In Vitro and In Silico Antiviral Activity of Di-Halogenated Compounds Derived from L-Tyrosine against Human Immunodeficiency Virus 1 (HIV-1).

HIV-1 infection is considered one of the major public health problems worldwide. Due to the limited access to antiretroviral therapy, the associated side effects, and the resistance that the virus can generate, it has become necessary to continue the development of new antiviral agents. The study aimed to identify potential antiviral agents for HIV-1 by evaluating the in vitro and in silico activity of 16 synthetic di-halogenated compounds derived from L-Tyrosine. The compounds were tested for cytotoxicity, which was determined using MTT, and a combined antiviral screening strategy (pre- and post-infection treatment) was performed against R5 and X4 strains of HIV-1. The most promising compounds were evaluated against a pseudotyped virus (HIV-GFP-VSV-G), and the effectiveness of these compounds was measured through GFP flow cytometry. Also, the antiviral effect of these compounds was evaluated in PBMCs using flow cytometry and ELISA for p24. The TODB-2M, TODC-2M, TODC-3M, and YDC-3M compounds showed low toxicity and significant inhibitory activity against HIV-1. In silico docking and molecular dynamics assays suggest that the compounds' antiviral activity may be due to interaction with reverse transcriptase, viral protease, or envelope gp120.

Programmed acoustic tags reveal novel information on late-phase marine life in Atlantic salmon, Salmo salar.

This pilot study used programmed acoustic tags implanted into Salmo salar smolts, in conjunction with an extensive offshore marine receiver array, to investigate late-stage migratory behaviour and survival of returning adult salmon. A total of 100 smolts were tagged in 2020, and a number of individuals were successfully detected as returning adults in 2021. After detection efficiency was accounted for, 5-9 adults were estimated to have returned to the offshore array c. 45 km from the river mouth. A total of three fish were subsequently detected in the river. Losses of between 40% and 66% were evident during the final stages of ocean migration, and one tagged fish provided direct evidence of a predation event.

A comparison of the behaviour and survival of angling vs. trap-sampled Salmo salar smolts.

An experiment was undertaken, using acoustic telemetry, to compare the survival and migratory timing of Salmo salar L. smolts sampled, under optimal conditions, in a traditional fixed Wolf trap against a sample of rod-caught fish captured using a sensitive angling technique. No significant difference was evident in survival with 83% of both samples detected in the river outflow, 67% of the trap and 76% of the rod samples were detected in coastal waters and finally 43% of the trap and 35% of the rod samples were detected on an offshore array c. 50 km from the river outlet. No significant difference was evident in the time taken for trap- and rod-sampled fish to reach either the river outflow, coastal or offshore waters. Angling, if undertaken sensitively, can provide an effective, resource-efficient and ethically justifiable sampling tool for juvenile salmonid age classes.

Adenosquamous cancer of the pancreas: A multicenter retrospective study.

INTRODUCTION: Adenosquamous cancer of the pancreas (ASCP) is an aggressive, infrequent subtype of pancreatic cancer that combines a glandular and squamous component and is associated with poor survival. METHODS: Multicenter retrospective observational study carried out at three Spanish hospitals. The study period was: January 2010-August 2020. A descriptive analysis of the data was performed, as well as an analysis of global and disease-free survival using the Kaplan-Meier statistic. RESULTS: Of a total of 668 pancreatic cancers treated surgically, twelve were ASCP (1.8%). Patient mean age was 69.2±7.4 years. Male/female ratio was 1:1. The main symptom was jaundice (seven patients). Correct preoperative diagnosis was obtained in only two patients. Nine pancreatoduodenectomies and three distal pancreatosplenectomies were performed. 25% had major complications. Mean tumor size was 48.6±19.4mm. Nine patients received adjuvant chemotherapy. Median survival time was 5.9 months, and median disease-free survival was 4.6 months. 90% of patients presented recurrence. Ten of the twelve patients in the study (83.3%) died, with disease progression being the cause in eight. Of the two surviving patients, one is disease-free and the other has liver metastases. CONCLUSION: ASCP is a very rare pancreatic tumor with aggressive behavior. It is rarely diagnosed preoperatively. The best treatment, if feasible, is surgery followed by the standard chemotherapy regimens for pancreatic adenocarcinoma.

Jaundice as a clinical presentation in liver hydatidosis increases the risk of postoperative biliary fistula.

PURPOSE: Echinococcosis, also known as hydatidosis, is a zoonosis that is endemic in many countries worldwide. Liver hydatid cysts have a wide variety of clinical manifestations, among which obstructive jaundice is one of the rarer forms. The aims of the study were to analyze the preoperative management of these patients and to record the kind of surgical treatment performed and the short- and long-term postoperative results. METHODS: A retrospective two-center observational study of patients operated upon for liver hydatidosis with initial symptoms of obstructive jaundice. Preoperative characteristics, surgical data, and postoperative complications, including biliary fistula, were recorded. RESULTS: Of 353 patients operated upon for liver hydatidosis, 44 were included in the study. Thirty-five patients (79.6%) were defined as CE2 or CE3 in the World Health Organization (WHO) classification. Preoperative endoscopic retrograde cholangiopancreatography (ERCP) was performed in 25 patients (56.8%) and identified intrabiliary communication in 29. Radical surgery was carried out in 29 of the total sample (65.9%). Severe postoperative complications (Clavien-Dindo grade IIIA or higher) were recorded in 25% of patients. The factors associated with greater postoperative morbidity were age above 65 (HR 8.76 [95% CI 0.78-97.85]), cyst location (HR 4.77 [95% CI 0.93-24.42]), multiple cysts (HR 14.58 [95% CI 1.42-149.96]), and cyst size greater than 5 cm (HR 6.88 [95% CI 0.95-50]). CONCLUSION: The presentation as obstructive jaundice causes greater postoperative morbidity. The main postoperative complication in these cases, despite radical surgery, is biliary fistula. In our series, routine preoperative ERCP did not show any benefit.

Effects of passive integrated transponder tags on short-term feeding patterns in European perch (Perca fluviatilis).

We tested the feeding behaviour of small European perch (Perca fluviatilis) in a laboratory study during the first 24 h after handling and 23 mm passive integrated transponder (PIT) tag implantation. Feeding commenced almost immediately following tagging and overall feeding patterns were unaffected by tagging. However, untagged perch had more feeding events than PIT-tagged individuals. This discrepancy could be attributed to post-tagging effects or/and reduced room for food due to the presence of the tag in the body cavity.

Melatonin Induces Apoptosis and Modulates Cyclin Expression and MAPK Phosphorylation in Pancreatic Stellate Cells Subjected to Hypoxia.

In certain diseases of the pancreas, pancreatic stellate cells form an important part of fibrosis and are critical for the development of cancer cells. A hypoxic condition develops within the tumor, to which pancreatic stellate cells adapt and are able to proliferate. The consequence is the growth of the tumor. Melatonin, the product of the pineal gland, is gaining attention as an agent with therapeutic potential against pancreatic cancers. Its actions on tumor cells lead, in general, to a reduction in cell viability and proliferation. However, its effects on pancreatic stellate cells subjected to hypoxia are less known. In this study, we evaluated the actions of pharmacological concentrations of melatonin (1 mM-1 µM) on pancreatic stellate cells subjected to hypoxia. The results show that melatonin induced a decrease in cell viability at the highest concentrations tested. Similarly, the incorporation of BrdU into DNA was diminished by melatonin. The expression of cyclins A and D also was decreased in the presence of melatonin. Upon treatment of cells with melatonin, increases in the expression of major markers of ER stress, namely BIP, phospho-eIF2α and ATF-4, were detected. Modulation of apoptosis was noticed as an increase in caspase-3 activation. In addition, changes in the phosphorylated state of p44/42, p38 and JNK MAPKs were detected in cells treated with melatonin. A slight decrease in the content of α-smooth muscle actin was detected in cells treated with melatonin. Finally, treatment of cells with melatonin decreased the expression of matrix metalloproteinases 2, 3, 9 and 13. Our observations suggest that melatonin, at pharmacological concentrations, diminishes the proliferation of pancreatic stellate cells subjected to hypoxia through modulation of cell cycle, apoptosis and the activation of crucial MAPKs. Cellular responses might involve certain ER stress regulator proteins. In view of the results, melatonin could be taken into consideration as a potential therapeutic agent for pancreatic fibrosis.

Pancreatic resection for metastatic renal cell carcinoma. A systematic review.

BACKGROUND: Renal cell carcinoma (RCC) can lead to secondary pancreatic tumors even years after nephrectomy was performed. Surgical resection in selected patients shows appropriate survival rates. METHODS: A systematic review was performed following PRISMA guidelines. This review finished in May 2019 and included patients with resected pancreatic metastasis(es). The main purpose was to evaluate the results of surgical resection of pancreatic tumors secondary to kidney cancer. RESULTS: After the screening process of articles, 21 were selected for the systematic review, which included 354 patients, whose disease-free interval (DFI) was 105.11 (0-361.56) months. Of these patients, 34.6% had additional metastases elsewhere at the time of the surgery, and 48.6% were symptomatic. Postoperative morbidity was 40.2%, The 5-year overall survival (OS) rate was 53.9% (26-75). CONCLUSION: Pancreatic surgery for the resection of RCC metastasis(es) is considered safe and shows low morbidity and mortality rates among selected patients in medical institutions where this type of procedure is commonly performed.

Leiomyoma of the round ligament of the liver: report of one case.

Tumoral conditions in the round ligament of the liver are very uncommon and exhibit nonspecific manifestations, hence a high level of suspicion is necessary for their diagnosis. We report the case of a 47-year-old female patient who presented with abdominal pain for several months; imaging studies showed a lesion of indeterminate nature likely connected with the falciform ligament, and only intraoperative findings acknowledged the presence of an apparently benign tumor in the round ligament of the liver, which biopsy confirmed. Following the excision of the round ligament the patient had a favorable course. As this is a pathologically benign lesion we deem its surgical management both advisable and sufficient. However, because of its small prevalence and the scarcity of literature involving this condition, further studies would be needed to provide information on natural history, treatment, and long-term prognosis.

A yeast-based high-throughput screen identifies inhibitors of trypanosomatid HRG heme transporters with potent leishmanicidal and trypanocidal activity.

OBJECTIVES: New drugs are required to treat neglected diseases caused by trypanosomatid parasites such as Leishmania, Trypanosoma brucei and Trypanosoma cruzi. An Achilles' heel of these parasites is their heme auxotrophy; they have an absolute dependence on scavenging this molecule from the host, and trypanosomatid HRG heme transporters (TrypHRG) play an important role in this process. As these proteins are essential for the parasites and have low similarity with their human orthologue, they have been proposed as attractive therapeutic targets. Here, we have developed two yeast-based assays that allow an inexpensive high-throughput screening of TrypHRG inhibitors within a cellular context. METHODS: We first assessed that Leishmania major, Leishmania donovani and T. brucei HRG proteins were heterologously expressed in the digestive vacuole membrane of a mutant heme auxotrophic yeast strain. Here, TrypHRG imports hemoglobinderived heme into the cytosol, allowing mutant yeast to grow in the presence of low hemoglobin concentrations and promoting the activity of hemeproteins such as catalase, which was used as a reporter of cytosolic heme levels. RESULTS: In the presence of a TrypHRG inhibitor, both catalase activity (test 1) and yeast growth (test 2) were diminished, being easily monitored. The assays were then tested on a pilot scale for HTS purposes using a collection of repurposing drugs and food antioxidants. Some of the TrypHRG inhibitors identified in yeast presented strong trypanocidal and leishmanicidal activity in the submicromolar range, proving the potential of this approach. CONCLUSIONS: Cumulatively, it was shown that the inhibition bioassays developed were robust and applicable to large-scale HTS.

Repeated pancreatic resection for pancreatic metastases from renal cell Carcinoma: A Spanish multicenter study (PANMEKID).

BACKGROUND AND OBJECTIVES: Recurrent isolated pancreatic metastasis from Renal Cell Carcinoma (RCC) after pancreatic resection is rare. The purpose of our study is to describe a series of cases of relapse of pancreatic metastasis from renal cancer in the pancreatic remnant and its surgical treatment with a repeated pancreatic resection, and to analyse the results of both overall and disease-free survival. METHODS: Multicenter retrospective study of patients undergoing pancreatic resection for RCC pancreatic metastases, from January 2010 to May 2020. Patients were grouped into two groups depending on whether they received a single pancreatic resection (SPS) or iterative pancreatic resection. Data on short and long-term outcome after pancreatic resection were collected. RESULTS: The study included 131 pancreatic resections performed in 116 patients. Thus, iterative pancreatic surgery (IPS) was performed in 15 patients. The mean length of time between the first pancreatic surgery and the second was 48.9 months (95 % CI: 22.2-56.9). There were no differences in the rate of postoperative complications. The DFS rates at 1, 3 and 5 years were 86 %, 78 % and 78 % vs 75 %, 50 % and 37 % in the IPS and SPS group respectively (p = 0.179). OS rates at 1, 3, 5 and 7 years were 100 %, 100 %, 100 % and 75 % in the IPS group vs 95 %, 85 %, 80 % and 68 % in the SPS group (p = 0.895). CONCLUSION: Repeated pancreatic resection in case of relapse of pancreatic metastasis of RCC in the pancreatic remnant is justified, since it achieves OS results similar to those obtained after the first resection.

Testing field adaptation strategies for delaying grape ripening and improving wine composition in a cv. Macabeo Mediterranean vineyard.

Under semiarid and warm climates, field practices for climate change adaptation have to be defined in order to modulate grape composition according to the desired wine styles. Under this context, the present study investigated several viticulture practices in cv. Macabeo for Cava production. The experiment was carried out over 3 years in a commercial vineyard located in the province of Valencia (eastern Spain). The techniques tested were (i) vine shading, (ii) double pruning (bud forcing), and (iii) the combined application of soil organic mulching and shading, all of them tested against a control. Double pruning significantly modified phenology and grape composition, improving the wine alcohol-to-acidity ratio and reducing the pH. Similar results were also achieved by shading. However, the shading strategy did not significantly affect yield, unlike double pruning, which reduced vine yield even in the year following its application. Shading alone or in combination with mulching significantly improved the vine water status, suggesting that these techniques can also be used to alleviate water stress. Particularly, we found that the effect of soil organic mulching and canopy shading on stem water potential was additive. Indeed, all the techniques tested were useful for improving wine composition for cava production, but double pruning is only recommended for premium Cava production.

Influence of the tumor site and histopathology after resection for non-colorectal non-neuroendocrine liver metastases. A single center experience.

INTRODUCTION: It remains unclear whether liver resection is justified in patients with non-colorectal non-neuroendocrine liver metastases (NCNNLM). A single-center study was conducted to analyse overall survival (OS), disease-free survival (DFS), and potential prognostic factors in patients with different types of NCNNLM. METHOD: A retrospective analysis of all patients who underwent liver resection of NCNNLM from January 2006 to July 2019 was performed. RESULTS: A total of 62 patients were analyzed. 82.3% presented metachronous metastases and 74.2% were unilobar. The most frequent primary tumor site (PTS) were breast (24.2%), urinary tract (19.4%), melanoma (12.9%), and pancreas (9.7%). The most frequent primary tumor pathologies were breast carcinoma (24.2%), non-breast adenocarcinoma (21%), melanoma (12.9%) and sarcoma (12.9%). The most frequent surgical procedure performed was minor hepatectomy (72.6%). R0 resection was achieved in 79.5% of cases. The major complications' rate was 9.7% with a 90-day mortality rate of 1.6%. The 1, 3 and 5-year OS/DFS rate were 65%/28%, 45%/36% and 46%/28%, respectively. We identified the response to neoadjuvant therapy and PTS as possible prognostic factors for OS (P =0.06) and DFS (P =0.06) respectively. CONCLUSION: Based on the results of our series, NCNNLM resection produces beneficial outcomes in terms of OS and DFS. PTS and the response to neoadjuvant therapy could be the main prognostic factors after resection.

Textbook outcome in the surgical treatment of liver hydatid cyst.

BACKGROUND: Textbook outcome is a composite measure used in surgery to define the ideal postoperative period and to assess the quality of care. The aim of this study was to analyze the incidence of textbook outcome and the factors independently associated with its achievement following surgical treatment of liver hydatid cysts. METHODS: Retrospective cohort study of patients operated on for liver hydatid cysts between January 2006 and December 2021. Textbook outcome was achieved when all the following criteria were fulfilled: no mortality within 90 days, no major complications within 90 days, no hospital readmission within 90 days, and no prolonged hospital stay. Univariable and multivariable analyses were performed to identify factors associated with textbook outcome. RESULTS: During the study period, 296 patients underwent surgery. Textbook outcome was recorded in 65.9% (195/296). Female gender (odds ratio 2.02; P = .010), noncomplicated cyst (odds ratio 3.97, P < .001), and radical surgery (odds ratio 2.26, P = .003) were the variables associated with a higher probability of achieving textbook outcome. CONCLUSION: Textbook outcome may be a useful measure to assess the variations in surgical management between different centers, and to improve quality of care after liver hydatid cysts resection.

Prediction of potential cysteine synthase inhibitors of Leishmania braziliensis and Leishmania major parasites by computational screening.

Leishmaniasis is a neglected tropical disease considered a public health problem that requires innovative strategies for its chemotherapeutic control. In the present investigation, a molecular docking approach was carried out using the protein cysteine synthase (CS) of Leishmania braziliensis (CSLb) and Leishmania major (CSLm) parasites to identify new compounds as potential candidates for the development of selective leishmaniasis therapy. CS protein sequence similarity, active site, structural modeling, molecular docking, and ADMET properties of compounds were analyzed using bioinformatics tools. Molecular docking analyses identified 1000 ligands with highly promising binding affinity scores for both CS proteins. A total of 182 compounds for CSLb and 173 for CSLm were selected for more detailed characterization based on the binding energy and frequency values and ADMET properties. Based on Principal Component Analysis (PCA) and K-means clusterization for both CS proteins, we classified compounds into 5 clusters for CSLb and 7 for CSLm, thus providing an excellent starting point for verification of enzyme inhibition in in vitro studies. We found the ZINC16524774 compound predicted to have a high affinity and stability for both CSLb and CSLm proteins, which was also evaluated through molecular dynamics simulations. Compounds within each of the five clusters also displayed pharmacological and structural properties that make them attractive drug candidates for the development of selective cutaneous leishmaniasis chemotherapy.

Retraction: Rendon-Marin et al. Canine Morbillivirus from Colombian Lineage Exhibits In Silico and In Vitro Potential to Infect Human Cells. Pathogens 2021, 10, 1199.

The authors retract the article "Canine Morbillivirus from Colombian Lineage Exhibits In Silico and In Vitro Potential to Infect Human Cells" [...].

Surgical treatment of liver hydatid cyst in elderly patients: A propensity score-matching retrospective cohort study.

BACKGROUND: Cystic echinococcosis is a clinically complex chronic parasitic disease and a major socioeconomic problem in endemic areas. The safety of liver resection in elderly patients is often debated among medical professionals. We analyzed the postoperative morbidity and mortality rates of elderly patients who underwent surgery at our unit. METHODS: We retrospectively evaluated patients with liver hydatid cysts which were surgically removed at our unit. Patients were divided into two groups: Group 1 (patients < 70 years), and Group 2 (patients ≥ 70 years). Propensity score matching (PSM) and comparative analyses between groups were performed. RESULTS: The unmatched cohort consisted of 279 patients (Group 1: 244; Group 2: 35). After PSM, we compared the outcomes for 56 patients from Group 1 to 31 patients from Group 2. A higher rate of severe complications was observed in Group 2 (25.8% vs 5.36%, p = 0.014). No difference was found in the rates of infectious, cardiorespiratory, or hemorrhagic complications between both groups, and in the mortality rate either (0.00% vs 6.45%, p = 0.124). CONCLUSIONS: Liver surgery in selected elderly patients is safe and practicable. The low postoperative morbidity rate in these patients is acceptable, albeit higher, due to their comorbidities.

Resection of isolated pancreatic metastases from pulmonary neoplasia: a systematic review.

Several types of cancers have been reported to metastasize to the pancreas. Lung cancer with isolated pancreatic metastasis is extremely rare. In selected patients, surgery is advocated. The aim of our study is to carry out a systematic review of the articles published on the surgical treatment of these patients. Our goal was to realize a systematic review in accordance with PRISMA guidelines. We conducted a literature search using MEDLINE (PubMed), EMBASE and SCOPUS databases to identify all studies published from 1967 to 2020 reporting patients with pancreatic resection for metastatic lung cancer to the pancreas. The data of the articles finally selected were represented in tables. The median age of included patients was calculated as well as the median survival. The proportion of patients was calculated according to sex, type of surgery performed and location of the lesion. 3150 articles were included at the beginning. After the screening process, 20 articles were selected for the systematic review. These articles reported data on 23 patients. Presentation was mainly metachronous, with a disease-free interval of 10 (0-54) months. Of these patients, 43.5% were symptomatic at diagnosis and 34.8% had extrapancreatic metastases. Mean overall survival was 17.65 (± 14.56) months. Based in this review, there is limited evidence on the treatment due to the small number of published articles, most of them being case report. Surgical resection of pancreatic metastases from lung cancer could be a safe procedure and it could improve survival rates in selected patients.

Prognostic value of pre-operative systemic immune-inflammation index and platelet to lymphocyte ratio in peritoneal carcinomatosis of ovarian origin.

BACKGROUND AND OBJECTIVES: The aim of this study was to investigate the impact of systemic immune-inflammation index (SII), platelet to lymphocyte ratio (PLR) and neutrophil to lymphocyte ratio (NLR) on the survival outcomes of patients who underwent to cytoreductive surgery (CRS) and HIPEC for ovarian peritoneal carcinomatosis. METHODS: A retrospective analysis of 68 cases following surgery at our department between 2015 and 2020 was performed. Receiver Operating Characteristic (ROC) curve was used with Youden index to calculate the optimal cutoff values for SII, PLR and NLR. RESULTS: Univariate analysis revealed that high preoperative values of SII, PLR and NLR were correlated with worse overall survival (OS) and disease-free survival (DFS) in these patients. In the multivariable analysis, high SII was recognized as an independent prognostic factor for OS (CI 95%: 0.002- 3.835, p = 0.097) and high PLR was recognized as an independent prognostic factor for DFS (CI 95%: 0.253-2.248, p = 0.007). CONCLUSION: SII and PLR could be useful prognostic tools to predict outcomes of patients who underwent to CRS and HIPEC for ovarian peritoneal carcinomatosis.