Cervidae antlers exploited to manufacture prehistoric tools and hunting implements as a reliable source of ancient DNA.

Antler is one of the primary animal raw materials exploited for technical purposes by the hunter-gatherer groups of the Eurasian Upper Palaeolithic (UP) all over the ecological range of deers, and beyond. It was exhaustively employed to produce one of the most critical tools for the survival of the UP societies: hunting weapons. However, antler implements can be made from diverse deer taxa, with different ecological requirements and ethological behaviours. Identifying the antler's origin at a taxonomic level is thus essential in improving our knowledge of humans' functional, practical and symbolic choices, as well as the human-animal interface during Prehistoric times. Nevertheless, palaeogenetics analyses have focused mainly on bone and teeth, with genetic studies of antler generally focused on modern deer conservation. Here we present the results of the first whole mitochondrial genome ancient DNA (aDNA) analysis by means of in-solution hybridisation capture of antlers from pre-Holocene archaeological contexts. We analysed a set of 50 Palaeolithic and Neolithic (c. 34-8ka) antler and osseous objects from South-Western Europe, Central Europe, South-Western Asia and the Caucasus. We successfully obtained aDNA, allowing us to identify the exploited taxa and demonstrate the archaeological relevance of those finds. Moreover, as most of the antlers were sampled using a minimally-invasive method, further analyses (morphometric, technical, genetic, radiometric and more) remain possible on these objects.

Meibum Lipidomic Analysis in Evaporative Dry Eye Subjects.

Meibomian Glands (MG) are sebaceous glands responsible for the production of meibum, the main component of the Tear Film Lipid Layer (TFLL). The TFLL facilitates the spread of the tear film over the ocular surface, provides stability and reduces tear evaporation. Alterations in meibum composition lead to different ocular alterations like Meibomian Gland Dysfunction (MGD) and subsequent Evaporative Dry Eye (EDE). The aim of the present study was to investigate the composition and abundance of meibum lipids and their relationship with eyelid margin abnormalities, lipid layer patterns and MG status. The study utilizes a lipidomic approach to identify and quantify lipids in meibum samples using an Elute UHPLC system. This system considered all four dimensions (mass/charge, retention time, ion mobility and intensity) to provide the accurate identification of lipid species. Samples were categorized as healthy or low/no signs of alteration (group 1) or severe signs of alteration or EDE/MGD (group 2). The current investigation found differences in Variable Importance in Projection lipid abundance between both groups for the MGD signs studied. Changes in meibum composition occur and are related to higher scores in eyelid margin hyperaemia, eyelid margin irregularity, MG orifice plugging, MG loss and lipid layer pattern.

CD8+ NKs as a potential biomarker of complete response and survival with lenalidomide plus R-GDP in the R2-GDP-GOTEL trial in recurrent/refractory diffuse large B cell lymphoma.

Background: Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma worldwide. DLBCL is an aggressive disease that can be cured with upfront standard chemoimmunotherapy schedules. However, in approximately 35-40% of the patients DLBCL relapses, and therefore, especially in this setting, the search for new prognostic and predictive biomarkers is an urgent need. Natural killer (NK) are effector cells characterized by playing an important role in antitumor immunity due to their cytotoxic capacity and a subset of circulating NK that express CD8 have a higher cytotoxic function. In this substudy of the R2-GDP-GOTEL trial, we have evaluated blood CD8+ NK cells as a predictor of treatment response and survival in relapsed/refractory (R/R) DLBCL patients. Methods: 78 patients received the R2-GDP schedule in the phase II trial. Blood samples were analyzed by flow cytometry. Statistical analyses were carried out in order to identify the prognostic potential of CD8+ NKs at baseline in R/R DLBCL patients. Results: Our results showed that the number of circulating CD8+ NKs in R/R DLBCL patients were lower than in healthy donors, and it did not change during and after treatment. Nevertheless, the level of blood CD8+ NKs at baseline was associated with complete responses in patients with R/R DLBCL. In addition, we also demonstrated that CD8+ NKs levels have potential prognostic value in terms of overall survival in R/R DLBCL patients. Conclusion: CD8+ NKs represent a new biomarker with prediction and prognosis potential to be considered in the clinical management of patients with R/R DLBCL. Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001620-29 EudraCT, ID:2014-001620-29.

Peritoneal tuberculosis in an immunocompetent patient: A case report.

Introduction: Tuberculosis is endemic in Colombia, the prevalence of its pulmonary form in immunocompetent hosts is high, and peritoneal compromise instead is rare and difficult to diagnose. Case presentation: A 24-year-old female patient living in a rural area presented to the emergency department with constitutional and gastrointestinal symptoms, including bloating, diarrhea, significant weight loss, nocturnal diaphoresis, and gradual onset of ascites with abdominal pain. Diagnostic workup, including paracentesis, a transvaginal ultrasound, and an abdominal CT scan, did not suggest malignancy or portal hypertension. However, diagnostic laparoscopy revealed a miliary pattern comprising the parietal and pelvic peritoneum, uterus, fallopian tubes, and major omentum suggestive of peritoneal tuberculosis. Anti-tuberculosis therapy was initiated with subsequent microbiological confirmation. Conclusion: Abdominal compromise by tuberculosis is a diagnostic challenge, especially in patients with no apparent risk factors. The clinical manifestations and paraclinical data may be unspecific or inconclusive, requiring peritoneal biopsy and empirical treatment before definitive confirmation.

Genetic linkage analysis of head and neck cancer in a Spanish family.

OBJECTIVES: To describe the genetic variants that may be associated with the development of head and neck cancer (HNC) and functionally validating the molecular implications. MATERIALS AND METHODS: A prospective observational study was carried out on a family of 3 generations in which 3 members had developed HNC. Peripheral blood sample was taken in a routine procedure for exome sequencing in one relative and genotyping in the remaining twelve relatives. For the functional analysis all-trans retinoic acid (atRA) was extracted from saliva and serum and measured using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The presence of HPV-DNA. RESULTS: None of the patients smoked or consumed alcohol. The presence of HPV DNA was not detected in any of the biopsied samples. A total amount of 6 members out of 13 (46.15%) carried out the same mutation of CYP26B1 (2p13.2; G>T). The mean plasma concentration of atRA was 3.3109 ± 1.4791 pg/mL for the study family and 4.7370 ± 1.5992 pg/mL for the controls (p = 0.042). CONCLUSION: Lower levels of atRA were confirmed in the study family, which may open the way to the possible relationship between the polymorphism CYP26B1 (2p13.2; G>T) and HNC.

SAFARI: shape analysis for AI-segmented images.

BACKGROUND: Recent developments to segment and characterize the regions of interest (ROI) within medical images have led to promising shape analysis studies. However, the procedures to analyze the ROI are arbitrary and vary by study. A tool to translate the ROI to analyzable shape representations and features is greatly needed. RESULTS: We developed SAFARI (shape analysis for AI-segmented images), an open-source R package with a user-friendly online tool kit for ROI labelling and shape feature extraction of segmented maps, provided by AI-algorithms or manual segmentation. We demonstrated that half of the shape features extracted by SAFARI were significantly associated with survival outcomes in a case study on 143 consecutive patients with stage I-IV lung cancer and another case study on 61 glioblastoma patients. CONCLUSIONS: SAFARI is an efficient and easy-to-use toolkit for segmenting and analyzing ROI in medical images. It can be downloaded from the comprehensive R archive network (CRAN) and accessed at https://lce.biohpc.swmed.edu/safari/ .

Maritime-oriented foragers during the Late Pleistocene on the eastern costa del sol (Southeast Iberia): Cueva Victoria (Málaga, Spain).

The Mediterranean coast of Spain is marked by several clusters of Palaeolithic sites: to the south of the Pyrenees, in the area around the Ebro River, in the central part, and on the south coast, one of the southernmost regions in Europe. The number of sites is small compared with northern Iberia, but like that region, the Palaeolithic occupations are accompanied by several rock art ensembles. The archaeological material (both biotic and abiotic resources) and radiocarbon dates presented here were obtained during archaeological fieldwork of professor J. Fortea in the Late Pleistocene deposits in Cueva Victoria, located near the modern coastline and about 150 km north of the Strait of Gibraltar. In the three occupation phases, marine resources were acquired by shell-fishing (focusing almost exclusively on the clam Ruditapes decussatus), fishing, and the use of beached marine mammals. This contrasts with the limited data about the exploitation of terrestrial resources by hunting and gathering animals and plants. The study is completed by the study of artefacts (lithic and bone industry and objects of adornment) that help to understand the subsistence strategies of the cave occupants and enable a comparison with other groups inhabiting the Mediterranean coasts of the Iberian Peninsula during Greenland Interstadial 1, between ca. 15.1 and 13.6 cal BP.

Lenalidomide plus R-GDP (R2-GDP) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Final Results of the R2-GDP-GOTEL Trial and Immune Biomarker Subanalysis.

PURPOSE: New therapeutic options are needed in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Lenalidomide-based schedules can reverse rituximab refractoriness in lymphoma. PATIENTS AND METHODS: In the phase II R2-GDP trial, 78 patients unsuitable for autologous stem cell transplant received treatment with the following schedule: lenalidomide 10 mg Days (D)1-14, rituximab 375 mg/m2 D1, cisplatin 60 mg/m2 D1, gemcitabine 750 mg/m2 D1 and D8, and dexamethasone 20 mg D1-3, up to 6 cycles (induction phase), followed by lenalidomide 10 mg (or last lenalidomide dose received) D1-21 every 28 days (maintenance phase). Primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and monitorization of key circulating immune biomarkers (EU Clinical Trials Register number: EudraCT 2014-001620-29). RESULTS: After a median follow-up of 37 months, ORR was 60.2% [37.1% complete responses (CR) and 23.1% partial responses (PR)]. Median OS was 12 months (47 vs. 6 months in CR vs. no CR); median PFS was 9 months (34 vs. 5 months in CR vs. no CR). In the primary refractory population, ORR was 45.5% (21.2% CR and 24.3% PR). Most common grade 3-4 adverse events were thrombocytopenia (60.2%), neutropenia (60.2%), anemia (26.9%), infections (15.3%), and febrile neutropenia (14.1%). Complete responses were associated with a sharp decrease in circulating myeloid-derived suppressor cells and regulatory T cells. CONCLUSIONS: R2-GDP schedule is feasible and highly active in R/R DLBCL, including the primary refractory population. Immune biomarkers showed differences in responders versus progressors.

Effects of the Combination of Music Therapy and Physiotherapy in the Improvement of Motor Function in Cerebral Palsy: A Challenge for Research.

BACKGROUND: There are different therapeutic strategies such as physiotherapy and music therapy for the treatment of cerebral palsy. Intervention protocols using both therapies to unify the measurement of motor function have not been investigated. Aims and scope: To summarize the effects of the treatment of cerebral palsy through the use of both for the improvement of motor function, analyse the challenges encountered, and submit proposals for improving them. METHODS: The systematic review was conducted following PRISMA guidelines and registered in the PROSPERO database (CRD42020162493). Clinical trials that described the results obtained in terms of motor function through physiotherapy and music therapy were included. RESULTS: Eight clinical trials with 234 participants were considered with a significant improvement in motor function. Results of meta-analysis suggested improvements in gait velocity in favour of the control group for cerebral palsy (mean differences = 0.03; 95% confidence interval = 0.01, 0.04, p = 0.001; I2 = 97%). However, high heterogeneity was identified in the meta-analysis due to the small number of studies included. CONCLUSIONS: The combination can be effective in subjects with cerebral palsy to improve motor function, although due to the diversity of studies analysed, it is complex to extrapolate results.

A worked bone assemblage from 120,000-90,000 year old deposits at Contrebandiers Cave, Atlantic Coast, Morocco.

The emergence of Homo sapiens in Pleistocene Africa is associated with a profound reconfiguration of technology. Symbolic expression and personal ornamentation, new tool forms, and regional technological traditions are widely recognized as the earliest indicators of complex culture and cognition in humans. Here we describe a bone tool tradition from Contrebandiers Cave on the Atlantic coast of Morocco, dated between 120,000-90,000 years ago. The bone tools were produced for different activities, including likely leather and fur working, and were found in association with carnivore remains that were possibly skinned for fur. A cetacean tooth tip bears what is likely a combination of anthropogenic and non-anthropogenic modification and shows the use of a marine mammal tooth by early humans. The evidence from Contrebandiers Cave demonstrates that the pan-African emergence of complex culture included the use of multiple and diverse materials for specialized tool manufacture.

Lower Survival and Increased Circulating Suppressor Cells in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma with Deficit of Vitamin D Levels Using R-GDP Plus Lenalidomide (R2-GDP): Results from the R2-GDP-GOTEL Trial.

The search of prognostic factors is a priority in diffuse large B-cell lymphoma (DLBCL) due to its aggressiveness. We have recently found that the level of circulating MDSCs is a good marker of survival in a translational study based on a trial (EudraCT Number: 2014-001620-29), using lenalidomide combined with R-GDP (rituximab plus gemcitabine, cisplatin, and dexamethasone). Since Vitamin D is a known immunomodulator, we have studied blood levels of these cell populations comparing patients with deficit of vitamin D levels (<15 ng/mL with those with normal levels >15 ng/mL. Mann-Whitney U test was used to compare cells distributions between groups, Wilcoxon test to compare cells distribution at different times and Spearman test to measure the association between cell populations. Patients with vitamin D deficit maintained the increased level of immune suppressor cells, whereas we observed a depletion of all immune suppressor cells in patients with normal vitamin D levels. In conclusion, we have confirmed the importance of vitamin D in the response to treatment in R/R DLBCL, suggesting that vitamin D deficit may be involved in the immune deficit of these patients, and thus, vitamin D supplementation in these patients may help to obtain a better response, warranting further investigation.

Circulating immune biomarkers in peripheral blood correlate with clinical outcomes in advanced breast cancer.

Identification of the different elements intervening at the tumor microenvironment seems key to explain clinical evolution in several tumor types. In this study, a set of immune biomarkers (myeloid derived suppressor cells, regulatory T cells, and OX40 + and PD-1 + T lymphocytes counts) in peripheral blood of patients diagnosed with advanced breast cancer were analyzed along of first line antineoplastic therapy. Subsequently, a comparison between groups with clinical benefit versus progression of disease and with a healthy women cohort was executed. Results reflected that patients showed higher basal levels of myeloid derived suppressor cells (35.43, IR = 180.73 vs 17.53, IR = 16.96 cells/µl; p = 0.001) and regulatory T cells (32.05, IR = 29.84 vs 22.61, IR = 13.57 cells/µl; p = 0.001) in comparison with healthy women. Furthermore, an increase in the number of activated T lymphocytes (expressing OX40), a decrease of immune inhibitory cells (MDSCs and Tregs) and inhibited T lymphocytes (expressing PD-1) were observed along the treatment in patients with clinical benefit (p ≤ 0.001). The opposite trend was observed in the case of disease progression. These findings suggest that some critical immune elements can be easily detected and measured in peripheral blood, which open a new opportunity for translational research, as they seem to be correlated with clinical evolution, at least in ABC.

Circulating myeloid-derived suppressor cells and regulatory T cells as immunological biomarkers in refractory/relapsed diffuse large B-cell lymphoma: translational results from the R2-GDP-GOTEL trial.

BACKGROUND: The search for immunological markers with ability of predicting clinical outcome is a priority in lymphomas, and in cancer in general. It is well known that some immunomodulatory cells, such as myeloid derived suppressor cells (MDSCs) or regulatory T cells (Tregs), are recruited by tumors, jeopardizing antitumor immunosurveillance. In this work, we have studied blood levels of these immunosuppressive cells in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), prior to and along the course of the experimental rituximab, gemcitabine, dexamethasone, and cisplatin (R2-GDP) schedule, as a translational substudy of the R2-GDP-GOTEL trial (EudraCT Number: 2014-001620-29), which included lenalidomide as an immunomodulator. METHODS: Blood samples were taken before treatment, at cycle 3 and end of induction. Samples were analyzed by flow cytometry. Non-parametric tests were used. Mann-Whitney U test was used to compare basal cells distributions, and Wilcoxon test was considered to compare cells distribution at different times. Spearman test was performed to measure the degree of association between cell populations. RESULTS: In this study, MDSC and Treg circulating concentration was found increased in all patients compared with a healthy control group and decreased after treatment only in patients with longest overall survival (>24 months), reaching the levels of the healthy group. Likewise, the number of inhibited T lymphocytes expressing Programmed Death-1 (PD-1) were increased in peripheral blood from patients and decreased on the treatment, whereas activated T lymphocytes increased after therapy in those with better overall survival. CONCLUSIONS: In conclusion, blood concentration of MDSCs and Treg cells may be good prognostic markers for overall survival after 2 years in R/R DLBCL. These results point to a possible role of these elements in the immunosuppression of these patients, as assessed by the circulating activated and inhibited T lymphocytes, and therefore, they may be considered as therapeutic targets in DLBCL.

Synthesis and antimalarial and anticancer evaluation of 7-chlorquinoline-4-thiazoleacetic derivatives containing aryl hydrazide moieties.

Twelve 7-chloroquinoline derivatives were designed and synthesized using the principle of molecular hybridization through the coupling of 2-[2-(7-chloroquinolin-4-ylthio)-4-methylthiazol-5-yl]acetic acid 1 with various benzoyl hydrazines 2a-l. The synthetic compounds were tested as antimalarials. Some of them showed an efficient in vitro activity as inhibitors of ß-hematin formation and an in vivo activity in a murine model, resulting in compounds 8 and 9 as the most active ones with IC50 values of 0.65 ± 0.09 and 0.64 ± 0.16 µM, respectively. The effects of the compounds on the cell viability, cell cycle, and apoptosis induction of A549 and MCF-7 cancer cell lines were also examined. Our data showed that compounds 6 and 12 were the most active agents, decreasing the cell viability of MCF-7 cells with IC50 values of 15.41 and 12.99 µM, respectively. None of the compounds analyzed significantly affected the viability of peripheral blood mononuclear cells. Also, significant induction of apoptosis was observed when both cancer cell lines were incubated with compounds 6 and 12. In MCF-7 cells, treatment with these compounds led to cell cycle arrest in the G0/G1 phase. The results obtained suggest that these structures may be useful in developing new therapies for malaria and cancer treatment.

Cannabinoid-Induced Brugada Syndrome: A Case Report.

Brugada syndrome, also called Pokkuri Death Syndrome, is an autosomal dominant electrophysiological phenomenon that increases the risk of spontaneous ventricular tachyarrhythmia and sudden cardiac death. Due to sodium channel mutations in the cardiac membrane, most commonly SCN5A and SCN10A, the heart can be triggered into a fatal arrhythmia. Brugada syndrome can be triggered by fever, and medications including antiarrhythmics, psychotropics, and recreational drugs like cocaine and marijuana. We report a case that demonstrates the diagnosis of Brugada syndrome in an otherwise very healthy 22-year-old African-American male. He presented after a syncopal event and developed spontaneous ventricular tachycardia and torsades de pointes. Electrocardiogram (EKG) findings documented a type I Brugada pattern and, once stabilized, the patient underwent an internal cardioverter defibrillator (ICD) placement.

Circulating T Follicular Helper Cell Abnormalities Associated to Different Clinical Forms of Chronic Chagas Disease.

Multiple perturbations of the immune response affecting a range of cells have been reported in Trypanosoma cruzi-infected individuals and associated to clinical manifestations of chronic Chagas disease. There is a paucity of knowledge about the role of T follicular helper (Tfh) cells in this infection. Here, we sought to characterize circulating Tfh (cTfh) cells in chronic Chagas disease patients and to identify potential associations with disease severity in humans. cTfh cells were characterized by flow cytometry in freshly isolated PBMCs from 7 T. cruzi-infected asymptomatic patients (ASYMP), 5 patients with chronic chagasic dilated cardiomyopathy (CCC) and 8 healthy controls, using antibodies against chemokine receptors CXCR5, CXCR3, CCR6, and CCR7. Our results showed significant expansion of CD4+CD45RO+CXCR5+CCR6+ cells in ASYMP and CCC patients, along with a contraction of CD4+CD45RO+CXCR5+CXCR3-CCR6- (cTfh2) cells. ASYMP patients further exhibited decreased CD4+CD45RO+CXCR5+CXCR3+CCR6- (cTfh1) cells and expanded CD4+CD45RO+CXCR5+CXCR3-CCR6+ (cTfh17) cells while CCC patients exhibited significantly increased frequencies of CD4+CD45RO+CXCR5+CCR7+ cells. Linear regression analysis revealed a positive trend of CD4+CD45RO+CXCR5+CXCR3+CCR6+ (cTfh1/17) cells and negative trends of cTfh1 and cTfh2 cells as disease was more severe. There was no correlation between the frequencies of cTfh cells and circulating CD19+IgD-IgG+ cells or serum levels of T. cruzi-specific IgG. These results demonstrate that the cTfh compartment of humans chronically infected with T. cruzi comprises expanded CCR6-expressing cells and reduced cTfh2 cells. The association of discrete phenotypic changes in cTfh subsets with different clinical forms suggests the potential contribution of T follicular helper cells to Chagas heart disease progression.

Game-Based Virtual Reality Interventions to Improve Upper Limb Motor Function and Quality of Life After Stroke: Systematic Review and Meta-analysis.

Stroke is the main cause of disability in adulthood. Recent advances in virtual reality (VR) technologies have led to its increased use in the rehabilitation of stroke patients. A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to determine the effectiveness of game-based reality on upper limb (UL) motor function and quality of life after stroke. In March 2018, a search of the following databases was performed: PubMed, PEDro, Web of Science, Scopus, The Cochrane Library, and Medline at EBSCO. The selection criteria were all RCTs published in English or Spanish during the past 10 years. The PEDro scale was used to evaluate the methodological quality of the studies. A total of 20 clinical trials were included in the systemic review, of which 15 contributed information to the meta-analysis. Favorable results were found for VR interventions on UL motor function (Fugl-Meyer Assessment for upper extremity, standardized mean difference [SMD] = 1.53, 95% CI [0.51-2.54]) and quality of life (functional independence measure, SMD = 0.77, 95% CI [0.05-1.49]). The results demonstrate the potential benefits of VR interventions on the recovery of UL motor function and on quality of life after stroke.

Circulating regulatory T cells from breast cancer patients in response to neoadjuvant chemotherapy.

BACKGROUND: Immune escape of tumor cells is a new hallmark of cancer in general, and breast cancer, in particular. Previous studies have demonstrated that the immunological profile in peripheral blood may be a prognostic and/or predictive biomarker in breast cancer. Thus, higher number of regulatory T cells (Tregs) in blood from patients with breast cancer has been reported in relation to normal donors. In the present study, we planned to evaluate the changes in different cell populations in peripheral blood: neutrophils, monocytes and lymphocytes, as well as lymphocyte subpopulations [natural killer (NK), B lymphocytes, T lymphocytes, both CD4+ and CD8+, and Tregs] from patients with local breast cancer (both Her2+ and Her2-), before, during and after neoadjuvant chemotherapy. METHODS: We have employed flow cytometry for the cell analysis of fresh samples obtained before and whilst the neoadjuvant treatment was accomplished. We have studied 50 successive patients from the Breast Cancer Unit of the Virgen Macarena University Hospital during 2 years. RESULTS: Neoadjuvant chemotherapy induced a significant reduction in B cells, especially in Her2- patients, and a reduction in NK cells. CD4+ T cells decreased, whereas CD8+ cells only decreased in Her2- patients. Tregs were also diminished, especially in Her2+ patients, in response to treatment. Thus, higher CD8/Treg ratio was observed in Her2+ patients. A higher percentage of Her2+ patients (66.6%) achieved complete response than Her2- patients (27.5%). Monocytes and neutrophils were not changed in peripheral blood. CONCLUSIONS: Even though the decrease in B cells and NK cells in response to chemotherapy may be deleterious in the neoadjuvant treatment of breast cancer, the decrease in Tregs and CD4 T cells, but not CD8 T cells, increasing the CD8/Treg ratio, especially in Her2+ patients, may reveal a new tool to monitor the immune response in breast cancer treated with chemotherapy in the neoadjuvant setting.