Promising Therapy For Prevention Research Articles

Effect of Chlorhexidine Gluconate (0.2%), Combination (0.2% Chlorhexidine and 0.05% Sodium Fluoride), and Green Tea Extract (0.5%) Mouth Rinses on Colony Count Changes of Streptococcus mutans and Lactobacillus in Saliva – A Randomized Controlled Trial

Abstract Introduction Streptococcus mutans and Lactobacillus acidophilus are the well-known etiological factors for dental caries. Chlorhexidine (CHX) gluconate is the “gold-standard” antimicrobial agent but having adverse effects such as brown staining of the teeth and altered taste. Thus, there is a need for an alternative herbal product. Objective This study was done to compare the efficacy of CHX gluconate (0.2%) and combination (0.2% CHX and 0.05% sodium fluoride [NaF]) mouth rinses to that of green tea extract (0.5%) mouth rinse in reducing the salivary count of S. mutans and L. acidophilus in dental students. Materials and Methods The sample size of the study was 75 dental students with ≥4 decayed, missing, and filled teeth (DMFT) index. They were divided into three equal groups to test various mouth rinses against S. mutans and Lactobacillus. Unstimulated salivary samples were collected at baseline and postrinse (14 days) and tested for the colony-forming units of S. mutans and Lactobacillus. The Chi-square test was used to ascertain the demographic characteristics of the study population. One-way ANOVA statistics and paired t-test were applied to calculate the inferential statistics between the variables. The statistical constant was fixed at P < 0.05. Results The results of the study indicated that there was a statistically significant reduction in S. mutans and Lactobacilli count in all the three study groups. Conclusion Green tea mouth rinse can be a promising preventive therapy worldwide for the prevention of dental caries but CHX mouthwashes are superior in reduction of S. mutans and Lactobacillus.

The potential role of SNHG16/ miRNA-146a/ TRAF6 signaling pathway in the protective effect of zoledronate against colorectal cancer and associated osteoporosis in mouse model

Bone fracture as a consequence of colorectal cancer (CRC) and associated osteoporosis (OP) is considered a risk factor for increasing the mortality rate among CRC patients. SNHG16/ miRNA-146a/ TRAF6 signaling pathway is a substantial contributor to neoplastic evolution, progression, and metastasis. Here, we investigated the effect of zoledronate (ZOL) on the growth of CRC and associated OP in a mouse model. Thirty Balb/c mice were divided into Naïve, azoxymethane (AOM)/dextran sodium sulfate (DSS), and ZOL groups. Body weight and small nucleolar RNA host gene 16 (SNHG16) expression, microRNA-146a, and TRAF6 in bone, colon, and stool were investigated. Samples of colon and bone were collected and processed for light microscopic, immunohistochemical staining for cytokeratin 20 (CK20), nuclear protein Ki67 (pKi-67), and caudal type homeobox transcription factor 2 (CDx2) in colon and receptor activator of nuclear factor kB (RANK) and osteoprotegerin (OPG) in bone. A computerized tomography (CT) scan of the femur and tibia was studied. ZOL produced a significant decrease in the expression of SNHG16 and TRAF6 and an increase in miRNA-146a in the colon and bone. ZOL administration improved the histopathological changes in the colon, produced a significant decrease in CK20 and Ki-67, and increased CDx2 expressions. In bone, ZOL prevented osteoporotic changes and tumour cell invasion produced a significant decrease in RANK and an increase in OPG expressions, alongside improved bone mineral density in CT scans. ZOL could be a promising preventive therapy against colitis-induced cancer and associated OP via modulation expression of SNHG16, miRNA-146a, and TRAF6.

Forensic Law in Hypoglycaemia-3

“Environmental Enrichment” (EE) is a proven alternative therapy for Type 2 diabetes related complications. EE preserves the Purkinje cells in the brain. The latter is a promising therapy for prevention of diabetes related mental disorders. Sensory nerves are at higher risk of damage in the hyperglycemic milieu leading to diabetic neuropathy. Patients lose sensation in their lower extremities making them vulnerable to injury because they do not feel the pain, which is a warning sign of tissue damage. That can lead to catastrophic outcomes because with high blood glucose, wounds get difficult to heal. Gas gangrene and tissue necrosis develop, leading to the only resort being amputation and life change challenge. Early diagnosis of diabetes is nevertheless crucial in prolonging the onset of diabetes and its complication. To date many candidate early biomolecules have been reported which are promising early indicators for diabetes. However, advancement in this field of research has not been reported. Holistically diet, lifestyle, mental health and clinical treatment of Diabetes and Thyroid Disease, including Addison’s Disease, plays an important role in patient welfare. Tragically many patients die young or go through life suffering from the old Victorian Stigma of being tainted by having to treat an uncurable illness. This is not a joke as suggested in September 2006 in ignorance by a Hertfordshire Insurance Broker describing Diabetes with Neuroglycopenia as a Joke and Nonsense. This caused Obstructed Justice in Law of a critical life-threatening complication of Diabetes and Endocrinology Disease in Hypoglycaemia Unawareness and now in 2023 Otitis Externa and Osteomyelitis as disclosed in a tragic young law student death with likely clinically undiagnosed Otitis Externa and Osteomyelitis. A patient requiring clinician prescribed Insulin justifies clinical respect and understanding in English Law which has been misunderstood since 1994 with sad consequences in this investigation. Today in recovering and managing the COVID-19 Pandemic of 2020 we move forward with new welfare ideas. It is a delight to be able to share some latest work for future research based on 44 years T1 Diabetes experience complimented by Purkinje Cell environmental welfare.

Fecal filtrate transplantation protects against necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is a life-threatening gastrointestinal disorder afflicting preterm infants, which is currently unpreventable. Fecal microbiota transplantation (FMT) is a promising preventive therapy, but the transfer of pathogenic microbes or toxic compounds raise concern. Removal of bacteria from donor feces by micropore filtering may reduce this risk of bacterial infection, while residual bacteriophages could maintain the NEC-preventive effects. We aimed to assess preclinical efficacy and safety of fecal filtrate transplantation (FFT). Using fecal material from healthy suckling piglets, we compared rectal FMT administration (FMT, n = 16) with cognate FFT by either rectal (FFTr, n = 14) or oro-gastric administration (FFTo, n = 13) and saline (CON, n = 16) in preterm, cesarean-delivered piglets as models for preterm infants. We assessed gut pathology and analyzed mucosal and luminal bacterial and viral composition using 16S rRNA gene amplicon and meta-virome sequencing. Finally, we used isolated ileal mucosa, coupled with RNA-Seq, to gauge the host response to the different treatments. Oro-gastric FFT completely prevented NEC, which was confirmed by microscopy, whereas FMT did not perform better than control. Oro-gastric FFT increased viral diversity and reduced Proteobacteria relative abundance in the ileal mucosa relative to control. An induction of mucosal immunity was observed in response to FMT but not FFT. As preterm infants are extremely vulnerable to infections, rational NEC-preventive strategies need incontestable safety profiles. We show in a clinically relevant animal model that FFT, as opposed to FMT, efficiently prevents NEC without any recognizable side effects.

Should children with sub-threshold ADHD predominantly inattentive subtype (ADHD-I) symptoms be treated with Sensory ıntegration therapy? A case-control study.

Objective: Sensory integration therapy is one of the promising preventive therapy options for behavioral and developmental disorders. Hypothesizing a degree of parallelism, this study provides an insight into the effectiveness of the sensory integration therapy potencies for school-aged children with subthreshold ADHD predominantly inattentive subtype. Method: The study was a single-arm clinical trial and 20 patients aged 7–10 years with subthreshold ADHD predominantly inattentive subtype, were included. The sensory integration intervention was prepared in accordance with sensory modulation principles and intervention strategies and lasted 12 weeks with two sessions per week. The effectiveness was assessed using the Conner’s teacher/parent scales, the Clinical Global Impression scale, the Canadian Sensory integration Performance Measure and the Sensory Profile. Results: The rate of patients with typical or better performance in auditory processing domain of the Sensory Profile was found significantly increased after sensory integration therapy; 9 patients (45%) before and 15 patients after (75%) (p=0.031). The rates of participants with typical or better performance in inattention–distractibility factor score of the Sensory Profile were found significantly increased after sensory integration therapy; 6 before (30%) and 16 after (80%) (p=0.006). Conclusion: Sensory integration therapy focuses on supporting persons with varied disability terms to engage in daily life activities that they find significant and purposeful. Difficulties experienced by individuals with subthreshold attention-deficit hyperactivity disorder are addressed in this study and aspects of daily life are explored while swiping through different sensory modalities. Impaired auditory processing improvable through sensory integration therapy was observed in these children.

Metformin Restores AMPK Alpha-Mediated Autophagy and Prevents Carfilzomib-Induced Cardiotoxicity In Vivo

Introduction: Carfilzomib (Cfz) significantly prolongs progression-free survival in relapsed or refractory multiple myeloma patients, as highlighted in the ENDEAVOR trial. However, Cfz has high incidences of cardiotoxicity and heart failure, leading to treatment cessation. Thus, there is an imperative need for preventive therapies. The study aimed to i) establish an in vivo Cfz cardiotoxicity protocol, ii) investigate the molecular mechanism, identify molecular targets and iii) based on initial results, investigate the potential protective effect and mechanism of Metformin (Met).Methods: Male, C57BL/6 mice, were randomized in groups as following: Acute protocol (6 days): Control (n=7), Cfz (n=8); Sub-chronic protocol (14 days): Control (n=5), Cfz (n=8); Pharmacological intervention protocol (6 days): Control (n=8), Cfz (n=8), Cfz+Met (n=8), Met (n=4). Cfz (8 mg/kg, ip) was administered on alternate days and Met (140 mg/kg, po) daily. Glucose levels were monitored following Met administration. Mice underwent echocardiography on baseline and at the end of treatments. Blood and myocardial tissue samples were obtained for histology, proteasome activity, PP2A activity and signaling pathways focused on PI3K/Akt/eNOS axis, NO homeostasis and AMPKα-mTOR-mediated autophagy.Results: Following acute administration, echocardiography in Cfz group presented a significant reduction in fractional shortening (FS%) vs. Control group (39.87±0.47 vs. 43.03±0.50 respectively, p<0.001), combined with reduced thickness in the left ventricular (LV) posterior wall (LVPW diastole (mm): 0.69±0.01 vs. 0.76±0.01, p<0.01; LVPW systole (mm): 1.17±0.01 vs. 1.24±0.02, p<0.01). Sub-chronic Cfz administration resulted in moderate LV dilation (LV end-diastole diameter (mm): 3.24±0.03 vs. 3.04±0.04, p<0.01; LV end-systole diameter (mm): 1.88±0.02 vs. 1.71±0.02, p<0.01) and borderline FS% reduction (42.07±0.46 vs. 43.52±0.25, p<0.05). Following both protocols, Cfz did not cause major tissue lesions.Signaling pathways were studied in the acute protocol that demonstrated suppressed myocardial contractility. Cfz resulted in significant inhibition of proteasome in both myocardium (55.5% inhibition, p<0.05) and peripheral mononuclear blood cells (PBMCs) (90.6% inhibition, p<0.001) - inhibitory effect was comparable to clinical practice. Cfz, independently of PTEN expression, reduced phospho-PI3K (p<0.05), phospho-Akt (p<0.001) and phospho-eNOS (p<0.001), and increased iNOS expression (p<0.01). Cfz reduced phospho-AMPKα (p<0.001) and phospho-Raptor (p<0.05) leading to inhibition of autophagy, indicated by reduced LC3-II expression (p<0.01), without affecting phospho-mTOR or Beclin 1.Co-administration of Met prevented FS% reduction (Cfz group: 41.55±0.43 vs. 43.24±0.50 and 43.39±0.56, Control and Cfz+Met respectively, p<0.05), without exerting glucose lowering actions. Met did not interfere with Cfz-induced proteasome inhibition; Cfz and Cfz+Met groups had significantly reduced proteasomal activity vs. Control group in myocardium (p<0.05) and PBMCs (p<0.001 and p<0.01 respectively). Histology presented mild to moderate vascular congestion in Cfz+Met and Met vs. Control and Cfz groups (p<0.05), appearing to be non-specific finding that did not collocate with haemorrhage, vascular obstruction or tissue lesions. On a molecular level, Cfz+Met group presented increased phospho-Akt (p<0.01) vs. Cfz group, independently of PTEN, PI3K and eNOS/iNOS. Cfz+Met group restored phospho-AMPKα (p<0.05), phospho-Raptor (p<0.001) and LC3-II expression (p<0.05) vs. Cfz group, without inducing changes in mTOR and Beclin 1. Cfz inactivated Akt and AMPKα through increased PP2A activity (p<0.05), without altering PP2A expression; Met did not interfere with PP2A activity.Conclusions: Cfz exhibits decreased global LV function in vivo, without inducing tissue lesions. The molecular mechanism consists of increased PP2A activity leading to inactivation of AMPKα-mTOR and PI3K/Akt/eNOS pathways - combined with NO homeostasis deregulation. In an intervention approach, Met preserved cardiac function via restoring AMPKα-mediated autophagy. Met administration did not restore NO production and homeostasis; these pathways require further investigation. Met emerges to be a promising preventive therapy for Cfz-induced cardiotoxicity. DisclosuresKastritis:Amgen: Consultancy, Honoraria, Research Funding; Genesis Pahrma: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Honoraria; Prothena: Consultancy, Honoraria. Dimopoulos:Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Terpos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; BMS: Consultancy; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding.

Mesenchymal Stem Cell Sheets Exert Antistenotic Effects in a Rat Arterial Injury Model

Restenosis after catheter or surgical intervention substantially affects the prognosis of arterial occlusive disease. Mesenchymal stem cells (MSCs) may have antistenotic effects on injured arteries. MSC transplantation from the adventitial side of an artery is safer than endovascular transplantation but has not been extensively examined. In this study, a rat model of femoral artery injury was used to compare the antistenotic effects of transplanted cell sheets and transplanted cell suspensions. Rat adipose-derived stem cells (ASCs) were used as the source of MSCs. For both cell sheets and suspensions, 6 × 106 MSCs were transplanted on the day of arterial injury. MSC sheets attenuated neointimal hyperplasia more than MSC suspensions (intima-to-media ratio in hematoxylin/eosin-stained sections: 0.55 ± 0.13 vs. 1.14 ± 0.12; p < 0.05). Cell engraftment (assessed by immunohistochemistry or bioluminescence imaging of luciferase-expressing cells), arterial re-endothelialization (evaluated by immunohistochemical staining for rat endothelial cell antigen-1), and restriction of vascular smooth muscle cell proliferation in the neointima (double-staining of alpha-smooth muscle actin and phospho-histone H3) were greater when MSC sheets were applied than when MSC suspensions were used. In conclusion, MSC sheets exhibited better antistenotic and cell engraftment properties than MSC suspensions. MSC sheet transplantation from the adventitial side is a promising therapy for prevention of arterial restenosis.

Photomodulation multiple sessions as a promising preventive therapy for medication-related osteonecrosis of the jaws after tooth extraction in rats

The aim of this study was to evaluate the effects of photobiomodulation (PBM) with multiple sessions of low-level laser on the alveolar repair process of rats with major risk factors for medication-related osteonecrosis of the jaws (MRONJ). Senile rats received 0.45 mL of vehicle (VEH and VEH-PBM) or 0.45 mL of 100 μg/kg zoledronate (ZOL and ZOL-PBM) administrated intraperitoneally every two days during seven weeks. After three weeks of initiation of drug treatment the first lower left molar was extracted. No local treatment was performed in VEH and ZOL. VEH-PBM and ZOL-PBM were submitted to laser irradiation (660 ± 10 nm; 0.035 W; 2.1 J; 60 s) on the extraction site at 0, 2 and 4 days postoperatively. Euthanasia was performed 28 days after tooth extraction. Histological sections of the hemimandible were submitted to histopathological and histomorphometric analysis, as well as to histochemistry for collagen fiber maturation and immunohistochemistry for pro-inflammatory cytokines. In ZOL, general impairment of tissue repair, areas with osteonecrosis, lower newly formed bone tissue (NFBT), smaller amount of mature collagen fibers and increased immunoreactivity for TNFα, IL-1β and IL-6 were observed when compared to VEH and VEH-PBM. ZOL-PBM showed significant improvement in some parameters compared to ZOL, such as positive repair tissue, higher NFBT, greater amount of mature collagen fibers, besides TNFα and IL-1β immunoreactivity decrease. Zoledronate treatment severely compromised the tissue repair process of the tooth extraction site in rats with major risk factors for MRONJ. Based on parameters employed in the present study, PBM in multiple sessions can improve the alveolar repair process, constituting a promising preventive therapy to avoid the onset of post-extraction MRONJ.

MCU-knockdown attenuates high glucose-induced inflammation through regulating MAPKs/NF-κB pathways and ROS production in HepG2 cells.

Mitochondrial Ca2+ is a key regulator of organelle physiology and the excessive increase in mitochondrial calcium is associated with the oxidative stress. In the present study, we investigated the molecular mechanisms linking mitochondrial calcium to inflammatory and coagulative responses in hepatocytes exposed to high glucose (HG) (33mM glucose). Treatment of HepG2 cells with HG for 24 h induced insulin resistance, as demonstrated by an impairment of insulin-stimulated Akt phosphorylation. HepG2 treatment with HG led to an increase in mitochondrial Ca2+ uptake, while cytosolic calcium remained unchanged. Inhibition of MCU by lentiviral-mediated shRNA prevented mitochondrial calcium uptake and downregulated the inflammatory (TNF-α, IL-6) and coagulative (PAI-1 and FGA) mRNA expression in HepG2 cells exposed to HG. The protection from HG-induced inflammation by MCU inhibition was accompanied by a decrease in the generation of reactive oxygen species (ROS). Importantly, MCU inhibition in HepG2 cells abrogated the phosphorylation of p38, JNK and IKKα/IKKβ in HG treated cells. Taken together, these data suggest that MCU inhibition may represent a promising therapy for prevention of deleterious effects of obesity and metabolic diseases.

Curcumin ameliorates palmitate-induced inflammation in skeletal muscle cells by regulating JNK/NF-kB pathway and ROS production.

Curcumin, a natural polyphenol compound, has the beneficial effects on several diseases such as metabolic syndrome, cancer, and diabetes. The anti-inflammatory property of curcumin has been demonstrated in different cells; however, its role in prevention of palmitate-induced inflammation in skeletal muscle C2C12 cells is not known. In this study, we examined the effect of curcumin on the inflammatory responses stimulated by palmitate in C2C2 cells. The results showed that palmitate upregulated the mRNA expression and protein release of IL-6 and TNF-α cytokines in C2C12 cells, while pretreatment with curcumin was able to attenuate the effect of palmitate on inflammatory cytokines. The anti-inflammatory effect of curcumin was associated with the repression of phosphorylation of IKKα-IKKβ, and JNK. Palmitate also caused an increase in reactive oxygen species (ROS) level that curcumin abrogated it. Collectively, these findings suggest that curcumin may represent a promising therapy for prevention of inflammation in skeletal muscle cells.

Resveratrol Ameliorates Palmitate-Induced Inflammation in Skeletal Muscle Cells by Attenuating Oxidative Stress and JNK/NF-κB Pathway in a SIRT1-Independent Mechanism.

Resveratrol has been shown to exert anti-inflammatory and anti-oxidant effects in a variety of cell types, however, its role in prevention of inflammatory responses mediated by palmitate in skeletal muscle cells remains unexplored. In the present study, we investigated the effects of resveratrol on palmitate-induced inflammation and elucidated the underlying mechanisms in skeletal muscle cells. The results showed that palmitate significantly enhanced TNF-α and IL-6 mRNA expression and protein secretion from C2C12 cells at 12, 24, and 36 h treatments. Increased expression of cytokines was accompanied by an enhanced phosphorylation of JNK, P38, ERK1/2, and IKKα/IKKβ. In addition, JNK and P38 inhibitors could significantly attenuate palmitate-induced mRNA expression of TNF-α and IL-6, respectively, whereas NF-κB inhibitor reduced the expression of both cytokines in palmitate-treated cells. Resveratrol pretreatment significantly prevented palmitate-induced TNF-α and IL-6 mRNA expression and protein secretion in C2C12 cells. Importantly, pre-treatment of the cells with resveratrol completely abrogated the phosphorylation of ERK1/2, JNK, and IKKα/IKKβ in palmitate treated cells. The protection from palmitate-induced inflammation by resveratrol was accompanied by a decrease in the generation of reactive oxygen species (ROS). N-acetyl cysteine (NAC), a known scavenger of ROS, could protect palmitate-induced expression of TNF-α and IL-6. Furthermore, inhibition of SIRT1 by shRNA or sirtinol demonstrated that the anti-inflammatory effect of resveratrol in muscle cells is mediated through a SIRT1-independent mechanism. Taken together, these findings suggest that resveratrol may represent a promising therapy for prevention of inflammation in skeletal muscle cells. J. Cell. Biochem. 118: 2654-2663, 2017. © 2017 Wiley Periodicals, Inc.

Molecular mechanisms contributing to the protective effect of levosimendan in liver ischemia-reperfusion injury

Ischemia-reperfusion injury (IRI) is an important cause of liver damage in many clinical situations. Levosimendan is a promising therapy for prevention of IRI. The present work investigated the possible contribution of nitric oxide (NO), cyclooxygenase (COX) enzymes, and adenosine triphosphate sensitive potassium channel (K-ATP) in the protective effect of levosimendan in liver IRI in rats. Rats were divided into 7 groups. Sham-operated group (negative control group); IR-nontreated group (positive control group), levosimendan-treated group (treated with levosimendan); indomethacin, nonselective COX inhibitor,+levosimendan group (cotreated with indomethacin+levosimendan); celecoxib (selective COX-2 inhibitor)+levosimendan group; L-NNA (Nitro- ω-L-arginine, nonselective NO synthase inhibitor)+levosimendan group; and glibenclamide (K-ATP blocker)+levosimendan group. Liver injury was evaluated biochemically (by serum level of alanine aminotransferase (ALT)) as well as by histopathology. Hepatic tissue content of oxidative stress markers, tumor necrosis factor-alpha (TNF-α), along with immunohistochemical expression of induced NO synthase (iNOS), endothelial NO synthase (eNOS), and caspase-3 in hepatic tissue were assayed. The study showed that levosimendan attenuated liver IRI as evidenced by a decrease in serum ALT level and confirmed by histopathology. The protective effect of levosimendan was associated with modulation of oxidative stress, TNF-α, iNOS, eNOS, and caspase-3. The hepatoprotective effect of levosimendan was partially attenuated by pretreatment by either nonselective COX inhibitor, NOS inhibitor, or K-ATP channel blocker; indicating that the hepatoprotective effect of levosimendan was attributed, at least in part to activation of COX-1, modulation of NO, and opening of K-ATP channel.

An oral vaccine for type 1 diabetes based on live attenuated Salmonella

Type 1 diabetes (T1D) is a metabolic disease that is initiated by the autoimmune destruction of pancreatic insulin-producing beta cells that is accompanied by the development of antigen-specific antibodies and cytotoxic T lymphocytes (CTLs). Several studies have shown that vaccination with diabetic autoantigens provides some protection against this process. In this report we describe a new oral vaccine that utilizes live attenuated Salmonella for simultaneous delivery of autoantigens in conjunction with immunomodulatory cytokine genes to immune cells in the gut mucosa. Recent data showed that live attenuated Salmonella is a safe, simple and effective vector for expression of antigens and cytokines by antigen-presenting cells (APCs) of gut-associated lymphatic tissue (GALT). This novel strategy was tested by fusion of the diabetic autoantigen preproinsulin with Salmonella secretory effector protein (SseF) of pathogenicity island-2 (SPI2). In this way the autoantigen is only expressed inside the host immune cells and translocated to the host cell cytosol. In addition Salmonella was used to deliver the gene for the immunomodulatory cytokine transforming growth factor beta (TGFβ) for host cell expression. Oral co-vaccination of 8 week-old non-obese diabetic (NOD) mice with three weekly doses of both the autoantigen and cytokine significantly reduced the development of diabetes, improved the response to glucose challenge, preserved beta cell mass, and reduced the severity of insulitis compared with controls and autoantigen alone. Combination therapy also resulted in increased circulating levels of IL10 four weeks post-vaccination and IL2 for 12 weeks post-vaccination, but without effect on proinflammatory cytokines IL6, IL12(p70), IL17 and IFNγ. However, in non-responders there was a significant rise in IL12 compared with responders. Future studies will examine the mechanism of this vaccination strategy in more detail. In conclusion, Salmonella-based oral vaccines expressing autoantigens combined with imunomodulatory cytokines appears to be a promising therapy for prevention of T1D.

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries

Oral Mucositis Prevention By Low-Level Laser Therapy in Head-and-Neck Cancer Patients Undergoing Concurrent Chemoradiotherapy: A Phase III Randomized Study

Oral mucositis is a major complication of concurrent chemoradiotherapy (CRT) in head-and-neck cancer patients. Low-level laser (LLL) therapy is a promising preventive therapy. We aimed to evaluate the efficacy of LLL therapy to decrease severe oral mucositis and its effect on RT interruptions. In the present randomized, double-blind, Phase III study, patients received either gallium-aluminum-arsenide LLL therapy 2.5 J/cm(2) or placebo laser, before each radiation fraction. Eligible patients had to have been diagnosed with squamous cell carcinoma or undifferentiated carcinoma of the oral cavity, pharynx, larynx, or metastases to the neck with an unknown primary site. They were treated with adjuvant or definitive CRT, consisting of conventional RT 60-70 Gy (range, 1.8-2.0 Gy/d, 5 times/wk) and concurrent cisplatin. The primary endpoints were the oral mucositis severity in Weeks 2, 4, and 6 and the number of RT interruptions because of mucositis. The secondary endpoints included patient-reported pain scores. To detect a decrease in the incidence of Grade 3 or 4 oral mucositis from 80% to 50%, we planned to enroll 74 patients. A total of 75 patients were included, and 37 patients received preventive LLL therapy. The mean delivered radiation dose was greater in the patients treated with LLL (69.4 vs. 67.9 Gy, p = .03). During CRT, the number of patients diagnosed with Grade 3 or 4 oral mucositis treated with LLL vs. placebo was 4 vs. 5 (Week 2, p = 1.0), 4 vs. 12 (Week 4, p = .08), and 8 vs. 9 (Week 6, p = 1.0), respectively. More of the patients treated with placebo had RT interruptions because of mucositis (6 vs. 0, p = .02). No difference was detected between the treatment arms in the incidence of severe pain. LLL therapy was not effective in reducing severe oral mucositis, although a marginal benefit could not be excluded. It reduced RT interruptions in these head-and-neck cancer patients, which might translate into improved CRT efficacy.

Adhesion reduction after knee surgery in a rat model by Mitomycin C

The purpose of this study was to investigate the effect of Mitomycin C on reduction in intra-articular fibrotic adhesion formation after knee surgery. Twenty female Wistar Albino rats were divided into two equal study groups. After skin incision, the right knees of animals were opened through a medial parapatellar approach, and the medial and lateral sides of the femoral condyle were exposed. A partial capsulotomy and synovectomy were performed. In group I, Mitomycin C was applied in the articular cavity of rats after hemostasis. An identical volume of sterile normal saline was applied in group II, which served as controls. All rats received weekly (6weeks) intra-articular both Mitomycin C and saline starting from the day of operation. Animals were killed at 45days after surgery. The presence and severity of osteo-capsular adhesion was assessed with both macroscopic and microscopic adhesion scoring systems. Results of macroscopic observations showed a significant reduction in both incidence and severity of adhesions in group I compared to group II. Histologically, adhesions in group I were thinner with less collagenic fibers. Microscopic determination of adhesion formation was less in group I, and the difference between groups was statistically significant. Our results suggest that post-operative administration of Mitomycin C may be considered a promising preventive therapy for the reduction in fibro-adhesive scars and consequent stiffness after knee surgery.

Supportive care in head and neck oncology

Survival gains were achieved in head and neck cancer patients treated with a multidisciplinary approach, including platinum-based concurrent chemoradiation, with a substantial increase in toxicity. The prompt diagnosis and treatment of these toxicities - the focus of this review - are essential aspects in the daily care of head and neck squamous cell carcinoma patients. Low-level laser is a promising therapy for prevention and treatment of mucositis. Amifostine, as an acute and late xerostomia-preventive agent, may be considered in patients undergoing fractionated radiation therapy alone. The incidence of xerostomia was significantly reduced in patients treated with intensity-modulated radiation therapy. Severe cutaneous reactions can occur when epidermal growth factor receptor-targeting agents are administered concurrently to radiation therapy. Erythropoiesis-stimulating agents should not be administered to head and neck cancer patients under radiation therapy or chemotherapy outside of the context of clinical trials. The best outcomes in head and neck squamous cell carcinoma patients treated in the multidisciplinary context can only be achieved with an adequate patient selection, an experienced and motivated team and if the best possible supportive care is offered. Randomized studies on promising supportive therapies must be encouraged.

Oral mucositis prevention by low-level laser therapy in head and neck cancer patients submitted to concurrent chemoradiation: A prospective randomized study

6019 Background: Oral mucositis is a major treatment-related complication of concurrent chemoradiation (CRT) in head and neck cancer (HNC) patients (pts), affecting nutrition, pain control, quality of life and adequate treatment delivery. Low level laser (LLL) is a promising preventive therapy. We aimed to evaluate the efficacy of LLL to decrease and delay severe oral mucositis and its impact on RT interruptions. Methods: In this prospective, randomized, double-blind, phase III trial, pts were treated with either daily He-Ne LLL 2.5 J/cm2, or placebo laser, before RT. Eligible pts had to be diagnosed with SCC or undifferentiated carcinoma of oral cavity, pharynx, larynx, or metastatic to the neck with unknown primary site (UPS); age &gt; 18 y; candidates to adjuvant or definitive CRT; signed informed consent. CRT consisted of conventional RT 60–70 Gy (1.8–2.0 Gy/d, 5 times/wk) + concurrent cisplatin 100 mg/m2 every 3 wks. Main endpoints were oral mucositis severity in wks 2, 4 and 6 (CTC-NCI v.2.0); RT interruptions due to mucositis; pain intensity (VAS). To detect a decrease in the incidence of grade 3 or 4 oral mucositis from 80 to 50%, we planned to enroll 74 pts, error I/II 5 and 20%, respectively. Results: 73 pts were included (77% male; mean age 53 y); primary site: oropharynx (31 pts), larynx (15), nasopharynx (10), hypopharynx (8), oral cavity (7 pts), UPS (2); 36 pts received prophylactic LLL. Mean delivered RT dose (Gy) was higher in pts treated with LLL (69.3 vs. 67.8, p = 0.04). The number of treatment fields was the same (6 vs. 6, p = 0.50) and the mean cisplatin dose-intensity was 40.9 and 40.1 mg/m2/wk (p = 0.3) between pts treated with LLL or placebo, respectively. During CRT, the number of pts diagnosed with grade 3 or 4 oral mucositis treated with LLL/placebo was 4/5 (wk 2, p = 1.0); 4/11 (wk 4, p = 0.08); and 8/9 (wk 6, p = 1.0), respectively. More pts treated with placebo had RT interruptions due to mucositis (6 vs. 0, p =0.02). The occurrence of severe pain did not differ between the study arms in wks 2, 4 and 6 (5/5, 8/8 and 8/8, p = 1.0). Conclusions: LLL therapy was effective in reducing grade 3 or 4 oral mucositis and in reducing RT interruptions in these HNC pts treated with concurrent CRT, which may translate into improved CRT efficacy and tolerance. No significant financial relationships to disclose.

Combined treatment with selective cyclooxygenase-2 inhibitor and fluorinated pyrimidines for liver metastasis of colon cancer

Liver metastasis is a major contributor to mortality in patients with colorectal cancer. Hence, it is essential to establish preventive therapy to control liver metastasis. Recently, it has become widely accepted that cyclooxygenase (COX)-2 inhibitors possess anti-cancer activity for various types of tumor, especially colorectal. The clinical application of COX-2 inhibitors may therefore be beneficial. In this study, we have developed a combined treatment with a selective COX-2 inhibitor and fluorinated pyrimidines for liver metastasis of colorectal cancer, and examined the effect of these agents on proliferation and invasion of a highly metastatic human colon cancer cell line, LM-H3. The COX-2 inhibitor etodolac was found to inhibit cell invasion of LM-H3. 5-Fluorouracil (5-FU) inhibited proliferation of this line in vitro. Etodolac did not increase the inhibitory effect of 5-FU on cell proliferation. We also examined the inhibitory effect of etodolac and UFT, belonging to the fluorinated pyrimidines, on liver metastasis by using a liver metastatic model in the nude mouse. Combined treatment with etodolac and UFT markedly reduced liver metastasis. Serious side effects were not observed. In conclusion, combined treatment with etodolac and UFT might be a promising preventive therapy for liver metastasis of colon cancer.

Drug-eluting stents for cardiovascular disorders.

Drug-eluting stents have emerged in recent years as a very promising therapy for prevention of restenosis after coronary implantation. Early randomized, clinical trials have suggested that stents eluting drugs, such as paclitaxel or sirolimus, released from polymeric and nonpolymeric coatings, are able to reduce restenosis in simple de novo lesions by more than 80% in comparison with bare metal stents. If restenosis can be indeed minimized globally by drug-eluting stents, coronary revascularization may expand to patients and lesions currently not considered for percutaneous intervention because of excessive recurrence, and may open possibilities for other stent-based endovascular treatments of atherosclerosis.