Potential antitumour effect of all-trans retinoic acid on regorafenib-treated human colon cancer cell lines.

Introduction: Colorectal cancer (CRC) is a significant contributor to cancer-related mortality worldwide, ranking as the second leading cause of such deaths. Central to the progression of this malignancy is angiogenesis - a complex process orchestrated by vascular endothelial growth factor (VEGF). Regorafenib, a potent multikinase inhibitor, acts as a critical antagonist of multiple kinases involved in angiogenesis, proliferation, and metastasis. Conversely, all-trans retinoic acid (ATRA) has demonstrated compelling antitumour effects across various cancer types. This study aims to comprehensively evaluate the combined antitumour potential of ATRA and regorafenib in human colon cancer cell lines while elucidating the intricate molecular mechanisms that underlie their action. Material and methods: Our investigative approach involved an enzyme-linked immunosorbent assay to meticulously analyse the levels of key players in the VEGF signalling pathway, including VEGF itself, activated protein kinase (AMPK), extracellular signal-regulated protein kinase 1 (ERK1), and nuclear factor kappa B (NF-κB). Additionally, we assessed caspase-3 activity as a fundamental marker of apoptosis. Results: The combined use of ATRA and regorafenib exhibited a remarkable augmentation in both AMPK and caspase-3 activities. This was accompanied by a significant reduction in VEGF, ERK1, and NF-κB levels within human colon cancer cell lines subjected to regorafenib treatment. Conclusions: Our findings underscore the remarkable antiproliferative, antiangiogenic, and proapoptotic effects resulting from the combined use of ATRA and regorafenib in the context of CRC. This modulation of tumourigenic processes is predominantly mediated through the VEGF signalling axis.

Electronic Cigarette-Related Injuries Presenting to Five Large Burn Centers, 2015-2019.

Electronic cigarettes are advertised as safer alternatives to traditional cigarettes yet cause serious injury. U.S. burn centers have witnessed a rise in both inpatient and outpatient visits to treat thermal injuries related to their use. A multicenter retrospective chart review of American Burn Association burn registry data from five large burn centers was performed from January 2015 to July 2019 to identify patients with electronic cigarette-related injuries. A total of 127 patients were identified. Most sustained less than 10% total body surface area burns (mean 3.8%). Sixty-six percent sustained second-degree burns. Most patients (78%) were injured while using their device. Eighteen percent of patients reported spontaneous device combustion. Two patients were injured while changing their device battery, and two were injured modifying their device. Three percent were injured by secondhand mechanism. Burn injury was the most common injury pattern (100%), followed by blast injury (3.93%). Flame burns were the most common (70%) type of thermal injury; however, most patients sustained a combination-type injury secondary to multiple burn mechanisms. The most injured body region was the extremities. Silver sulfadiazine was the most common agent used in the initial management of thermal injuries. Sixty-three percent of patients did not require surgery. Of the 36% requiring surgery, 43.4% required skin grafting. Multiple surgeries were uncommon. Our data recognize electronic cigarette use as a public health problem with the potential to cause thermal injury and secondary trauma. Most patients are treated on an inpatient basis although most patients treated on an outpatient basis have good outcomes.

Association study of apoptosis gene polymorphisms in mitochondrial diabetes: A potential role in the pathogenicity of MD.

Mitochondrial diabetes (MD) is a heterogeneous disorder characterized by a chronic hyperglycemia and is maternally transmitted. Syndromic MD is a subgroup of MD including diabetic microangiopathy and macroangiopathy, in addition to extrapancreatic disorder. MD is caused by genetic mutations and deletions affecting mitochondrial DNA. This mitochondrial damage initiates apoptosis. In this study, we hypothesized that functional polymorphisms in genes involved in apoptotic pathway could be associated with the development of apoptosis in MD disease and increased its risk. Detection of apoptosis was confirmed on muscle biopsies taken from MD patients using the TUNEL method and the Cytochrome c protein expression level. We genotyped then 11 published SNPs from intrinsic and extrinsic apoptotic pathway and assessed the signification of these polymorphisms in 43 MD patients and 100 healthy controls. We found 10 selected polymorphisms (p53 (rs1042522 and rs17878362), BCL2 (rs2279115), BAX (rs1805419), BAK1 (rs210132 and rs2227925), CASP3 (rs1405937), CASP7 (rs2227310), CASP8 (rs1045485) and CASP10 (rs13006529)) with a potential apoptosis effect in MD patients compared to control population. Specifically, SNPs involved in the intrinsic pathway (p53, BCL2, BAK1 and CASP3) presented the highest risk of apoptosis. Our result proved that apoptosis initiated by mtDNA mutations, can be emphasized by a functional apoptotic polymorphisms associated with high expression of cytochrome c protein and more myofibers with apoptosis in syndromic MD subgroup compared with non-syndromic MD subgroup.

In a canine pneumonia model of exchange transfusion, altering the age but not the volume of older red blood cells markedly alters outcome.

BACKGROUND: Massive exchange transfusion of 42-day-old red blood cells (RBCs) in a canine model of Staphylococcus aureus pneumonia resulted in in vivo hemolysis with increases in cell-free hemoglobin (CFH), transferrin-bound iron (TBI), non-transferrin-bound iron (NTBI), and mortality. We have previously shown that washing 42-day-old RBCs before transfusion significantly decreased NTBI levels and mortality, but washing 7-day-old RBCs increased mortality and CFH levels. We now report the results of altering volume, washing, and age of RBCs. STUDY DESIGN AND METHODS: Two-year-old purpose-bred infected beagles were transfused with increasing volumes (5-10, 20-40, or 60-80 mL/kg) of either 42- or 7-day-old RBCs (n = 36) or 80 mL/kg of either unwashed or washed RBCs with increasing storage age (14, 21, 28, or 35 days; n = 40). RESULTS: All volumes transfused (5-80 mL/kg) of 42-day-old RBCs resulted in alike (i.e., not significantly different) increases in TBI during transfusion as well as in CFH, lung injury, and mortality rates after transfusion. Transfusion of 80 mL/kg RBCs stored for 14, 21, 28, and 35 days resulted in increased CFH and NTBI in between levels found at 7 and 42 days of storage. However, washing RBCs of intermediate ages (14-35 days) does not alter NTBI and CFH levels or mortality rates. CONCLUSIONS: Preclinical data suggest that any volume of 42-day-old blood potentially increases risks during established infection. In contrast, even massive volumes of 7-day-old blood result in minimal CFH and NTBI levels and risks. In contrast to the extremes of storage, washing blood stored for intermediate ages does not alter risks of transfusion or NTBI and CFH clearance.

Raxibacumab augments hemodynamic support and improves outcomes during shock with B. anthracis edema toxin alone or together with lethal toxin in canines.

BACKGROUND: Lethal and edema toxin contribute to shock and lethality with Bacillus anthracis. We showed previously in a 96-h sedated canine model that raxibacumab, a monoclonal antibody against protective antigen, augmented hemodynamic support (HS) and improved survival with lethal toxin challenge. Here we study raxibacumab further. Using this model, we have now studied raxibacumab with 24 h edema toxin challenges (Study 1), and lethal and edema toxin challenges together (Study 2). METHODS: Using our canine model, we have now studied raxibacumab with 24h edema toxin challenges (Study-1), and lethal and edema toxin challenges together (Study-2). RESULTS: In Study 1, compared to no treatment, HS (titrated fluid and norepinephrine) increased mean arterial blood pressure (MAP, p ≤ 0.05) but not survival [0 of 10 (0/10) animals survived in each group] or median survival time [43.8 h (range 16.8 to 80.3) vs. 45.2 h (21.0 to 57.1)]. Compared to HS, HS with raxibacumab treatment at or 6 h after the beginning of edema toxin increased MAP and survival rate (6/7 and 7/8, respectively) and time [96.0 h (39.5 to 96.0) and 96.0 h (89.5 to 96.0), respectively]; (p ≤ 0.05). HS with raxibacumab at 12 h increased MAP (p ≤ 0.05) but not survival [1/5; 55.3 h (12.6 to 96.0)]. In Study-2, survival rate and time increased with HS and raxibacumab at 0 h (4/4) or 6 h after (3/3) beginning lethal and edema toxin compared to HS [0/5; 71.5 h (65 to 93)] (p = 0.01 averaged over raxibacumab groups). CONCLUSIONS: Raxibacumab augments HS and improves survival during shock with lethal and edema toxin.

Acetabular component thickness does not affect mid-term clinical results in hip resurfacing.

BACKGROUND: The benefits of using thin acetabular components for hip resurfacing have been shown in terms of bone conservation, but there currently are little data available in the literature addressing the mid-term clinical results of these devices. QUESTIONS/PURPOSES: We aimed to determine whether thinner acetabular components altered mid-term postoperative clinical scores, complication rates, survivorship, radiographic appearance, and metal ion levels. METHODS: Two hundred eighty-one patients with unilateral disease received a 5-mm thick acetabular shell and 223 received a 3.5-mm shell. The femoral component implanted in both groups was identical. We compared clinical scores, complication rates, survivorship, radiographic results, and ion levels between these two groups. RESULTS: UCLA hip scores were similar (pain, p = 0.0976; walking, p = 0.9571; function, p = 0.9316; activity, p = 0.2085). Complications were higher in the 5-mm group (6.4% versus 1.8%, p = 0.0431). Both groups were similar regarding survivorship (p = 0.3181), cup radiolucency at 5 years (p = 0.107), and metal ion levels (cobalt p = 0.404, chromium p = 0.250). CONCLUSIONS: With comparable mid-term clinical results, there is no tangible reason to abstain from using the 3.5-mm acetabular component. LEVEL OF EVIDENCE: Level III, retrospective comparative study. See the Guidelines for Authors for a complete description of levels of evidence.

Long-term outcome of a metal-on-polyethylene cementless hip resurfacing.

Due to the well-documented problems surrounding metal-on-metal bearings, the use of hip resurfacing has declined. Since the potential benefits of hip resurfacing remain desirable, it may be beneficial to investigate the long-term outcome of hip resurfacings using metal-on-polyethylene in the 1980's. We report the long-term survivorship and modes of failure of a cementless metal-on-polyethylene resurfacing (n = 178) with different porous ingrowth surfaces. While acetabular loosening was absent, a high incidence of femoral failures (femoral loosening = 18.1%, osteolytic neck fracture = 21%) occurred despite using the same ingrowth surface for both components. Ongoing developments using the lessons learned from these previous generation components and utilizing modern low wear materials, e.g., cross-linked polyethylene, may lead to improved implants for future hip resurfacings.

Bacillus anthracis cell wall peptidoglycan but not lethal or edema toxins produces changes consistent with disseminated intravascular coagulation in a rat model.

BACKGROUND: Disseminated intravascular coagulation (DIC) appears to be important in the pathogenesis of Bacillus anthracis infection, but its causes are unclear. Although lethal toxin (LT) and edema toxin (ET) could contribute, B. anthracis cell wall peptidoglycan (PGN), not the toxins, stimulates inflammatory responses associated with DIC. METHODS AND RESULTS: To better understand the pathogenesis of DIC during anthrax, we compared the effects of 24-hour infusions of PGN, LT, ET, or diluent (control) on coagulation measures 6, 24, or 48 hours after infusion initiation in 135 rats. No control recipient died. Lethality rates (approximately 30%) did not differ among PGN, LT, and ET recipients (P = .78). Thirty-three of 35 deaths (94%) occurred between 6 and 24 hours after the start of challenge. Among challenge components, PGN most consistently altered coagulation measures. Compared with control at 6 hours, PGN decreased platelet and fibrinogen levels and increased prothrombin and activated partial thromboplastin times and tissue factor, tissue factor pathway inhibitor, protein C, plasminogen activator inhibitor (PAI), and thrombin-antithrombin complex levels, whereas LT and ET only decreased the fibrinogen level or increased the PAI level (P ≤ .05). Nearly all effects associated with PGN infusion significantly differed from changes associated with toxin infusion (P ≤ .05 for all comparisons except for PAI level). CONCLUSION: DIC during B. anthracis infection may be related more to components such as PGN than to LT or ET.

Metal ion levels in total hip arthroplasty versus hip resurfacing.

Recent studies suggest that the tapered interface between stem and femoral head may be a substantial source of cobalt and chromium ion release after metal-on-metal (MOM) total hip arthroplasty (THA). This study compared patient ion levels after MOM hip resurfacing (HR) and MOM THA performed with identical acetabular components. 110 HRs were compared with 22 THAs. All had well-oriented components, unilateral implants, and serum ion studies beyond one year post-operatively. The HR group's median cobalt value was 1.11 µg/L vs. 2.86 µg/L for the THA patients. The HR group's median chromium value was 1.49 µg/L vs. 2.94 µg/L for THA. Significantly higher THA ion levels suggest a source of ions other than the MOM bearing itself.

Lack of association of VDR gene polymorphisms with thyroid autoimmune disorders: familial and case/control studies.

We study the association between three Vitamin D receptor gene polymorphisms (rs10735810, rs1544410, rs731236) and susceptibility to thyroid autoimmune diseases. Seventy-six affected subjects, belonging to a large family, as well as one hundred unrelated Tunisian patients and one hundred healthy Tunisian controls were genotyped. A family-based association test and a standard chi-square test were used to assess association in family and case-control data, respectively. Our results showed no significant association of the Vitamin D receptor gene polymorphisms with the susceptibility to thyroid autoimmune diseases in the family. Moreover, allele frequencies for the three polymorphisms in the Tunisian population were similar to those reported in the Tunisian control population and none was associated with the disease. These results suggest a lack of association between the Vitamin D receptor gene polymorphisms and susceptibility to thyroid autoimmune diseases in Tunisian population, in agreement with data from the UK, but in conflict with studies from the Far East.