) challenged mice exhibited elevated levels of HO, superoxide, and NO in parallel with lower antioxidant activity. LPS treatment increased P-gp expression through increased TLR4/expression. However, LPS challenged mice treated with vitexin (5 mg/kg body weight) + verapamil (5 mg/kg body weight) showed higher anti-oxidant enzyme activity (SOD, CAT and GRx) resulting in reduced oxidative stress. This combination treatment also elevated TNFR2, concomitant with down-regulation of TLR4, NF-κB and P-gp expression in murine peritoneal macrophages, resulting in a switch from M1 to M2 polarisation of macrophages and reduced inflammatory responses. In conclusion, combined vitexin and verapamil treatment could be used as a promising therapy to regulate P-gp expression and protection against LPS mediated sepsis and inflammatory damages.
Topics: Mice; Animals; NF-kappa B; Lipopolysaccharides; Toll-Like Receptor 4; Receptors, Tumor Necrosis Factor, Type II; Verapamil; Hydrogen Peroxide; Molecular Docking Simulation; Macrophages; Glycoproteins; Sepsis; ATP Binding Cassette Transporter, Subfamily B; Body Weight; Apigenin
PubMed: 38103391
DOI: 10.1016/j.imbio.2023.152767 -
BMC Surgery Dec 2023It is difficult to definitively determine the degree of ischemia in the bowel in which an incarcerated groin hernia is embedded. Failure to diagnose and intervene...
BACKGROUND
It is difficult to definitively determine the degree of ischemia in the bowel in which an incarcerated groin hernia is embedded. Failure to diagnose and intervene promptly and accurately increases the rate of bowel resection and patient mortality. The aim of this study is to investigate the risk factors for incarcerated inguinal hernia complicating bowel necrosis with resection and to establish a predictive model as a reference for clinical work.
METHODS
Patients with incarcerated groin hernia who were admitted to our hospital were retrospectively analyzed. They were divided into bowel resection and non-bowel resection groups based on whether bowel resection was performed in the surgical record and postoperative pathological results. Risk factors for the development of bowel resection in incarcerated groin hernia were analyzed by univariate analysis and multivariate logistic regression, respectively. The screened independent risk factors were used to establish a prediction model, and finally, the predictive ability and accuracy of the model were validated and the clinical benefit was analyzed.
RESULTS
A total of 345 patients with incarcerated groin hernia were included, of whom 58 underwent bowel resection for bowel necrosis and 287 did not. Multifactorial logistic regression analysis identified bowel obstruction (OR, 7.285 [95% CI, 2.254-23.542], P = 0.001), peritonitis (OR, 16.786 [95% CI, 5.436-51.838], P = 0.000), duration of incarcerated groin hernia (OR, 1.009 [95% CI, 1. 001-1.018], P = 0.034), heart rate (OR, 1.109 [95% CI, 1.021-1.205], P = 0.014), and preoperative total protein (OR, 0.900 [95% CI, 0.836-0.969], P = 0.005) were independent risk factors for bowel resection in incarcerated groin hernia. The predictive value of the established prediction model was basically in agreement with the measured value with a consistency index of 0.938 (0.901-0.974) and had a good clinical benefit.
CONCLUSION
Clinical screening and management of independent risk factors for bowel resection in patients with incarcerated groin hernia should be strengthened. The predictive model developed in this study has high diagnostic efficacy for bowel resection associated with incarcerated inguinal hernia, with the aim of reducing the incidence of bowel resection and unplanned secondary surgery.
Topics: Adult; Humans; Hernia, Inguinal; Retrospective Studies; Groin; Intestines; Herniorrhaphy; Necrosis
PubMed: 38082259
DOI: 10.1186/s12893-023-02245-7 -
Journal of Clinical Medicine Nov 2023Cytoreductive surgery (CRS), combined with hyperthermic intraperitoneal chemotherapy, has significantly improved survival outcomes in patients with peritoneal...
Effect of Intraperitoneal Chemotherapy with Regorafenib on IL-6 and TNF-α Levels and Peritoneal Cytology: Experimental Study in Rats with Colorectal Peritoneal Carcinomatosis.
Cytoreductive surgery (CRS), combined with hyperthermic intraperitoneal chemotherapy, has significantly improved survival outcomes in patients with peritoneal carcinomatosis from colorectal cancer (CRC). Regorafenib is an oral agent administered in patients with refractory metastatic CRC. Our aim was to investigate the outcomes of intraperitoneal administration of regorafenib for intraperitoneal chemotherapy (IPEC) or/and CRS in a rat model of colorectal peritoneal metastases regarding immunology and peritoneal cytology. A total of 24 rats were included. Twenty-eight days after carcinogenesis induction, rats were randomized into following groups: group A: control group; group B: CRS only; group C: IPEC only; and group D: CRS + IPEC. On day 56 after carcinogenesis, euthanasia and laparotomy were performed. Serum levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) as well as peritoneal cytology were investigated. Groups B and D had statistically significant lower mean levels of IL-6 and TNF-α compared to groups A and C, but there was no significant difference between them. Both B and D groups presented a statistically significant difference regarding the rate of negative peritoneal cytology, when compared to the control group, but not to group C. In conclusion, regorafenib-based IPEC, combined with CRS, may constitute a promising tool against peritoneal carcinomatosis by altering the tumor microenvironment.
PubMed: 38068319
DOI: 10.3390/jcm12237267