Medicinal plant extracts interfere in gastric cancer stem cells fluorescence-based assays.

Fluorescence is used in various biological assays due to its high sensitivity, versatility, and precision. In recent years, studies using medicinal plant extracts have increased. However, fluorescence-based assays could be biased by plant metabolites autofluorescence. To address this issue, this study investigated the interference caused by methanolic extracts and chloroform fractions of three medicinal plants in three fluorescence-based assays on gastric cancer stem cells(CSC): resazurin reduction, confocal microscopy, and flow cytometry. CSC were isolated based on CD44 surface marker, incubated with methanolic extracts and chloroform fractions of Buddleja incana, Dracontium spruceanum, Piper aduncum. Resazurin assay evidenced that CSC exposed to extracts and fractions from the three plants showed significant differences in relative fluorescence units (RFU) levels (p < 0.001) compared to the unexposed groups after a 3-hour incubation. In addition, DMSO-treated CSC exposed to extracts and fractions had significantly lower fluorescence levels than living ones, but higher than extracts and fractions without cells. In confocal microscopy, cancer stem cells exposed to extracts and fractions of B. incana and P. aduncum were observed in the same emission spectra of the CSC markers. In flow cytometry, CSC exposed to extracts and fractions without any fluorescent dyes were detected in the double positive quadrants for CSC markers (CD44+/CD133 + ). Among the three plants, D. spruceanum exhibited the least interference. These results show that methanolic extracts and chloroform fractions contain autofluorescent metabolites that interfere with fluorescence-based assays. These results highlight the importance of a prior evaluation for possible fluorescence interference to avoid interpretation biases in fluorescence assays.

EFFICACY AND SAFETY OF BIOLOGICAL TREATMENT FOR INFLAMMATORY BOWEL DISEASE IN ELDERLY PATIENTS: RESULTS FROM A GETECCU COHORT.

INTRODUCTION: Biological therapies used for the treatment of inflammatory bowel disease (IBD) have shown to be effective and safe, although these results were obtained from studies involving mostly a young population, who are generally included in clinical trials. The aim of our study was to determine the efficacy and safety of the different biological treatments in the elderly population. METHODS: Multicenter study was carried out in the GETECCU group.Patients diagnosed with IBD and aged over 65 years at the time of initiating biological therapy (infliximab, adalimumab, golimumab, ustekinumab or vedolizumab) were retrospectively included. Among the patients included, clinical response was assessed after drug induction (12 weeks of treatment) and at 52 weeks. Patients' colonoscopy data in week 52 were assesment, where available. Regarding complications, development of oncological events during follow-up and infectious processes occurring during biological treatment were collected (excluding bowel infection by cytomegalovirus). RESULTS: A total of 1090 patients were included. After induction, at approximately 12-14 weeks of treatment, 419 patients (39.6%) were in clinical remission, 502 patients (47.4%) had responded without remission and 137 patients (12.9%) had no response. At 52 weeks of treatment 442 patients (57.1%) had achieved clinical remission, 249 patients had responded without remission (32.2%) and 53 patients had no response to the treatment (6.8%). Before 52 weeks, 129 patients (14.8%) had discontinued treatment due to inefficacy, this being significantly higher (p<0.0001) for Golimumab - 9 patients (37.5%) - compared to the other biological treatments analysed. With respect to tumor development, an oncological event was observed in 74 patients (6.9%): 30 patients (8%) on infliximab, 23 (7.14%) on adalimumab, 3 (11.1%) on golimumab, 10 (6.4%) on ustekinumab, and 8 (3.8%) on vedolizumab. The incidence was significantly lower (p = 0.04) for the vedolizumab group compared to other treatments.As regards infections, these occurred in 160 patients during treatment (14.9%), with no differences between the different biologicals used (p = 0.61): 61 patients (19.4%) on infliximab, 39 (12.5%) on adalimumab, 5 (17.8%) on golimumab, 22 (14.1%) on ustekinumab, and 34 (16.5%) on vedolizumab. CONCLUSIONS: Biological drug therapies have response rates in elderly patients similar to those described in the general population, Golimumab was the drug that was discontinued most frequently due to inefficacy.

Proposal and Validation of a New Index to Assess the Difficulty of Lower Third Molar Extraction.

There is no current consensus on the parameters that determine the difficulty of mandibular third molar extraction in terms of the time required, which is essential to prevent complications and optimize the time of the intervention. This study aims to obtain, using the mathematical method of multiple linear regression, an equation that allows estimating the extraction time of a lower third molar according to its complexity, as well as to validate this equation in a sample of external wisdom teeth. METHODS: A prospective cohort study on a sample of patients of the Master of Oral Surgery of the University of Seville in which multiple linear regression coefficients were calculated with a subsequent validation study of the results in the sample of patients operated in the Hospital Palmaplanas of Mallorca. RESULTS: The regression line obtained after applying the statistical methodology to the cohort of patients from the University of Seville obtained significant dependent variables such as depth, roots, and odontosection. Once applied to the cohort of patients from the Palmaplanas Hospital in Mallorca, a regression coefficient was obtained between the data received and the estimated 0.770. CONCLUSIONS: The formula proposed in this article presents significant validity in the prediction of the surgical time of extraction of the lower third molars included.

Role of second look endoscopy in endoscopic submucosal dissection and peptic ulcer bleeding: Meta-analysis of randomized controlled trials.

BACKGROUND: Second-look endoscopy (SLE) to prevent recurrent bleeding in patients with peptic ulcer disease (PUD) and those undergoing endoscopic submucosal dissection (ESD) is routinely being performed. Conflicting evidence exists regarding efficacy, risk, benefit, and cost-effectiveness. AIM: To identify the role and effectiveness of SLE in ESD and PUD, associated rebleeding and PUD-related outcomes like mortality, hospital length of stay, need for endoscopic or surgical intervention and blood transfusions. METHODS: A systematic review of literature databases PubMed, Cochrane, and Embase was conducted from inception to January 5, 2023. Randomized controlled trials that compared patients with SLE to those who did not have SLE or evaluated the role of prophylactic hemostasis during SLE compared to other conservative interventions were included. The study was conducted per PRISMA guidelines, and the protocol was registered in PROSPERO (ID CRD42023427555:). RevMan was used to perform meta-analysis, and Mantel-Haenszel Odds ratio (OR) were generated using random effect models. RESULTS: A total of twelve studies with 2687 patients were included in our systematic review and meta-analysis, of which 1074 patients underwent SLE after ESD and 1613 patients underwent SLE after PUD-related bleeding. In ESD, the rates of rebleeding were 7% in the SLE group compared to 4.4% in the non-SLE group with OR 1.65, 95% confidence intervals (CI) of 0.96 to 2.85; P = 0.07, whereas it was 11% in the SLE group compared to 13% in the non-SLE group with OR 0.8 95%CI: 0.50 to 1.29; P = 0.36. The mean difference in the blood transfusion rates in the SLE and no SLE group in PUD was OR 0.01, 95%CI: -0.22 to 0.25; P = 0.91. In SLE vs non-SLE groups with PUD, the OR for Endoscopic intervention was 0.29, 95%CI: 0.08 to 1.00; P = 0.05 while it was OR 2.03, 95%CI: 0.95 to 4.33; P = 0.07, for surgical intervention. The mean difference in the hospital length of stay was -3.57 d between the SLE and no SLE groups in PUD with 95%CI: -7.84 to 0.69; P = 0.10, denoting an average of approximately 3 fewer days of hospital stay among patients with PUD who underwent SLE. For mortality between SLE and non-SLE groups in PUD, the OR was 0.88, 95%CI: 0.45 to 1.72; P = 0.70. CONCLUSION: SLE does not confer any benefit in preventing ESD and PUD-associated rebleeding. SLE also does not provide any significant improvement in mortality, need for interventions, or blood transfusions in PUD patients. SLE decreases the hospital length of stay on average by 3.5 d in PUD patients.

Enhanced neuronal survival and BDNF elevation via long-term co-activation of galanin 2 (GALR2) and neuropeptide Y1 receptors (NPY1R): potential therapeutic targets for major depressive disorder.

BACKGROUND: Major Depressive Disorder (MDD) is a prevalent and debilitating condition, necessitating novel therapeutic strategies due to the limited efficacy and adverse effects of current treatments. We explored how galanin receptor 2 (GALR2) and Neuropeptide Y1 Receptor (NPYY1R) agonists, working together, can boost brain cell growth and increase antidepressant-like effects in rats. This suggests new ways to treat Major Depressive Disorder (MDD). RESEARCH DESIGN AND METHODS: In a controlled laboratory setting, adult naive Sprague-Dawley rats were administered directly into the brain's ventricles, a method known as intracerebroventricular (ICV) administration, with GALR2 agonist (M1145), NPYY1R agonist, both, or in combination with a GALR2 antagonist (M871). Main outcome measures included long-term neuronal survival, differentiation, and behavioral. RESULTS: Co-administration of M1145 and NPYY1R agonist significantly enhanced neuronal survival and maturation in the ventral dentate gyrus, with a notable increase in Brain-Derived Neurotrophic Factor (BDNF) expression. This neurogenic effect was associated with an antidepressant-like effect, an outcome partially reversed by M871. CONCLUSIONS: GALR2 and NPYY1R agonists jointly promote hippocampal neurogenesis and exert antidepressant-like effects in rats without adverse outcomes, highlighting their therapeutic potential for MDD. The study's reliance on an animal model and intracerebroventricular delivery warrants further clinical exploration to confirm these promising results.

The impact of alpha-1 antitrypsin deficiency alleles on lung cancer survival.

Different studies have shown that carrying an alpha-1 antitrypsin (AAT) deficiency allele is an independent risk factor for developing lung cancer (LC). However, to date, little is known regarding whether carrying a deficiency allele may be a prognostic factor in the evolution of LC. A prospective observational study was carried out which consecutively included patients diagnosed with LC in University Hospital "Nuestra Señora de Candelaria" between December 2017 and August 2020. A blood sample was taken from each of the patients in order to determine both AAT serum concentration and genotype. Based on AAT genotype, patients were divided into the deficiency (Pi*≠MM) or non-deficiency (Pi*=MM) group. One hundred and sixty-four patients were included. The average length of follow-up was 13±10 months. Patients were classified as stage I (4.2%), stage II (8.3%), stage III (31.2%) and stage IV (56.3%), according to tumour, node and metastasis (TNM) staging. Twenty-eight patients (17%) were carriers of a deficiency allele (6 Pi*MS, 1 Pi*MZ, 1 Pi*MMheerlen). No significant differences were found with respect to baseline characteristics between Pi*≠MM and Pi*=MM. Patients in the Pi*≠MM group had a higher risk of death in the first 6 months after the LC diagnosis compared to Pi*=MM subjects (HR =2.04; 95% CI: 1.04-4.0; P=0.038). The presence of an AAT deficiency genotype could be a potential prognostic marker in LC. However, larger studies that justify these findings are needed.

Potent, selective and reversible hMAO-B inhibition by benzalphthalides: Synthesis, enzymatic and cellular evaluations and virtual docking and predictive studies.

Monoaminooxidases (MAOs) are important targets for drugs used in the treatment of neurological and psychiatric disorders and particularly on Parkinson's Disease (PD). Compounds containing a trans-stilbenoid skeleton have demonstrated good selective and reversible MAO-B inhibition. Here, twenty-two (Z)-3-benzylidenephthalides (benzalphthalides, BPHs) displaying a trans-stilbenoid skeleton have been synthesised and evaluated as inhibitors of the MAO-A and MAO-B isoforms. Some BPHs have selectively inhibited MAO-B, with IC50 values ranging from sub-nM to µM. The most potent compound with IC50 = 0.6 nM was the 3',4'-dichloro-BPH 16, which showed highly selective and reversible MAO-B inhibitory activity. Furthermore, the most selective BPHs displayed a significant protection against the apoptosis, and mitochondrial toxic effects induced by 6-hydroxydopamine (6OHDA) on SH-SY5Y cells, used as a cellular model of PD. The results of virtual binding studies on the most potent compounds docked in MAO-B and MAO-A were in agreement with the potencies and selectivity indexes found experimentally. Additionally, related to toxicity risks, drug-likeness and ADME properties, the predictions found for the most relevant BPHs in this research were within those ranges established for drug candidates.

The S-REAL study: Spanish real-world data on unresectable stage III NSCLC patients treated with durvalumab after chemoradiotherapy.

OBJECTIVES: The S-REAL study aimed to assess the effectiveness of durvalumab as consolidation therapy after definitive chemoradiotherapy (CRT) in a real-world cohort of patients with locally advanced, unresectable stage III non-small cell lung cancer (LA-NSCLC) included in a Spanish early access program (EAP). METHODS: In this multicentre, observational, retrospective study we analysed data from patients treated in 39 Spanish hospitals, who started intravenous durvalumab (10 mg/kg every 2 weeks) between September 2017 and December 2018. The primary endpoint was progression-free survival (PFS). Secondary endpoints included patient characterization and adverse events of special interest (AESI). RESULTS: A total of 244 patients were followed up for a median of 21.9 months [range 1.2-34.7]. Median duration of durvalumab was 45.5 weeks (11.4 months) [0-145]. Median PFS was 16.7 months (95% CI 12.2-25). No remarkable differences in PFS were observed between patients with programmed cell death-ligand 1 (PD-L1) expression ≥ 1% or < 1% (16.7 versus 15.6 months, respectively). However, PFS was higher in patients who had received prior concurrent CRT (cCRT) versus sequential CRT (sCRT) (20.6 versus 9.4 months). AESIs leading to durvalumab discontinuation were registered in 11.1% of patients. CONCLUSIONS: These results are in line with prior published evidence and confirm the benefits of durvalumab in the treatment of LA-NSCLC patients in a real-world setting. We also observed a lower incidence of important treatment-associated toxicities, such as pneumonitis, compared with the pivotal phase III PACIFIC clinical study.

A novel presentation of diaphragmatic flutter in a patient with obstructive sleep apnea and recurrent cerebellar hemangioblastoma.

We report a unique case of diaphragmatic flutter in a patient with obstructive sleep apnea who had no respiratory symptoms related to flutter and a history of recurrent cerebellar hemangioblastoma. The flutter was detected during a routine follow-up monitoring through the built-in software of the positive airway pressure device; the flow and pressure curves showed abnormal and curious oscillations. The ultrasound confirmed the diagnosis and ruled out other causes of abnormal diaphragmatic movements. This case report contributes to the scientific literature by presenting a novel case of diaphragmatic flutter associated with recurrent cerebellar hemangioblastoma. It also emphasizes the need for more research on the pathophysiology and treatment of this rare condition. CITATION: Ciorba C, Espinoza Perez JA, Alfonso Imizcoz M, Errasti Viader J, Cebollero Rivas P, De Vito EL. A novel presentation of diaphragmatic flutter in a patient with obstructive sleep apnea and recurrent cerebellar hemangioblastoma. J Clin Sleep Med. 2024;20(2):313-317.

Enhancing disinfection and microcontaminant removal by coupling LED driven UVC and UVA/photo-Fenton processes in continuous flow reactors.

For the first time, the sequential combination of UVC-LED (276 nm) and photo-Fenton/UVA-LED (376 nm) process has been assessed in continuous flow mode for wastewater reclamation according to the new European Regulation for reuse in agricultural irrigation (EU 2020/741). The results show that it is possible to obtain water quality class B (Escherichia coli ≤ 100 CFU/100 mL) by UVC-LED irradiation alone, operating the system with a hydraulic residence time (HRT) of 6.5 min and liquid depth of 5 cm in the case of secondary effluents with low Escherichia coli load (8.102-3.1.103 CFU/100 mL). As for high bacteria concentrations (1.2-4.2.104 CFU/100 mL), HRTs longer than 30 min are required. The bacterial load has not influenced decontamination, removing 18 ± 4 % of microcontaminants. Coupling the UVC (30-min HRT and 5.0 cm liquid depth) and the UVA/photo-Fenton (60-min and 15-cm liquid depth) systems allows 58 ± 4 % of real organic microcontaminants to be removed, in addition to achieving water quality class B.

Oncological outcomes in robot-assisted radical prostatectomy: the value of PSA density as a preoperative predictive factor.

Background: Pretreatment assessment of patients diagnosed with localized prostate cancer (PCa) is essential for therapeutic decision-making. Currently available staging systems based on prostate-specific antigen (PSA), Gleason score, and clinical stage allow for determining the prognostic characteristics of these patients. Several studies have evaluated the preoperative use of prostate-specific antigen density (PSAD) as a prognostic factor for further risk stratification. To date, the role of PSAD in this setting is still an object of debate. Objectives: The present analysis aimed to assess the predictive potential of PSAD for adverse oncological outcomes after robot-assisted radical prostatectomy (RARP) and to compare its accuracy to preoperative PSA (pPSA). Design and methods: We retrospectively reviewed 427 patients diagnosed with localized PCa who underwent RARP at a single institution between January 2015 and January 2020. Generating receiver operator characteristic (ROC) curves, calculating areas under the curves (AUCs), and using a linear regression model, we analyzed the association of PSAD and pPSA with postoperative positive surgical margins (PSM), Gleason score ⩾ 7, persistent PSA, and biochemical recurrence (BCR), with a median follow-up of 47 months. Results: PSAD showed a significant association with PSM (p < 0.0001), PSA persistence (p < 0.0001), and Gleason ⩾ 7 (p < 0.0001), without being statistically significant in predicting BCR (p = 0.098). The predictive value of PSAD was comparable to pPSA for outcomes of PSA persistence (AUC 0.727 versus 0.771) and Gleason ⩾ 7 (AUC 0.683 versus 0.649). Conclusion: PSAD is a predictive factor for postoperative oncological outcomes of PSM, Gleason score ⩾ 7, and persistence of PSA. Despite the need for further studies, PSAD could be useful as a prognostic parameter in conjunction with established staging systems.

Oncological outcomes in robot-assisted radical prostatectomy: the value of PSA density as a preoperative predictive factor Prostate-specific antigen density (PSAD) has an established role in the diagnostic process of prostate cancer (PCa). However, controversy remains on the assessment of its value as a pretreatment prognostic factor. The aim of our study was to evaluate the predictive ability of PSAD for oncological outcomes in PCa patients treated with robot-assisted radical prostatectomy (RARP) and to compare with the value of preoperative PSA (pPSA). The present analysis showed a significant association of PSAD with positive surgical margins (PSM), Gleason Score >=7 and prostate-specific antigen (PSA) persistence after RARP. Moreover, PSAD demonstrated to perform comparably to pPSA in predicting the outcomes of clinically significant PCa (csPCa) and post-RARP PSA persistence. Therefore, PSAD is considered a preoperative predictive factor potentially useful in conjunction with other previously established prognostic criteria and clinical features.

Structure-Antitumor Activity Relationships of Aza- and Diaza-Anthracene-2,9,10-Triones and Their Partially Saturated Derivatives.

The 1,8-Diazaanthracene-2,9,10-triones, their 5,8-dihydro derivatives, and 1,8-diazaanthracene-2,7,9,10-tetraones, structurally related to the diazaquinomycin family of natural products, were synthesized in a regioselective fashion employing Diels-Alder strategies. These libraries were studied for their cytotoxicity in a variety of human cancer cell lines in order to establish structure-activity relationships. From the results obtained, we conclude that some representatives of the 1,8-diazaanthracene-2,9,10-trione framework show potent and selective cytotoxicity against solid tumors. Similar findings were made for the related 1-azaanthracene-2,9,10-trione derivatives, structurally similar to the marcanine natural products, which showed improved activity over their natural counterparts. An enantioselective protocol based on the use of a SAMP-related chiral auxiliary derived was developed for the case of chiral 5-substituted 1,8-diazaanthracene-2,9,10-triones, and showed that their cytotoxicity was not enantiospecific.

Polatuzumab vedotin plus rituximab and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma: a cohort of a multicentre, single-arm, phase 1b/2 study.

BACKGROUND: Diffuse large B-cell lymphoma comprises nearly 30% of non-Hodgkin lymphoma cases and patients with relapsed or refractory diffuse large B-cell lymphoma who are ineligible for stem-cell transplantation have few treatment options and poor prognoses. We aimed to determine whether the novel combination of polatuzumab vedotin in combination with rituximab and lenalidomide (Pola+R+Len) would provide a tolerable treatment option with enhanced antitumour response in patients with relapsed or refractory diffuse large B-cell lymphoma. METHODS: This completed phase 1b/2, open-label, multicentre, single-arm study (GO29834) evaluated the safety and efficacy of Pola+R+Len in patients with relapsed or refractory diffuse large B-cell lymphoma at 19 sites in three countries (USA, Spain, and UK). Patients (≥18 years old) were eligible for inclusion if they had histologically documented CD20-positive relapsed or refractory diffuse large B-cell lymphoma and Eastern Cooperative Oncology Group performance status of 2 or lower, had received at least one previous line of chemoimmunotherapy, including an anti-CD20 agent, and were ineligible for stem-cell transplantation. The dose-escalation phase (1b) used escalating doses of lenalidomide to find the recommended phase 2 dose. Patients received six 28-day cycles of induction treatment with intravenous rituximab 375 mg/m2 and intravenous polatuzumab vedotin 1·8 mg/kg (all cohorts) plus oral lenalidomide at the following doses: 10 mg (cohort A); 15 mg (cohort B); and 20 mg (cohort C). Rituximab and polatuzumab vedotin were administered on day 1 and lenalidomide on days 1-21 of each 28-day cycle. During the dose-expansion phase (2), patients received six 28-day cycles of Pola+R+Len at the recommended phase 2 dose established during dose escalation. In both phases, patients with a complete response or partial response at the end of induction were eligible for post-induction therapy with rituximab 375 mg/m2 on day 1 and lenalidomide 10 mg/day on days 1-21 of each 28-day cycle for a maximum of 6 cycles. The primary safety objective of the dose-escalation phase was identification of the maximum tolerated dose through incidence of dose-limiting toxic effects. The primary efficacy outcome of the dose-expansion phase was Independent Review Committee-assessed complete response rate at end of induction, based on PET-CT. Analyses were conducted in the safety population, which included all patients who received at least one dose of any study drug, and the efficacy population, which included all patients who received at least one dose of any study drug at the recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02600897. FINDINGS: Between July 11, 2017 and Feb 3, 2020, 57 patients were enrolled (median age 71 years [IQR 60-75]; 38 [67%] were male and 19 (33%) were female; 47 [82%] were not Hispanic or Latino; and the median previous lines of therapy was 2 [IQR 1-3]). 18 participants were included in phase 1b and 39 were included in phase 2. Phase 1b confirmed a 20 mg recommended phase 2 dose for lenalidomide. After a median follow-up of 11·8 months (IQR 4·7-25·8), the complete response rate, as assessed by the Independent Review Committee, was 31% (90% CI 20-43). The most common grade 3-4 adverse events were neutropenia (35 [61%] of 57) and thrombocytopenia (eight [14%] of 57). Serious adverse events were reported in 23 (40%) of 57 patients and one patient died due to a treatment-related adverse event (neutropenic sepsis). INTERPRETATION: Although the combination of Pola+R+Len did not meet the prespecified activity threshold, some patients derived clinical benefit and the regimen had a tolerable safety profile in patients with relapsed or refractory diffuse large B-cell lymphoma. FUNDING: Genentech/F Hoffmann-La Roche.

Graft-versus-host disease after an outpatient peripheral blood hematopoietic cell transplant using reduced-intensity conditioning: a single-center LATAM experience.

BACKGROUND: HLA compatibility predicts allogeneic hematopoietic cell transplant (allo-HCT) and graft-versus-host disease (GvHD) outcomes. There is insufficient information regarding GvHD outcomes for outpatient HLA-identical and haploidentical-HCT employing reduced-intensity conditioning (RIC). RESEARCH DESIGN AND METHODS: We compare GvHD outcomes between donor types and report risk factors associated with GvHD. Stem cell source was T-cell replete peripheral blood. GvHD prophylaxis was post-transplant cyclophosphamide (PT-CY), mycophenolic acid, and calcineurin inhibitors for haploidentical (n = 107) and oral cyclosporine (CsA) plus methotrexate i.v. for HLA-identical (n = 89) recipients. RESULTS: One hundred and ninety-six HCT transplant patients were included. aGvHD and cGvHD frequency were similar between HCT types. aGvHD severity was comparable, but severe cGvHD was less frequent in the haploidentical group (p = .011). One-hundred-day cumulative incidence (CI) of aGvHD for haploidentical and HLA-identical was 31% and 33% (p = .84); 2-year CI of cGvHD was 32% and 38% (p = .6), respectively. Haploidentical recipients had less steroid-refractory cGvHD (p = .043). Patients with cGvHD had less 2-year relapse (p = .003); both aGvHD and cGvHD conferred higher OS (p = .010 and p = .001), respectively. Male sex was protective for steroid-refractory cGvHD (p = .028). CONCLUSIONS: Acute and chronic GvHD rates were comparable between HLA-identical and haploidentical transplant groups. cGvHD severity was lower in the haploidentical group.

Molecular details of ruthenium red pore block in TRPV channels.

Transient receptor potential vanilloid (TRPV) channels play a critical role in calcium homeostasis, pain sensation, immunological response, and cancer progression. TRPV channels are blocked by ruthenium red (RR), a universal pore blocker for a wide array of cation channels. Here we use cryo-electron microscopy to reveal the molecular details of RR block in TRPV2 and TRPV5, members of the two TRPV subfamilies. In TRPV2 activated by 2-aminoethoxydiphenyl borate, RR is tightly coordinated in the open selectivity filter, blocking ion flow and preventing channel inactivation. In TRPV5 activated by phosphatidylinositol 4,5-bisphosphate, RR blocks the selectivity filter and closes the lower gate through an interaction with polar residues in the pore vestibule. Together, our results provide a detailed understanding of TRPV subfamily pore block, the dynamic nature of the selectivity filter and allosteric communication between the selectivity filter and lower gate.

Value of inflammatory response and oxidative damage in the diagnosis of infections in severe alcoholic hepatitis.

Severe alcoholic hepatitis is the most lethal complication in alcohol dependent patients. The concurrence of infections in these patients is very frequent. Both produce a systemic inflammatory response syndrome (SIRS), secondary to intense release of inflammatory cytokines, which can complicate the diagnosis. In our study, Interleukin (IL)-6 and IL-10 levels are higher in patients with SIRS (p<0.001 and p = 0.033, respectively). IL-4, IL-6, Interferon-gamma (IFNγ), Tumor necrosis factor alpha (TNFα) and IL-17 levels correlate with liver function, as estimated by MELD-Na (p = 0.018, p = 0.008, p = 0.009, p = 0.016 and p = 0.006, respectively). Malondialdehyde (MDA), a product of lipid peroxidation and marker of cell damage, also correlates with liver function (p = 0.002), but not with SIRS or infections. Only elevated IL-6 correlates independently with the presence of infections (RR=1.023 IC 95% 1.000-1.047), so it may be useful for the correct diagnosis in these patients. Values greater than 30 pg/mL have a sensitivity: 86.7% and specificity: 94.7% for the diagnosis of infections.

A Dynamic Endonasal Columellar Strut Placement.

The dynamic retrograde intercrural columellar strut graft placement is a novel technique for a columellar strut insertion via a hemi-transfixion incision in patients undergoing endonasal functional or cosmetic surgery. It has a maximally concealed incision and does not disrupt major or minor tip support mechanisms. In our article, we give a detailed description of this unique surgical technique. Laryngoscope, 134:1246-1248, 2024.

Buenas Prácticas de Manufactura de carnicerías y prevalencia de Escherichia coli productor de toxina Shiga y Salmonella spp. aisladas en carne molida de carnicerías de Asunción, Paraguay

La inocuidad de la carne comercializada debe estar garantizada en la cadena de producción, para evitar enfermedades transmitidas por alimentos (ETA). Escherichia coli productor de toxina Shiga (STEC) y Salmonella spp. pueden encontrarse en el tracto gastrointestinal de los bovinos y contaminar la carne de consumo humano, pudiendo causar enfermedades en el hombre. Este trabajo tuvo como objetivo evaluar las condiciones higiénico-sanitarias de 52 carnicerías localizadas en Asunción y detectar la frecuencia de STEC y Salmonella spp. en muestras de carne molida. Las condiciones higiénico-sanitarias se evaluaron mediante la estimación del riesgo, utilizando una escala de clasificación por categorías. La detección de STEC y Salmonella spp. se realizó por PCR en tiempo real. En la evaluación inicial, se clasificaron a 33% de las carnicerías como de alto y moderado riesgo. Se detectó STEC no-O157 en un 50% (130/258) de las muestras y Salmonella spp. en un 11% (29/258). Se realizaron acciones de mejora. En la etapa post-intervención, no se detectaron carnicerías de alto riesgo. En el muestreo de seguimiento se detectó un 29% (66/237) de muestras positivas para STEC no-O157 y 7% (16 /237) para Salmonella spp. Este estudio permitió realizar recomendaciones específicas y detalladas a cada carnicería, lo que tuvo un efecto significativo en la mejora de sus condiciones. Esta situación resalta la importancia de continuar fortaleciendo la vigilancia multisectorial y multidisciplinaria. Es imperativo que los establecimientos que se dedican al rubro, implementen las Buenas Prácticas de Manufactura (BPM) como una medida para reducir los riesgos asociados.

The safety of marketed meat must be guaranteed in the production chain, to avoid foodborne illness. Shiga toxin-producing Escherichia coli (STEC) and Salmonella spp. can be found in the gastrointestinal tract of cattle and contaminate meat for human consumption, potentially causing diseases in humans. This work aimed to evaluate the hygienic-sanitary conditions of 52 butcher shops located in Asunción and detect the frequency of STEC and Salmonella spp. in ground beef samples. Hygienic-sanitary conditions were evaluated by estimating risk, using a categorical classification scale. The detection of STEC and Salmonella spp. was performed by real-time PCR. In the initial evaluation, 33% of the butcher shops were classified as high and moderate risk. STEC non-O157 was detected in 50% (130/258) of the samples and Salmonella spp. in 11% (29/258). Improvement actions were carried out. In the post-intervention stage, no high-risk butcher shops were detected. In the follow-up sampling, 29% (66/237) of positive samples were detected for STEC non-O157 and 7% (16/237) for Salmonella spp. This study allowed specific and detailed recommendations to be made to each butcher shop, which had a significant effect on improving their conditions. This situation highlights the importance of continuing to strengthen multisectoral and multidisciplinary surveillance. It is imperative that establishments dedicated to the sector implement Good Manufacturing Practices (GMP) as a measure to reduce associated risks.

Repurposing Study of 4-Acyl-1-phenylaminocarbonyl-2-substituted-piperazine Derivatives as Potential Anticancer Agents-In Vitro Evaluation against Breast Cancer Cells.

Breast cancer is the most common type of cancer in women. Although current treatments can increase patient survival, they are rarely curative when the disease is advanced (metastasis). Therefore, there is an urgent need to develop new cytotoxic drugs with a high selectivity toward cancer cells. Since repurposing approved drugs for cancer therapy has been a successful strategy in recent years, in this study, we screened a library of antiviral piperazine-derived compounds as anticancer agents. The compounds included a piperazine ring and aryl urea functions, which are privileged structures present in several anti-breast cancer drugs. The selective cytotoxic activity of a set of thirty-four 4-acyl-2-substituted piperazine urea derivatives against MCF7 breast cancer cells and MCF 10A normal breast cells was determined. Compounds 31, 32, 35, and 37 showed high selective anticancer activity against breast cancer cells and were also tested against another common type of cancer, non-small cell lung cancer (A549 lung cancer cells versus MRC-5 lung normal cells). Compounds 35 and 37 also showed selectivity against lung cancer cells. These results suggest that compounds 35 and 37 may be promising hit compounds for the development of new anticancer agents.