Bromelain, a mixture of proteases derived from pineapple stem, has been reported to have therapeutic benefits in a variety of inflammatory diseases, including murine inflammatory bowel disease. The purpose of this work was to understand potential mechanisms for this anti-inflammatory activity. Exposure to bromelain in vitro has been shown to remove a number of cell surface molecules that are vital to leukocyte trafficking, including CD128a/CXCR1 and CD128b/CXCR2 that serve as receptors for the neutrophil chemoattractant IL-8 and its murine homologues. We hypothesized that specific proteolytic removal of CD128 molecules by bromelain would inhibit neutrophil migration to IL-8 and thus decrease acute responses to inflammatory stimuli. Using an in vitro chemotaxis assay, we demonstrated a 40% reduction in migration of bromelain-vs. sham-treated human neutrophils in response to rhIL-8. Migration to the bacterial peptide analog fMLP was unaffected, indicating that bromelain does not induce a global defect in leukocyte migration. In vivo bromelain treatment generated a 50 -85% reduction in neutrophil migration in 3 different murine models of leukocyte migration into the inflamed peritoneal cavity. Intravital microscopy demonstrated that although in vivo bromelain treatment transiently decreased leukocyte rolling, its primary long-term effect was abrogation of firm adhesion of leukocytes to blood vessels at the site of inflammation. These changes in adhesion were correlated with rapid re-expression of the bromelain-sensitive CD62L/L-selectin molecules that mediate rolling following in vivo bromelain treatment and minimal re-expression of CD128 over the time period studied. Taken together, these studies demonstrate that bromelain can effectively decrease neutrophil migration to sites of acute inflammation and support the specific removal of the CD128 chemokine receptor as a potential mechanism of action.

Microwave based temperature imaging is a non-invasive temperature measurement method which is necessary during hyperthermia treatment for monitoring purposes and dose evaluation. This thermometer imaging system is still a problem that must be solved before hyperthermia can be launched as an effective tool for cancer treatment. Some clinically available applications today such as MRI or invasive catheters have many problems, while the advantage of microwave monitoring system is that the same antenna array can be simultaneously used in thermal imaging and hyperthermia treatment. However, the aim of this thesis is to determine the feasibility of using microwave thermal imaging in order to estimate its sensitivity to temperature changes. This thesis is based on both simulated and experimental data which were performed to estimate the temperature changes of single heated tumor object inside the phantom. Simulations were implemented in two configurations, first one without defining the containers which include the phantom and the internal tumor object. Second configuration was performed by defining the two containers which have been implemented to verify the experimental results. Later, experimental measurements were performed by using containers due to the liquid phantoms to find out systems feasibility to measure temperature changes practically. The internal tumor object was tested with different diameters, temperatures and positions. Dielectric probe was used to determine thermal dependence of dielectric properties for eye, blood and muscle phantoms in the frequency range 100MHz to 2GHz. Different simulations were performed using finite difference time domain FDTD method based on the conductivity and permittivity of specific phantoms. Later, twenty monopole antennas arranged in a 200mm diameter circle were used to generate microwaves in the frequency range 0.4 to 2GHz. This system could reveal tumor's temperature changes under certain conditions while it still requires more improvements under some other conditions. The results showed that the system has high potential to estimate temperature changes without using the containers. Moreover, tumor object diameter is considered as primarily factor that affects the results, where at 32mm diameter the results began to demonstrate an appropriate transmission coefficient difference between two various temperatures up to 7dB. Simulation and measurement results displayed high decline in the temperature changes by using the containers. The results showed however a good transmission coefficients agreement between simulation and experimental results.

Purpose: Resveratrol (3,4',5-tri-hydroxy-trans-stilbene) is an antioxidant constituent of a wide variety of plant species including grapes. It has gained considerable attention because of its anticancer properties, as shown in solid and hematologic malignancies. Whether resveratrol could inhibit proliferation or induce cytotoxicity in Waldenström's macroglobulinemia (WM) was investigated. Experimental Design: We studied resveratrol-induced inhibition of proliferation and induction of cytotoxicity in WM cell lines, WM primary tumor cells, IgM-secreting cells, and peripheral blood mononuclear cells. The mechanisms of action and different signaling pathways involved were studied using Western blot and gene expression profile analysis. Resveratrol activity was also evaluated in the bone marrow microenvironment. We finally investigated whether or not resveratrol could have any synergistic effect if used in combination with other drugs widely used in the treatment of WM. Results:...

This course, titled "The Origins of Minimally Invasive and Robotic Surgery and Their Impact on Surgical Practice: A Sociological and Technological History," is a comprehensive exploration of the evolution of surgical techniques, particularly focusing on minimally invasive and robotic methods. It covers the historical progression from early surgical innovations, including the development of the endoscope and the first laparoscopic procedures, to the advent of robotic surgery systems like the da Vinci robot.

The course emphasizes the significant technological advancements that have shaped modern surgery, as well as the sociological impact these innovations have had on surgical practice, education, and patient care. Through the study of various key milestones—from the pre-industrial era to the current widespread use of robotic surgery—the course provides valuable insights into how these advancements have enhanced surgical outcomes, education, and the overall practice of surgery. It also critically discusses the challenges and disadvantages of these technologies, including the loss of tactile feedback and the potential for a less intuitive surgical experience.

By the end of the course, participants gain an understanding of the historical, technological, and sociological contexts of modern surgery, with a focus on the continuing evolution of minimally invasive and robotic surgical techniques.

Hec1 (High Expression in Cancer 1) is an oncogene overly expressed in many human cancers. Small molecule INH (Inhibitor of Nek2/Hec1) targeting the Hec1 and its regulator, Nek2, in the mitotic pathway was identified to inactivate Hec1/Nek2 function mediated by protein degradation that subsequently leads to chromosome mis-segregation and cell death. To further improve the efficacy of INH, a series of INH analogues was designed, synthesized and evaluated. Among these 33 newlysynthesized analogues, three of them, 6, 13 and 21, have 6-8 fold more potent cell killing activity than the previous lead compound INH1. Compounds 6 and 21 were chosen for analyzing the underlying action mechanism. They target directly the Hec1/Nek2 pathway and cause chromosome mis-alignment as well as cell death, a mechanism similar to that of INH1. This initial exploration of structural/functional relationship of INH may advance the progress for developing clinically applicable INH analogue.

The marine environment is a rich source of both biological and chemical diversity. It is very much likely that marine organisms would be wonderful source of biologically active molecules The collection of the marine therapeutics includes molecules with antibiotic, antiviral, antiphrastic, analgesic and anticancer agent from bacteria, cyanobacteria, tunica, fungi, sponge This reviewfocuses on the latest studies and critical research in this field and evidences the immense potential ofmarine organisms as sources of bioactive peptides and other anticancer biomolecules Various anticancer compounds like Aplidine, Bryostatin-1, Didemin B, Dolastation, Ecteinascidine with diverse modes of action, such as, anti-proliferative, antioxidant, anti-microtubule havebeen isolated from marine sources. Traditional chemotherapeutic agents have a range of side effects likefatigue, gastrointestinal distress and depression of immune system which introduces the these sources have been shown to have antioxidantactivity and cytotoxic effect on several human cancers such as leukemia, lymphoma, ovarian, melanoma, breast, bladder, neuroendocrine, prostatic, colon and non-small cell lung cancer very potently.

Melatonin is a remarkable molecule with diverse physiological functions. Some of its effects are mediated by receptors while other, like cytoprotection, seem to depend on direct and indirect scavenging of free radicals not involving receptors. Among melatonin´s many effects, its antinociceptive actions have attracted attention. When given orally, intraperitoneally, locally, intrathecally or through intracerebroventricular routes, melatonin exerts antinociceptive and antiallodynic actions in a variety of animal models. These effects have been demonstrated in animal models of acute pain like the tail-flick test, formalin test or endotoxin-induced hyperalgesia as well as in models of neuropathic pain like nerve ligation. Glutamate, gamma-aminobutyric acid, and particularly, opioid neurotransmission have been demonstrated to be involved in melatonin´s analgesia. Results using melatonin receptor antagonists support the participation of melatonin receptors in melatonin´s analgesia. However, discrepancies between the affinity of the receptors and the very high doses of melatonin needed to cause effects in vivo raise doubts about the uniqueness of that physiopathological interpretation. Indeed, melatonin could play a role in pain through several alternative mechanisms including free radicals scavenging or nitric oxide synthase inhibition. The use of melatonin analogs like the MT 1 /MT 2 agonist ramelteon, which lacks free radical scavenging activity, could be useful to unravel the mechanism of action of melatonin in analgesia. Melatonin has a promising role as an analgesic drug that could be used for alleviating pain associated with cancer, headache or surgical procedures.

Class 3 antiarrhythmic agents exhibit reverse rate-dependent lengthening of the action potential duration (APD), i.e. changes in APD are greater at longer than at shorter cycle lengths. In spite of the several theories developed to explain this reverse rate-dependency, its mechanism has been clarified only recently. The aim of the present study is to elucidate the mechanisms responsible for reverse rate-dependency in mammalian ventricular myocardium. Action potentials were recorded using conventional sharp microelectrodes from human, canine, rabbit, guinea pig, and rat ventricular myocardium in a ratedependent manner. Rate-dependent drug-effects of various origen were studied using agents known to lengthen or shorten action potentials allowing thus to determine the drug-induced changes in APD as a function of the cycle length. Both drug-induced lengthening and shortening of action potentials displayed reverse rate-dependency in human, canine, and guinea pig preparations, but not in rabbit and rat myocardium. Similar results were obtained when repolarization was modified by injection of inward or outward current pulses in isolated canine cardiomyocytes. In contrast to reverse rate-dependence, druginduced changes in APD well correlated with baseline APD values (i.e. that measured before the superfusion of drug or injection of current) in all of the preparations studied. Since the net membrane current (I net ), determined from the action potential waveform at the middle of the plateau, was inversely proportional to APD, and consequently to cycle length, it is concluded that that reverse rate-dependency may simply reflect the inverse relationship linking I net to APD. In summary, reverse rate-dependency is an intrinsic property of drug action in the hearts of species showing positive APD -cycle length relationship, including humans. This implies that development of a pure K + channel blocking agent without reverse ratedependent effects is not likely to be successful.

Two new 1-acridin-9-yl-3-methylthiourea Au(I) DNA intercalators [Au(ACRTU)2]Cl (2) and [Au(ACRTU) (PPh3)]PF6 (3) have been prepared. Both complexes were highly active in the human ovarian carcinoma cisplatin-sensitive A2780 cell line, exhibiting IC50 values in the submicromolar range. Compounds 2 and 3 are also cytotoxic toward different phenotypes of breast cancer cell lines MDA-MB-231 (triple negative), SK-BR-3 (HER2+, ERα-, and ERβ-), and MCF-7 (ER+). Both complexes induce apoptosis through activation of caspase-3 in vitro. While inhibition of some proteins (thiol-containing enzymes) seems to be the main mechanism of action for cytotoxic gold complexes, 2 and 3 present a DNA-dependent mechanism of action. They locate in the cell nucleus according to confocal microscopy and transmission electronic microscopy. The binding to DNA resulted to be via intercalation as shown by spectroscopic methods and viscometry, exhibiting a dose-dependent response on topoisomerase I mediated DNA unw...

We investigated the cytotoxic activity and some aspects of the mode of action of 5-aza-2'deoxycytidine (Aza-dC) in 21 primary cultures of leukemic cells freshly obtained from patients with chronic myeloid leukemia (CML) in blast crisis. The cytotoxic potency of Aza-dC was comparable or even greater than that of 1-fl-D-arabinofuranosylcytosine (Ara-C) in most cases, suggesting that this drug has potential in the therapy of blast crisis of CML. Drug incorporation into DNA was evaluated by exposing leukemic cells simultaneously to 3H-Aza-dC at the concentration of 0.1 ~tg/ml and 14Cthymidine (TdR) used as internal standard. Incorporation of Aza-dC into DNA was detectable in all cases. In 17 samples we evaluated the DNA integrity of leukemic cells exposed to Aza-dC using alkaline elution techniques. The drug caused a detectable amount of DNA alkali labile sites (ALS). DNA-ALS increased in cells exposed to Aza-dC concentrations from 0.1 to 1 Ixg/ml but did not further increase at 10 p.g/ml. A plateau in the levels of DNA-ALS was also seen in human K562 cells exposed to increasing concentrations of Aza-dC from 5 to 10 Ixg/ml, whereas in these cells Aza-dC incorporation into DNA increased with increasing Aza-dC concentrations. Therefore, DNA-ALS caused by Aza-dC are not simply the result of the chemical decomposition of azacytosine molecules incorporated into DNA, but are presumably the result of a saturable DNA repair mechanism (e.g., glycosylases) leading to formation of the apyrimidinic sites.

An increase in the engine lubricant soot levels has recently been noticed. This increase in soot content of lubricating oils has caused a series of problems in the overall performance of the engine. In a practical context, sooted oils consist of carbonaceous matter suspended in engine oil forming a system commonly known as a colloid sol. The objective of this paper is to better understand the mechanism of action of oil containing soot particles in the lubricated contacts and to identify how the colloidal nature of the sooted oil is related to its performance. This study has shown by means of ultra-thin film interferometry and image analysis techniques that soot colloid particles are entrained in the contact inlet where they can influence the friction and wear characteristics of the base stock. This study shows that soot primary particles are entrained into the contact at slow speeds, affecting the film characteristics of clean engine oils. This entrainment of particles is more pronounced at high temperatures.

Background: Repetitive transcranial magnetic stimulation (rTMS) has been found to exert modest to moderate therapeutic effects in major depression, but mechanism of action and its clinical relevance have not been clarified yet. Previous trials have reported patterns of symptomatology predicting response to rTMS. As most patients also received concomitant antidepressant medication these response patterns may rather refer to combined treatment than rTMS alone. Thus, this study aims to replicate previous findings and explore patterns of response in drug-free patients. Methods: In the Munich-Berlin Predictor Study data of 79 patients from two open clinical trials evaluating effects of high-frequency rTMS of the left dorsolateral prefrontal cortex were pooled. Previous models predicting the response to rTMS [

We have examined the effects of the immunosuppressive drug cyclosporin A (CsA) on the phenotypic maturation of T cells in thymic organ cultures begun at day 16 of gestation. CsA specifically inhibited the generation of cells expressing high levels of α/β TcR/CD3 complexes and a mature phenotype defined by CD4 and CD8 surface markers. Adding interleukin (IL) 1β, IL 2 or IL 4 failed to reverse the effects of CsA, and major histocompatibility complex class II expression in the thymic medulla was preserved. Possible mechanisms of CsA‐mediated inhibition of T cell development are discussed.

The mechanism of action of DNA methylation inhibitor 5-aza-2′-deoxycytidine (5-aza-CdR), a potential anticancer agent is believed to be activated by the demethylation of tumor suppressor genes. We tested here the hypothesis that demethylating agents also demethylate and activate genes involved in invasion and metastasis and therefore might increase the risk of developing tumor metastasis. The effect of 5-aza-CdR on noninvasive human breast cancer cells MCF-7 and ZR-75-1 was evaluated by cell proliferation, invasion, and migration assay. The ability of 5-aza-CdR to activate a panel of silenced prometastatic and tumor suppressor genes was evaluated using reverse transcriptionpolymerase chain reaction and bisulfite DNA sequence analysis in vitro and for change in tumor growth and gene expression in vivo. Treatment of MCF-7 and ZR-75-1 with 5-aza-CdR diminished cell proliferation, induced tumor suppressor RASSF1A, and altered cell cycle kinetics' G 2 /M-phase cell cycle arrest. While these effects of 5-aza-CdR slowed the growth of tumors in nude mice, it also induced a battery of prometastatic genes, namely, uPA, CXCR4, HEPARANASE, SYNUCLEIN γ, and transforming growth factor-beta (TGF-β), by demethylation of their promoters. These results draw attention to the critical role of demethylation as a potential mechanism that can promote the development and progression of tumor metastasis after demethylation therapy as an anticancer treatment.

Transcranial magnetic stimulation (TMS) is a promising noninvasive brain stimulation intervention. Transcranial magnetic stimulation has been proposed for obsessive-compulsive disorder (OCD) with auspicious results. To assess the efficacy of TMS for OCD in randomized clinical trials (RCTs). Systematic review using MEDLINE and EMBASE from the first RCT available until March 11, 2016. The main outcome was the Hedges g for continuous scores for Yale-Brown Obsessive Compulsive Scale in a random-effects model. Heterogeneity was evaluated with the I and the χ test. Publication bias was evaluated using the Begg funnel plot. Metaregression was performed using the random-effects model modified by Knapp and Hartung. We included 15 RCTs (n = 483), most had small-to-modest sample sizes. Comparing active versus sham TMS, active stimulation was significantly superior for OCD symptoms (Hedges g = 0.45; 95% confidence interval, 0.2-0.71). The funnel plot showed that the risk of publication bias was...

Background: After age, the second largest risk factor for Alzheimer’s disease (AD) is apolipoprotein E (APOE) genotype, where APOE4 is associated with lower apoE protein levels, more severer brain pathology, enhanced inflammation and disease. Small peptides corresponding to the receptor-binding region of apoE mimic the anti-inflammatory activity of the apoE holoprotein. These apoE mimetics greatly improve behavioral outcomes and neuronal survival in head trauma models that display AD pathology and neuronal loss. Objective: To determine whether apoE mimetics change behavior, inflammation and pathology in CVND-AD (SwDI-APP/NOS2–/–) transgenic mice. Methods: Starting at 9 months, apoE peptides were subcutaneously administered 3 times per week for 3 months followed by behavioral, histochemical and biochemical testing. Results: Treatment with apoE mimetics significantly improved behavior while decreasing the inflammatory cytokine IL-6, neurofibrillary tangle-like and amyloid plaque-like ...

We have examined the effect on respiration of the steroid hormone progesterone, administered either intra- venously or directly into the medulla oblongata in anesthetized and paralyzed male and female cats. The carotid sinus and vagus nerves were cut, and end-tidal Pco2 and temperature were kept constant with servo-controllers. Phrenic nerve activity was used to quantitate central respiratory activity. Repeated doses of progesterone (from 0.1 to 2.0 ,ug/kg, cumulative) caused a sustained (>45 min) facilitation of phrenic nerve activity in female and male cats; however, the response was much more variable in females. Progesterone injected into the region of nucleus tractus solitarii, a respira- tory-related area in the medulla oblongata, also caused a prolonged stimulation of respiration. Progesterone adminis- tration at high concentration by both routes also caused a substantial hypotension. Identical i.v. doses of other classes of steroid hormones (17f8-estradiol, testosterone, and cortisol) did not elicit the same respiratory effect. Pretreatment with RU 486, a progesterone-receptor antagonist, blocked the facilita- tory effect of progesterone. We conclude that progesterone acts centrally through a steroid receptor-mediated mechanism to facilitate respiration.

The main treatment for cancer is by using chemotherapy and radiotherapy which themselves are toxic to other viable cells of the body. Recently, there are many studies focusing on the use of natural products for cancer prevention and treatment. Of these natural products, honey has been extensively researched. The mechanism of the anti-cancer activity of honey as chemopreventive and therapeutic agent has not been completely understood. The possible mechanisms are due to its apoptotic, antiproliferative, antitumor necrosis factor (anti-TNF), antioxidant, anti-inflammatory, estrogenic and immunomodulatory activities. We collate the findings of several studies published in the literature in order to understand the mechanism of its action.

Daily, organophosphorus compounds (OPs) in human life, has found wide applications. Although OPs have biodegradability potential, they induce clinical problems in humans and other organism. Different methods are used to detoxify these compounds. In the meantime, biodegradation is preferred as a compatible way to the environment since it produces less toxic compounds. Enzymes capable to degrade the OPs are of the most important items in the biodegradation. Genetic manipulation involved in the production of these enzymes has been employed in bacteria, and finally, is used for the mass production of recombinant microorganisms. In this paper, the role of organophosphates on human life and the ways to destroy toxic organophosphates are studied.

A series of 116 small-molecule 1-hydroxynaphthalene-2-carboxanilides was designed based on the fragment-based approach and was synthesized according to the microwave-assisted protocol. The biological activity of all of the compounds was tested on human colon carcinoma cell lines including a deleted TP53 tumor suppressor gene. The mechanism of activity was studied according to the p53 status in the cell. Several compounds revealed a good to excellent activity that was similar to or better than the standard anticancer drugs. Some of these appeared to be more active against the p53 null cells than their wild-type counterparts. Intercalating the properties of these compounds could be responsible for their mechanism of action.

Bipolar disorder is a major medical, social and economic burden worldwide. However, the biochemical basis of the disorder and the mechanisms of action of effective antibipolar disorder drugs remain elusive. In this paper, we review how combining a kinetic approach to studying the turnover of fatty acids within brain phospholipids of unanesthetized rats along with chronic administration of antimanic drugs (lithium, valproate and carbamazepine) at therapeutically relevant doses, shows that the brain arachidonic acid cascade is a common target of these drugs. The overlapping effects of the three drugs are decreased turnover of arachidonic acid but not of docosahexaenoic acid in rat brain phospholipids, and decreased brain cyclooxygenase-2 and prostaglandin E(2). Whereas lithium and carbamazepine target the transcription of the arachidonic acid-selective calcium-dependent cytosolic phospholipase A(2), valproate is a non-competitive inhibitor of an arachidonic acid-selective acyl-CoA syn...

Two new brominated bis(indole) alkaloids, dragmacidins I (1) and J (2), showing low micromolar cytostatic activity, along with three known congeners were isolated from the Tanzanian sponge sp. and their structures determined by the analysis of their NMR and MS data. From the study of their mechanism of action, it can be concluded that the mitotic arrest at metaphase in treated tumor cells, mediated by inhibition of PP1 and/or PP2A phosphatases is involved in the observed antiproliferative activity. Differences in their bioactivities were rationalized, and a plausible binding mode is proposed on the basis of computational simulations.

Anaplastic Lymphoma Kinase-Tyrosine Kinase Inhibitors (ALKTKIs) are highly effective in treating ALK-positive patients with
advanced non-small cell lung cancer (NSCLC). However, ALKTKI neoadjuvant therapy in ALK-positive NSCLC has not been
fully explored to date. In this case, the treatment of a patient initially diagnosed with stage IIB (T2bN1M0) lung adenocarcinoma
has been described. This patient harbor an ALK mutationt and was
treated with lorlatinib for three cycles. Consequently, the mass and
mediastinal lymph nodes shrank significantly, compared with the
previous findings. Following the surgery, the patient continued
lorlatinib adjuvant treatment; a subsequent review did not show
any recurrence or metastasis. Therefore, our results suggest that
lorlatinib neoadjuvant therapy is a viable option for ALK-positive
NSCLC patients

The ubiquitin system regulates essential cellular processes in eukaryotes. Ubiquitin is ligated to substrate proteins as monomers or chains and the topology of ubiquitin modifications regulates substrate interactions with specific proteins. Thus ubiquitination directs a variety of substrate fates including proteasomal degradation. Deubiquitinase enzymes cleave ubiquitin from substrates and are implicated in disease; for example, ubiquitin-specific protease-7 (USP7) regulates stability of the p53 tumour suppressor and other proteins critical for tumour cell survival. However, developing selective deubiquitinase inhibitors has been challenging and no co-crystal structures have been solved with small-molecule inhibitors. Here, using nuclear magnetic resonance-based screening and structure-based design, we describe the development of selective USP7 inhibitors GNE-6640 and GNE-6776. These compounds induce tumour cell death and enhance cytotoxicity with chemotherapeutic agents and targete...