Endoscopic submucosal dissection vs. endoscopic mucosal resection in the treatment of early Barrett's neoplasia: Systematic review and meta-analysis.

OBJECTIVES: Endoscopic resection is the preferred approach to treat early Barrett's neoplasia, reducing the need for surgical interventions. However, the best choice between endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) remains unclear. The study aimed to compare the efficacy and safety of EMR vs. ESD for early Barrett's neoplasia. METHODS: An electronic search was conducted in MEDLINE, Central Cochrane, EMBASE, and LILACS until November 2023. Studies comparing ESD vs. EMR in the treatment of patients with early Barrett's neoplasia were included. This study was performed according to the Preferred Report Items for Systematic Reviews and Meta-Analyses guidelines. The ROBIN-I tool was used to analyze the risk of bias and GRADE to measure the quality of the evidence. RESULTS: A total of 9352 patients from 15 observational studies were included. Patients undergoing ESD had significantly higher rates of en-bloc (odds ratio [OR] 25.96, 95% confidence interval [CI] 13.82, 48.74; I2 = 52%; P < 0.00001) and R0 (OR 5.10, 95% CI 3.29, 7.91; I2 = 73%; P < 0.00001) with a higher risk of adverse events, including bleeding, stricture formation, and perforation. In a subgroup analysis of patients who did not receive radiofrequency ablation, ESD had a lower recurrence rate than EMR (OR 0.22, 95% CI 0.05, 0.94; I2 = 88%; P = 0.04). CONCLUSION: Endoscopic submucosal dissection is more effective than EMR in treating early Barrett's neoplasia at the expense of higher adverse events rates.

Patient-Related Factors Associated With Long-Term Outcomes After Successful Endoscopic Balloon Dilation For Crohn's Disease-Associated Ileo-Colic Strictures: A Systematic Review and Meta-analysis.

Background: Successful Crohn's disease (CD) therapy relies on timely and precise management strategies. Endoscopic balloon dilation (EBD) has been applied as a first-line treatment for symptomatic CD-associated strictures due to its minimally invasive nature and the possibility of preserving intestinal length. Objective: The aim of the present study was to determine patient-related predictive factors associated with the need for surgery for CD-associated ileocolic strictures after technically successful EBD. Methods: All original studies published before December 2023 that reported the outcomes of patients treated with EBD for ileocolic strictures secondary to CD and described follow-up for at least 1 year were included. The difference in risk of needing surgery was calculated for 8 different patient characteristics (Sex, smoking habit, previous surgery, biologic therapy, steroids, immunosuppressors, nature of the stricture, and endoscopic disease activity). Results: There were significant differences in the risk of needing surgery after EBD among patients who underwent surgery and patients without a history of surgery (RD: -0.20 [-0.31, -0.08]), patients with endoscopic mucosal activity and patients in remission at the time of EBD (RD: 0.19 [0.04, 0.34]), patients using biologics at the time of EBD and patients not using biologics (RD: -0.09 [-0.16, -0.03]), and patients using steroids and those not using steroids at the time of EBD (RD: 0.16 [0.07, 0.26]). Conclusions: The use of biologics and endoscopic disease remission at the time of EBD were protective factors against the need for surgery. No previous surgery or use of steroids at the time of EBD was associated with the need for surgery during follow-up.

High expression of PD-L1 on conventional dendritic cells in tumour-draining lymph nodes is associated with poor prognosis in oral cancer.

INTRODUCTION: Oral squamous cell carcinoma (OSCC), while common and with a favorable prognosis in early stages, presents a marked reduction in survival rate upon metastasis to lymph nodes. Early detection of lymph node metastasis via biomarkers could enhance the therapeutic strategy for OSCC. Here, we explored dendritic cells (DCs) and cytotoxic T-cells in tumour-draining lymph nodes (TDLNs) as potential biomarkers. METHOD: Dendritic cells and cytotoxic T-cells in 33 lymph nodes were analyzed with multi-parameter flow cytometry in TDLNs, regional non-TDLNs surgically excised from 12 OSCC patients, and compared to 9 lymph nodes from patients with benign conditions. RESULTS: Our results displayed a higher proportion of conventional cDC1s with immunosuppressive features in TDLN. Further, high PD-L1 expression on cDC1 in TDLNs was associated with metastasis and/or recurrent disease risk. Also, elevated levels of memory CD8+ T-cells and terminally exhausted PD-1+TCF-1-CD8+ T-cells were observed in TDLNs and non-TDLNs compared to healthy lymph nodes. CONCLUSIONS: We conclude that TDLNs contain cells that could trigger an anti-tumor adaptive response, as evidenced by activated cDC1s and progenitor-like TCF-1+ T-cells. The detection of high PDL1 expression on cDC1s was indicative of TDLN metastasis and an adverse prognosis, proposing that PD-L1 on dendritic cells in TDLN could serve as a predictive biomarker of OSCC patients with a worse prognosis.

Antinociceptive and anti-inflammatory activities of Ayapana triplinervis essential oil rich in thymohydroquinone dimethyl ether from Brazil.

Ayapana triplinervis (M.Vahl) R.M.King & H.Rob. (Asteraceae), popularly known as japana, is a tropical, aromatic subshrub widely used as tea to combat some diseases. The essential oil was obtained from the leaves by hydrodistillation (3 h), and the chemical composition was analyzed by gas chromatography coupled to mass spectrometry. For in vivo assays, Mus musculus/Swiss mice were used to evaluate oral acute toxicological (at dose of 2000 mg/kg); peripheral and central analgesic for abdominal contortion (doses of 6.25, 12.5, 25, 50 and 100 mg/kg), hot plate test (12.5, 25, 50, and 100 mg/kg) and formalin (25, 50 and 100 mg/kg); open field test (100 mg/kg); and anti-inflammatory by ear swelling induced by xylene (6.25,12.5, 25, 50, and 100 mg/kg). The yield of A. triplinervis essential oil (AtEO) was 4.6%, and the oxygenated monoterpene 2,5-dimethoxy-p-cymene was the major compound in this study (63.6%). AtEO at a dose of 2,000 mg/kg orally did not change the behavior patterns or mortality of the animals; liver and kidney biochemical levels were similar to the control group, indicating no liver and kidney toxicity. Moreover, AtEO, at doses of 6.25, 12.5, 25, 50, and 100 mg/kg, reduced abdominal contortions by 21%, 54%, 91%, 58%, and 55%, respectively. In the hot plate test, AtEO showed a significant increase in latency time in the 60-min interval at doses of 25 mg/kg (11.3 ± 3.3 s) and 100 mg/kg (11.9 ± 0.9 s). In the first phase of the formalin test, AtEO decreased paw licking time at doses of 25, 50, and 100 mg/kg, with inhibition of 22%, 38%, and 83%; in the second phase, the same doses, decreased licking time with inhibition of 24%, 34%, and 76%. AtEO did not present a significant change in the spontaneous locomotor activity of the animals. Doses of 6.25, 12.5, 25, 50, and 100 mg/kg significantly reduced ear edema induced by topical application of xylene with percentages of 40%, 39%, 54%, 45%, and 45%, respectively. So, AtEO demonstrated low acute oral toxicity and exhibited significant antinociceptive and anti-inflammatory actions, consistent with the use of A. triplinervis in traditional medicine.

Scissor-assisted vs. conventional endoscopic submucosal dissection for colorectal lesions: Systematic review and meta-analysis.

OBJECTIVES: Colorectal endoscopic submucosal dissection (ESD) is a technically complex procedure. The scissor knife mechanism may potentially provide easier and safer colorectal ESD. The aim of this meta-analysis is to evaluate the efficacy and safety of scissor-assisted vs. conventional ESD for colorectal lesions. METHODS: A search strategy was conducted in MEDLINE, Embase, and Lilacs databases from January 1990 to November 2023 according to PRISMA guidelines. Fixed and random-effects models were used for statistical analysis. Heterogeneity was assessed using I2 test. Risk of bias was assessed using the ROBINS-I and RoB-2 tools. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation tool. RESULTS: A total of five studies (three retrospective and two randomized controlled trials, including a total of 1575 colorectal ESD) were selected. The intraoperative perforation rate was statistically lower (risk difference [RD] -0.02; 95% confidence interval [CI] -0.04 to -0.01; P = 0.001; I2 = 0%) and the self-completion rate was statistically higher (RD 0.14; 95% CI 0.06, 0.23; P = 0.0006; I2 = 0%) in the scissor-assisted group compared with the conventional ESD group. There was no statistical difference in R0 resection rate, en bloc resection rate, mean procedure time, or delayed bleeding rate between the groups. CONCLUSION: Scissor knife-assisted ESD is as effective as conventional knife-assisted ESD for colorectal lesions with lower intraoperative perforation rate and a higher self-completion rate.

Lippia alba essential oil: A powerful and valuable antinociceptive and anti-inflammatory medicinal plant from Brazil.

ETHNOPHARMACOLOGICAL RELEVANCE: In Brazilian popular medicine, Lippia alba leaves are used in teas to treat pain and inflammatory diseases. AIM OF THE STUDY: to evaluate the chemical composition, antinociceptive, and anti-inflammatory activities of Lippia alba essential oil and its major compound geraniol. MATERIAL AND METHODS: Lippia alba leaves were collected in Pará state, Brazil. The leaf essential oil was obtained using a modified Clevenger-type extractor. Then, the oil was analyzed by GC and GC-MS analyses. To evaluate the toxicity of LaEO and geraniol, the doses of 50, 300, and 2000 mg/kg were used in a mouse model. For antinociception tests, abdominal contortion, hot plate, and formalin tests were used; all groups were treated with LaEO and geraniol at doses of 25, 50, and 100 mg/kg; and to evaluate inflammation using the ear edema model. RESULTS: The constituents identified in the highest content were oxygenated monoterpenes: geraniol (37.5%), geranial (6.7%) and neral (3.8%). The animals treated with LaEO and geraniol demonstrated atypical behaviors with aspects of lethargy and drowsiness, characteristics of animals in a state of sedation; the relative weights showed no significant difference compared to the controls. In the abdominal contortion test, LaEO at 25 mg/kg, 50 mg/kg doses, and 100 mg/kg reduced the number of contortions, representing a percentage reduction of 84.64%, 81.23%, and 66.21% respectively. In the hot plate test, LaEO and geraniol increased the latency time at doses of 25, 50, and 100 mg/kg in all test periods; there was no statistical difference between LaEO and geraniol. In the first phase of the formalin test, only doses of 25 mg/kg and 100 mg/kg of LaEO showed significant activity, reducing the latency time by 53.40% and 58.90%. LaEO at doses of 25 mg/kg and 100 mg/kg reduced the size of the edema, demonstrating an anti-inflammatory activity of 59.38% (25 mg/kg) and 50% (100 mg/kg). CONCLUSION: Lippia alba essential oil and geraniol showed central/peripheral analgesic and anti-inflammatory potential and can be used as an alternative or complementary treatment to conventional drugs. More studies are needed to evaluate its action mechanisms and its analgesic effects.

Binding Evolution of the Dengue Virus Envelope Against DC-SIGN: A Combined Approach of Phylogenetics and Molecular Dynamics Analyses Over 30 Years of Dengue Virus in Brazil.

The Red Queen Hypothesis (RQH), derived from Lewis Carroll's "Through the Looking-Glass", postulates that organisms must continually adapt in response to each other to maintain relative fitness. Within the context of host-pathogen interactions, the RQH implies an evolutionary arms race, wherein viruses evolve to exploit hosts and hosts evolve to resist viral invasion. This study delves into the dynamics of the RQH in the context of virus-cell interactions, specifically focusing on virus receptors and cell receptors. We observed multiple virus-host systems and noted patterns of co-evolution. As viruses evolved receptor-binding proteins to effectively engage with cell receptors, cells countered by altering their receptor genes. This ongoing mutual adaptation cycle has influenced the molecular intricacies of receptor-ligand interactions. Our data supports the RQH as a driving force behind the diversification and specialization of both viral and host cell receptors. Understanding this co-evolutionary dance offers insights into the unpredictability of emerging viral diseases and potential therapeutic interventions. Future research is crucial to dissect the nuanced molecular changes and the broader ecological consequences of this ever-evolving battle. Here, we combine phylogenetic inferences, structural modeling, and molecular dynamics analyses to describe the epidemiological characteristics of major Brazilian DENV strains that circulated from 1990 to 2022 from a combined perspective, thus providing us with a more detailed picture on the dynamics of such interactions over time.

Cellular energy regulates mRNA degradation in a codon-specific manner.

Codon optimality is a major determinant of mRNA translation and degradation rates. However, whether and through which mechanisms its effects are regulated remains poorly understood. Here we show that codon optimality associates with up to 2-fold change in mRNA stability variations between human tissues, and that its effect is attenuated in tissues with high energy metabolism and amplifies with age. Mathematical modeling and perturbation data through oxygen deprivation and ATP synthesis inhibition reveal that cellular energy variations non-uniformly alter the effect of codon usage. This new mode of codon effect regulation, independent of tRNA regulation, provides a fundamental mechanistic link between cellular energy metabolism and eukaryotic gene expression.

Identification of Peptides in Spider Venom Using Mass Spectrometry.

Spider venoms are composed of hundreds of proteins and peptides. Several of these venom toxins are cysteine-rich peptides in the mass range of 3-9 kDa. Small peptides (<3 kDa) can be fully characterized by mass spectrometry analysis, while proteins are generally identified by the bottom-up approach in which proteins are first digested with trypsin to generate shorter peptides for MS/MS characterization. In general, it is sufficient for protein identification to sequence two or more peptides, but for venom peptidomics it is desirable to completely elucidate peptide sequences and the number of disulfide bonds in the molecules. In this chapter, we describe a methodology to completely sequence and determine the number of disulfide bonds of spider venom peptides in the mass range of 3-9 kDa by multiple enzyme digestion, mass spectrometry of native and digested peptides, de novo analysis, and sequence overlap alignment.

Exploring the impact of seasonal variations on the chemical composition, antinociceptive, and anti-inflammatory properties of Pogostemon heyneanus Benth. essential oil.

Background: Pogostemon heyneanus leaves infusions are relevant in ethnopharmacology for treating colds, coughs, headaches, and asthma. Purpose: The essential oil chemical composition of a Pogostemon heyneanus specimen was monthly monitored from October 2021 to July 2022 to evaluate the climatic influences on its yield and chemical composition and antinociceptive, andanti-inflammatory properties. Methods: The leaves, collected monthly over a 10-month period, were submitted to hydrodistillation. The oils obtained were analyzed by gas chromatography coupled to a mass spectrometer and gas chromatography coupled to flame ionization detector. The P. heyneanus essential oil (PhEO) was tested in vivo to evaluate its peripheral analgesic actions through the abdominal writhing test induced by acetic acid, and peripheral analgesia by tail immersion. Neurogenic and inflammatory pain were evaluated by formalin test, and acute oral toxicity of the oil was also verified. Results: PhEO presented 27 chemical constituents with the highest predominance of patchoulol (43.6%-76.9%), α-bulnesene (0.2%-12.7%), α-guaiene (0.4%-8.9%), seychellene (3.8%-5.1%) and pogostol (0.0%-8.2%). The climatic parameters insolation, humidity, rainfall, and temperature did not influence the essential oil yield or the main chemical constituents, except for pogostol, which presented a strong (r = 0.73) and statistically significant (p < 0.05) correlation with temperature. PhEO did not display toxicity at the maximum 300 mg/kg dosage. The oil showed low peripheral and central analgesic action at 100 mg/kg, while in the neurogenic and inflammatory pain inhibition tests, no actions related to PhEO were observed. In the carrageenan-induced peritonitis test, PhEO did not reduce the migration of leukocytes to the peritoneal cavity compared to the control group. Conclusion: Pogostemon heyneanus is a resistant plant to seasonal influences and a source of patchoulol. Despite ethnopharmacological indications, no in-vivo biological activities such as neurogenic or inflammatory pain were identified in the present work. So, the low influence of the climatic parameters on chemical composition can infer that the low pharmacological activity is also not subject to climatic variations, that is, it does not change due to the climate.

An electric field modeling study with meta-analysis to understand the antidepressant effects of transcranial direct current stimulation (tDCS)

Objective: Transcranial direct current stimulation (tDCS) has mixed effects for major depressive disorder (MDD) symptoms, partially owing to large inter-experimental variability in tDCS protocols and their correlated induced electric fields (E-fields). We investigated whether the E-field strength of distinct tDCS parameters was associated with antidepressant effect. Methods: A meta-analysis was performed with placebo-controlled clinical trials of tDCS enrolling MDD patients. PubMed, EMBASE, and Web of Science were searched from inception to March 10, 2023. Effect sizes of tDCS protocols were correlated with E-field simulations (SimNIBS) of brain regions of interest (bilateral dorsolateral prefrontal cortex [DLPFC] and bilateral subgenual anterior cingulate cortex [sgACC]). Moderators of tDCS responses were also investigated. Results: A total of 20 studies were included (21 datasets, 1,008 patients), using 11 distinct tDCS protocols. Results revealed a moderate effect for MDD (g = 0.41, 95%CI 0.18-0.64), while cathode position and treatment strategy were found to be moderators of response. A negative association between effect size and tDCS-induced E-field magnitude was seen, with stronger E-fields in the right frontal and medial parts of the DLPFC (targeted by the cathode) leading to smaller effects. No association was found for the left DLPFC and the bilateral sgACC. An optimized tDCS protocol is proposed. Conclusions: Our results highlight the need for a standardized tDCS protocol in MDD clinical trials. Registration number: PROSPERO CRD42022296246.

Tuberculosis testing patterns in South Africa to identify groups that would benefit from increased investigation.

The National Health Laboratory Service (NHLS) collects all public health laboratory test results in South Africa, providing a cohort from which to identify groups, by age, sex, HIV, and viral suppression status, that would benefit from increased tuberculosis (TB) testing. Using NHLS data (2012-2016), we assessed levels and trends over time in TB diagnostic tests performed (count and per capita) and TB test positivity. Estimates were stratified by HIV status, viral suppression, age, sex, and province. We used logistic regression to estimate the odds of testing positive for TB by viral suppression status. Nineteen million TB diagnostic tests were conducted during period 2012-2016. Testing per capita was lower among PLHIV with viral suppression than those with unsuppressed HIV (0.08 vs 0.32) but lowest among people without HIV (0.03). Test positivity was highest among young adults (aged 15-35 years), males of all age groups, and people with unsuppressed HIV. Test positivity was higher for males without laboratory evidence of HIV than those with HIV viral suppression, despite similar individual odds of TB. Our results are an important national baseline characterizing who received TB testing in South Africa. People without evidence of HIV, young adults, and males would benefit from increased TB screening given their lower testing rates and higher test positivity. These high-test positivity groups can be used to guide future expansions of TB screening.

Discovery of an Insect Neuroactive Helix Ring Peptide from Ant Venom.

Ants are among the most abundant terrestrial invertebrate predators on Earth. To overwhelm their prey, they employ several remarkable behavioral, physiological, and biochemical innovations, including an effective paralytic venom. Ant venoms are thus cocktails of toxins finely tuned to disrupt the physiological systems of insect prey. They have received little attention yet hold great promise for the discovery of novel insecticidal molecules. To identify insect-neurotoxins from ant venoms, we screened the paralytic activity on blowflies of nine synthetic peptides previously characterized in the venom of Tetramorium bicarinatum. We selected peptide U11, a 34-amino acid peptide, for further insecticidal, structural, and pharmacological experiments. Insecticidal assays revealed that U11 is one of the most paralytic peptides ever reported from ant venoms against blowflies and is also capable of paralyzing honeybees. An NMR spectroscopy of U11 uncovered a unique scaffold, featuring a compact triangular ring helix structure stabilized by a single disulfide bond. Pharmacological assays using Drosophila S2 cells demonstrated that U11 is not cytotoxic, but suggest that it may modulate potassium conductance, which structural data seem to corroborate and will be confirmed in a future extended pharmacological investigation. The results described in this paper demonstrate that ant venom is a promising reservoir for the discovery of neuroactive insecticidal peptides.

Transient Coma and Signs of Encephalopathy Related to 5-Fluorouracil and Carboplatin: A Case Report.

Chemotherapy-related encephalopathy is a rare but severe side effect of cancer therapy. Few reports exist on the course of encephalopathy due to 5-fluorouracil (5FU)/carboplatin treatment. Here, we report on a patient in his 70s, who received first-line palliative treatment with carboplatin followed by continuous infusion of 5FU against a metastasized cancer of the base of the tongue. During the first 5FU infusion, the patient developed a coma with sudden onset. In contrast to earlier reports of 5FU-induced encephalopathy, serum ammonium levels were near-normal, despite a slightly increased bilirubin. The electroencephalogram showed signs of general encephalopathy, for which no other probable cause than chemotherapy could be identified. Based on historical reports, the patient's encephalopathy was likely due to 5FU treatment rather than carboplatin. While initially in a coma with a Glasgow Coma Scale score of three, the patient regained consciousness within 3 days of supportive therapy. This case highlights the potentially benign clinical course of 5FU-induced encephalopathy, characterized by fulminant clinical deterioration and quick recovery. Such a rapid deterioration in a palliative setting can pose a clinical dilemma, where invasive treatments such as intubation must be weighed against a limited prognosis, for which this case may provide guidance.

Intravitreal acetazolamide implant for pseudophakic cystoid macular edema.

BACKGROUND: Pseudophakic cystoid macular edema (PCME) is the most common cause of visual acuity deterioration after uncomplicated cataract surgery. There is no consensus regarding how to manage recurrent or refractory cases. REPORT: A 54-year-old woman complained of decreased vision and central metamorphopsia in the right eye (OD) 3 months after uneventful cataract surgery. Visual acuity was 0.3 logMAR (20/40) OD and 0.1 logMAR (20/25) OS. Reduced macular brightness was seen OD on funduscopy associated with increased macular thickness on optical coherence tomography (OCT). Pseudophakic cystoid macular edema (PCME) was diagnosed, and treatment with oral acetazolamide was tried without success. The patient underwent a single intravitreal injection of an acetazolamide implant (260 µg) OD as off-label treatment. Four weeks following the injection, she reported complete resolution of her metamorphopsia and visual loss OD. Four months later, her visual acuity was 0.0 logMAR (20/20) in OD and 0.1 logMAR (20/25) in OS. The patient reported no discomfort after the injection procedure. Laboratory and ophthalmologic tests did not identify any adverse effects of the medication. CONCLUSION: We show that PCME refractory to conventional treatment improved after intravitreal acetazolamide implant injection. Further investigation is warranted to confirm these preliminary findings.

Toxicological safety, antioxidant activity and phytochemical characterization of leaf and bark aqueous extracts of Commiphora leptophloeos (Mart.) J.B. Gillett.

This study aimed to characterize the phytochemical profile of bark and leaves aqueous extract Commiphora leptophloeos, and conduct in vivo and in vitro assays to determine the presence of any toxicological consequences due to exposure. The phytochemical analysis was carried out using high-performance liquid chromatography (HPLC). The antioxidant activity was estimated utilizing DPPH free radical scavenging and phosphomolybdenum assays. Cell viability was measured by the MTT method on J774 and human adenocarcinoma cells, which were treated with concentrations of 12,5, 25, 50, 100 or 200 µg/ml of both extracts. Acute oral toxicity, genotoxicity, and mutagenicity assays were determined using a single oral dose of 2000 g/kg in male Swiss albino mice (Mus musculus). Biochemical analysis of the blood and histological analyses of the kidneys, liver, spleen, pylorus, duodenum and jejunum were undertaken. Genotoxicity and mutagenicity were determined utilizing blood samples. Gallic acid, catechin, and epicatechin were identified in the bark and chlorogenic acid in leaves. Data demonstrated a high content of phenolic compounds and flavonoids associated with significant antioxidant potential. No significant signs in damage or symptoms of toxicity were detected. No marked reduction in cell viability was found at lower concentrations tested. On histomorphometry, only the gastrointestinal organs exhibited significant difference. Renal hepatic and blood parameters were within the normal range. No apparent signs of toxicity, genotoxicity, mutagenicity or cytotoxicity were found in vivo and in vitro experiments.

Chemical composition, antinociceptive and anti-inflammatory activities of the curzerene type essential oil of Eugenia uniflora from Brazil.

ETHNOPHARMACOLOGICAL RELEVANCE: The Eugenia uniflora leaf infusion is widely used in folk medicine to treat gastroenteritis, fever, hypertension, inflammatory and diuretic diseases. AIM OF THE STUDY: This work evaluated the acute oral toxic, antinociceptive, and anti-inflammatory activities of the curzerene chemotype of Eugenia uniflora essential oil (EuEO). MATERIAL AND METHODS: EuEO was obtained by hydrodistillation and analyzed by GC and GC-MS. The antinociceptive action in mice was evaluated for the peripheral and central analgesic activity using abdominal contortion and hot plate tests (50, 100, and 200 mg/kg); xylene-induced ear swelling was carried out for the nociception test, and carrageenan-induced cell migration test. Spontaneous locomotor activity was assessed in the open field test to rule out any nonspecific sedative or muscle relaxant effects of EuEO. RESULTS: The EuEO displayed a yield of 2.6 ± 0.7%. The major compounds classes were oxygenated sesquiterpenoids (57.3 ± 0.2%), followed by sesquiterpene hydrocarbons (16.4 ± 2.6). The chemical constituents with the highest concentrations were curzerene (33.4 ± 8.5%), caryophyllene oxide (7.6 ± 2.8%), ß-elemene (6.5 ± 1.8%), and E-caryophyllene (4.1 ± 0.3%). Oral treatment with EuEO, at doses of 50, 300, and 2000 mg/kg, did not change the behavior patterns or mortality of the animals. EuEO (300 mg/kg) did not cause a reduction in the number of crossings in the open field compared to the vehicle group. The aspartate aminotransferase (AST) level was higher in EuEO-treated groups (50 and 2000 mg/kg) when compared to the control group (p < 0.05). EuEO, at doses of 50, 100, and 200 mg/kg, reduced the number of abdominal writhings by 61.66%, 38.33%, and 33.33%. EuEO did not show increased hot plate test time latency in any of the intervals analyzed. At 200 mg/kg, EuEO decreased paw licking time, with inhibition of 63.43%. In formalin-induced acute pain, EuEO decreased paw licking time at doses of 50, 100, and 200 mg/kg in the first phase, with inhibition of 30.54%, 55.02%, and 80.87%. The groups treated with EuEO at doses of 50, 100, and 200 mg/kg showed ear edema reduction of 50.26%, 55.17%, and 51.31%, respectively. Moreover, EuEO inhibited leukocyte recruitment only at a dose of 200 mg/kg. The inhibitory values of leukocyte recruitment after 4 h of carrageenan application were 4.86%, 4.93%, and 47.25% for 50, 100, and 200 mg/kg of essential oil, respectively. CONCLUSION: The EuEO, curzerene chemotype, has significant antinociceptive and anti-inflammatory activities and low acute oral toxicity. This work confirms the antinociceptive and anti-inflammatory of this species as the traditional use.

Regulatory B cells producing IL-10 are increased in human tumor draining lymph nodes.

The contribution of different immune cell subsets, especially T cells, in anti-tumor immune response is well established. In contrast to T cells, the anti-tumor contribution of B cells has been scarcely investigated. B-cells are often overlooked, even though they are important players in a fully integrated immune response and constitute a substantial fraction of tumor draining lymph nodes (TDLNs) known also as Sentinel Nodes. In this project, samples including TDLNs, non-TDLNs (nTDLNs) and metastatic lymph nodes from 21 patients with oral squamous cell carcinoma were analyzed by flow cytometry. TDLNs were characterized by a significantly higher proportion of B cells compared with nTDLNs (P = .0127). TDLNs-associated B cells contained high percentages of naïve B cells, in contrary to nTDLNs which contained significantly higher percentages of memory B cells. Patients having metastases in TDLNs showed a significantly higher presence of immunosuppressive B regulatory cells compared with metastasis-free patients (P = .0008). Elevated levels of regulatory B cells in TDLNs were associated with the advancement of the disease. B cells in TDLNs were characterized by significantly higher expression of an immunosuppressive cytokine-IL-10 compared with nTDLNs (P = .0077). Our data indicate that B cells in human TDLNs differ from B cells in nTDLNs and exhibit more naïve and immunosuppressive phenotypes. We identified a high accumulation of regulatory B cells within TDLNs which may be a potential obstacle in achieving response to novel cancer immunotherapies (ICIs) in head and neck cancer.

Radiotherapy-Dose Escalated for Large Volume Primary Tumors-And Cetuximab with or without Induction Chemotherapy for HPV Associated Squamous Cell Carcinoma of the Head and Neck-A Randomized Phase II Trial.

The leading cause of death for patients with HPV associated squamous cell carcinoma of the head and neck (SCCHN) after treatment with chemoradiotherapy (CRT) nowadays is peripheral metastasis. This study investigated whether induction chemotherapy (IC) could improve progression free survival (PFS) and impact on relapse pattern after CRT. METHODS: Eligible patients in this multicenter, randomized, controlled, phase 2 trial had p16-positive locoregionally advanced SCCHN. Patients were randomized in a 1:1 ratio to either RT with cetuximab (arm B) versus the same regimen preceded by two cycles of taxotere/cisplatin/5-FU (arm A). The RT dose was escalated to 74.8 Gy for large volume primary tumors. Eligibility criteria included patients of 18-75 years, an ECOG performance status 0-1, and adequate organ functions. RESULTS: From January 2011 to February 2016, 152 patients, all with oropharyngeal tumors were enrolled, 77 in arm A and 75 in arm B. Two patients, one in each group, withdrew their consent after randomization, leaving 150 patients for the ITT analysis. PFS at 2 years was 84.2% (95% CI 76.4-92.8) in arm A and 78.4% (95% CI 69.5-88.3) in arm B (HR 1.39, 95% CI 0.69-2.79, p = 0.40). At the time of analysis, there were 26 disease failures, 9 in arm A and 17 in arm B. In arm A, 3 patients had local, 2 regional, and 4 distant relapses as first sites of recurrence, and in arm B, 4, 4, and 9 relapses in corresponding sites. Eight out of 26 patients with disease progression had salvage therapy and 7 were alive NED (no evidence of disease), at 2 years. Locoregional control was 96% in arm A and 97.3% in arm B and OS 93% and 90.5%, respectively. Local failure as first site of recurrence was low, in 4.6% of patients and was similar for T1/T2 and T3/T4 tumors (n.s). Nevertheless, out of 7 patients with primary local failures, 4 were treated with the escalated RT dose. Toxicity was low and similar in the treatment arms. There was one fatal event in arm A where the combined effects of the drugs used in chemotherapy and cetuximab could not be ruled out. CONCLUSIONS: PFS, locoregional control and toxicity did not differ between the two arms, OS was high, and there were few local relapses. In arm B, more than twice as many patients had distant metastasis as the first site of relapse compared to arm A. The response to IC was found to define 29% of patients in arm A who did not have a tumor relapse during follow-up. An escalated dose of 74.8 Gy could mitigate the negative impact of large tumor volume but for some patients, even this intensified treatment was insufficient.

Residues of Legume AG41 Peptide Crucial to Its Bio-Insecticidal Activity.

Currently, crop protection relies heavily on chemical treatments, which ultimately leads to environmental contamination and pest resistance. Societal and public policy considerations urge the need for new eco-friendly solutions. In this perspective, biopesticides are effective alternatives to chemical insecticides for the control of various insect pests. Legumes contain numerous insecticidal proteins aimed at protecting their high nitrogen content from animal/insect predation. Investigating one such protein family at genome scale, we discovered a unique diversity of the albumin 1 family in the (model) barrel medic genome. Only some members retained very high insecticidal activity. We uncovered that AG41 peptide from the alfalfa roots displays an outstanding insecticidal activity against several pests such as aphids and weevils. Here we report the 3D structure and activity of AG41 peptide. Significant insights into the structural/functional relationships explained AG41 high insecticidal activity. Such observations pave the way for the development of bio-insecticides, with AG41 peptide as the lead compound.