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NK-cell resistance to transduction is a major technical hurdle for developing NK-cell immunotherapy. By using Baboon envelope pseudotyped lentiviral vectors (BaEV-LVs) encoding eGFP, we obtained a transduction rate of 23.0 ± 6.6% (mean ± SD) in freshly-isolated human NK-cells (FI-NK) and 83.4 ± 10.1% (mean ± SD) in NK-cells obtained from the NK-cell Activation and Expansion System (NKAES), with a sustained transgene expression for at least 21 days. BaEV-LVs outperformed Vesicular Stomatitis Virus type-G (VSV-G)-, RD114- and Measles Virus (MV)- pseudotyped LVs ( < 0.0001). mRNA expression of both BaEV receptors, ASCT1 and ASCT2, was detected in FI-NK and NKAES, with higher expression in NKAES. Transduction with BaEV-LVs encoding for CAR-CD22 resulted in robust CAR-expression on 38.3 ± 23.8% (mean ± SD) of NKAES cells, leading to specific killing of NK-resistant pre-B-ALL-RS4;11 cell line. Using a larger vector encoding a dual CD19/CD22-CAR, we were able to transduce and re-expand dual-CAR-expressing NKAES, even with lower viral titer. These dual-CAR-NK efficiently killed both CD19 - and CD22 -RS4;11 cells. Our results suggest that BaEV-LVs may efficiently enable NK-cell biological studies and translation of NK-cell-based immunotherapy to the clinic.

Through the example of the Faudoas family, who settled in Maine at the end of the sixteenth century, this article examines some of the consequences for the provincial military middle nobility of changes in the concept of noble kinship. The «house», which referred to a complex of ideal and material possessions united under a name that was generally that of a seigneury, all of which was transmitted in a direct line, including female line in the absence of a male heir, became synonymous with patrilineage. This was accompanied by changes in inheritance practices as well as in ways of conceiving the past and the links between the different branches of these patrilineal houses. The Faudoas of Maine shed light on the social discontinuities that appeared within the second order, masked by an apparent continuity in military careers. It also higlights the importance of the patrilineal ideology and the forms of transmission that it inspired, as well as on its limitations in the real lives of noble families and in the way they represented themselves. A travers l'exemple de la famille Faudoas, installée dans le Maine à la fin du XVIe siècle, cet article examine quelques-unes des conséquences de l'évolution de la parenté nobiliaire pour la moyenne noblesse militaire provinciale. La \"maison\", qui désigne un ensemble de biens idéaux et matériels réunis sous un nom, généralement celui d'une seigneurie principale, le tout transmis en ligne directe, y compris féminine en l'absence d'héritier mâle, devient synonyme de patrilignage. Cette évolution s'est accompagnée de changements dans les pratiques successorales et dans la manière de concevoir le passé et les liens entre les différentes branches de ces maisons patrilinéaires. Les Faudoas du Maine jettent un éclairage sur les discontinuités sociales qui apparaissent au sein du second ordre, masquées par une apparente continuité des carrières militaires, sur l'importance de l'idéologie patrilinéaire et des formes de transmission qui lui sont liées, mais aussi sur ses limites dans la vie concrète des familles nobles et dans les représentations qu'elles se font d'elles-mêmes.

Natural Killer (NK) cells hold the potential to shift cell therapy from a complex autologous option to a universal off-the-shelf one. Although NK cells have demonstrated efficacy and safety in the treatment of leukemia, the limited efficacy of NK cell-based immunotherapies against solid tumors still represents a major hurdle. In the immunosuppressive tumor microenvironment (TME), inhibitory interactions between cancer and immune cells impair antitumoral immunity. gene encodes the NK cell inhibitory receptor NKG2A, which is a potent NK cell immune checkpoint. NKG2A specifically binds HLA-E, a non-classical HLA class I molecule frequently overexpressed in tumors, leading to the transmission of inhibitory signals that strongly impair NK cell function. To restore NK cell cytotoxicity against HLA-E tumors, we have targeted the NKG2A/HLA-E immune checkpoint by using a CRISPR-mediated gene editing. knockout resulted in a reduction of 81% of NKG2A cell frequency in expanded human NK cells post-cell sorting. , the overexpression of HLA-E by tumor cells significantly inhibited wild-type (WT) NK cell cytotoxicity with -values ranging from 0.0071 to 0.0473 depending on tumor cell lines. In contrast, NK cells exhibited significantly higher cytotoxicity when compared to WT NK cells against four different HLA-E solid tumor cell lines, with -values ranging from<0.0001 to 0.0154. Interestingly, a proportion of 43.5% to 60.2% of NKG2A NK cells within the edited NK cell population was sufficient to reverse at its maximum the HLA-E-mediated inhibition of NK cell cytotoxicity. The expression of the activating receptor NKG2C was increased in NK cells and contributed to the improved NK cell cytotoxicity against HLA-E tumors. , the adoptive transfer of human NK cells significantly delayed tumor progression and increased survival in a xenogeneic mouse model of HLA-E metastatic breast cancer, as compared to WT NK cells ( = 0.0015). Our results demonstrate that knockout is an effective strategy to improve NK cell antitumor activity against HLA-E tumors and could be applied in the development of NK cell therapy for solid tumors.

In chronic granulomatous disease allogeneic haemopoietic stem-cell transplantation (HSCT) in adolescents and young adults and patients with high-risk disease is complicated by graft-failure, graft-versus-host disease (GVHD), and transplant-related mortality. We examined the effect of a reduced-intensity conditioning regimen designed to enhance myeloid engraftment and reduce organ toxicity in these patients. This prospective study was done at 16 centres in ten countries worldwide. Patients aged 0–40 years with chronic granulomatous disease were assessed and enrolled at the discretion of individual centres. Reduced-intensity conditioning consisted of high-dose fludarabine (30 mg/m2 [infants <9 kg 1·2 mg/kg]; one dose per day on days −8 to −3), serotherapy (anti-thymocyte globulin [10 mg/kg, one dose per day on days −4 to −1; or thymoglobuline 2·5 mg/kg, one dose per day on days −5 to −3]; or low-dose alemtuzumab [<1 mg/kg on days −8 to −6]), and low-dose (50–72% of myeloablative dose) or targeted busulfan administration (recommended cumulative area under the curve: 45–65 mg/L × h). Busulfan was administered mainly intravenously and exceptionally orally from days −5 to −3. Intravenous busulfan was dosed according to weight-based recommendations and was administered in most centres (ten) twice daily over 4 h. Unmanipulated bone marrow or peripheral blood stem cells from HLA-matched related-donors or HLA-9/10 or HLA-10/10 matched unrelated-donors were infused. The primary endpoints were overall survival and event-free survival (EFS), probabilities of overall survival and EFS at 2 years, incidence of acute and chronic GVHD, achievement of at least 90% myeloid donor chimerism, and incidence of graft failure after at least 6 months of follow-up. 56 patients (median age 12·7 years; IQR 6·8–17·3) with chronic granulomatous disease were enrolled from June 15, 2003, to Dec 15, 2012. 42 patients (75%) had high-risk features (ie, intractable infections and autoinflammation), 25 (45%) were adolescents and young adults (age 14–39 years). 21 HLA-matched related-donor and 35 HLA-matched unrelated-donor transplants were done. Median time to engraftment was 19 days (IQR 16–22) for neutrophils and 21 days (IQR 16–25) for platelets. At median follow-up of 21 months (IQR 13–35) overall survival was 93% (52 of 56) and EFS was 89% (50 of 56). The 2-year probability of overall survival was 96% (95% CI 86·46–99·09) and of EFS was 91% (79·78–96·17). Graft-failure occurred in 5% (three of 56) of patients. The cumulative incidence of acute GVHD of grade III–IV was 4% (two of 56) and of chronic graft-versus-host disease was 7% (four of 56). Stable (≥90%) myeloid donor chimerism was documented in 52 (93%) surviving patients. This reduced-intensity conditioning regimen is safe and efficacious in high-risk patients with chronic granulomatous disease. None.

Background Post-malaria neurological syndrome (PMNS) is a debated entity, defined by neurological complications following a post-malaria symptom-free period and a negative blood smear. Four cases of PMNS are hereby reported and a review the literature performed to clarify the nosological framework of this syndrome. Methods A French teaching hospital infectious diseases database was investigated for all PMNS cases occurring between 1999 and 2016 and the PubMed database for cases reported by other institutions after 1997. A case was defined by the de novo appearance of neurological signs following a post-malaria symptom-free period, a negative blood smear, and no bacterial or viral differential diagnoses. Results Four patients from the database and 48 from PubMed, including 4 following Plasmodium vivax infection were found matching the definition. In the institution, the estimated PMNS incidence rate was 1.7 per 1000 malaria cases overall. Of the 52 patients (mean age 33 years), 65% were men. Malaria was severe in 85% of cases, showed neurological involvement in 53%, and treated with quinine in 60%, mefloquine in 46%, artemisinin derivatives in 41%, antifolic drugs in 30%, doxycycline in 8% and other types in 8%. The mean symptom-free period was 15 days. PMNS signs were confusion (72%), fever (46%), seizures (35%), cerebellar impairment (28%), psychosis (26%), and motor disorders (13%). Cerebrospinal fluid analyses showed high protein levels in 77% (mean 1.88 g/L) and lymphocytic meningitis in 59.5% (mean 48 WBC/mm 3 ) of cases. Electroencephalograms were pathological in 93% (14/15) of cases, and brain MRIs showed abnormalities in 43% (9/21) of cases with white matter involvement in 100%. Fourteen patients were treated with steroids. The 18 patients with follow-up data showed no sequelae . The mean time to recovery was 17.4 days. Conclusion PMNS is a rare entity englobing neurological signs after severe or non-severe malaria. It appears after a symptom-free period. PMNS occurred following treatment of malaria with a wide range of anti-malarials. The disease is self-limiting and associated with good outcome. MRI patterns underline a possible link with acute disseminated encephalomyelitis (ADEM) or auto-immune encephalitis. Plasmodium falciparum and Plasmodium vivax should be added to the list of pathogens causing ADEM.

1960, following as it did the last CIAM meeting, signalled a turning point for the Modern Movement. From then on, architecture was influenced by seminal texts by Aldo Rossi and Robert Venturi, and gave rise to the first revisionary movement following Modernism. Bringing together leading experts in the field, this book provides a comprehensive, critical overview of the developments in architecture from 1960 to 2010. It consists of two parts: the first section providing a presentation of major movements in architecture after 1960, and the second, a geographic survey that covers a wide range of territories around the world. This book not only reflects the different perspectives of its various authors, but also charts a middle course between the 'aesthetic' histories that examine architecture solely in terms of its formal aspects, and the more 'ideological' histories that subject it to a critique that often skirts the discussion of its formal aspects. Dr Elie G. Haddad is the Dean of the School of Architecture and Design at the Lebanese American University, Lebanon and Dr David Rifkind is a Lecturer in Architecture at the Florida International University, USA. Contents: Introduction: modernism and beyond: the plurality of contemporary architectures, Elie G. Haddad and David Rifkind. Part I Major Developments After Modernism: Modern (or contemporary) architecture circa 1959, Peter L. Laurence; Post-modernism: critique and reaction, David Rifkind; High-tech: modernism redux, Sarah Deyong; Deconstruction: the project of radical self-criticism, Elie G. Haddad; Greening architecture: the impact of sustainability, Phillip Tabb; Postcolonial theories in architecture, Esra Akcan. Part II Architectural Developments Around the World: Architecture in North America since 1960, Brendan Moran; Architectural developments in Latin America: 1960-2010, Zeuler R.M. de A. Lima; The place of commonplace: the ordinary as alternative architectural lens in Western Europe, Tom Avermaete; Dutch modern architecture: from an architecture of consensus to the culture of congestion, Frances Hsu; Metaphorical peripheries: architecture in Spain and Portugal, Xavier Costa; Architecture in Switzerland: a natural history, Laurent Stalder; Architecture in Eastern Europe and the former Soviet Union since 1960, Kimberley Elman Zarecor; Finland: architecture and cultural identity, Taisto H. Mäkelä; Architecture in Africa: situated modern and the production of locality, Iain Low; Global conflict and global glitter: architecture of West Asia (1960-2010), Esra Akcan; Old sites, new frontiers: modern and contemporary architecture in Iran, Pamela Karimi; Beyond tropical regionalism: the architecture of Southeast Asia, Kelly Shannon; Internationalism and architecture in India after Nehru, Amit Srivastava and Peter Scriver; Architecture in China in the reform era: 1978-2010, Tao Zhu; Architecture in post-World War II Japan, Ken Tadashi Oshima; Edge of centre: architecture in Australia and New Zealand after 1965, Philip Goad. Index. With modern architecture's collapse as a unified body of thought and practice by the 1960s, the global field of architectural production has been marked by extraordinary diversity and innovation. This substantial volume ranges over wide territory, providing insightful critical and geographic perspectives on the last half century of architecture and locating the most significant points of reference for a revised historical understanding. The more than twenty contributors belong to a new generation of scholars. Carefully edited by Elie Haddad and David Rifkind and generously illustrated, this is an invaluable guide to architecture's recent past as well as to its present.　 Joan Ockman, Author of Architecture Culture 1943-1968: A Documentary Anthology.

Introduction While maintaining a relatively low HIV prevalence, Lebanon continues to face significant sociocultural barriers related to HIV. People living with HIV (PLHIV) often experience discrimination, which may impact their quality of life (QoL) and their ability to engage effectively with healthcare providers. This study aimed to evaluate the QoL of PLHIV in Lebanon, examine their experiences with stigma, and assess how their relationships with physicians influence their access to care and information. Methods A cross-sectional study was conducted among 91 Lebanese adults living with HIV/AIDS, recruited from the National AIDS Program Center, NGOs, and outpatient clinics. Participants completed a comprehensive questionnaire including the WHOQOL-Brief, the HIV Symptom Index and the HIV Stigma Scale, as well as a demographic section and a section on the relationship with the physician. Results Most of the sample was male, unmarried, and asymptomatic. The mean age was 35.5 years (SD = 10.4). The mean WHOQOL-BREF score was 56.32% (SD = 17.2), with the highest score for physical health and the lowest for social relationships. The mean stigma score was 34.21 and the mean HIV symptom index was 1.91. Symptom prevalence and perceived stigma were negative predictors of quality of life, while being employed was a positive predictor of quality of life. The quality of social relationships had a positive impact on stigma. Choosing a physician based on word-of-mouth recommendations had a positive impact on access to health information and services. Discussion While clinical management has improved physical health outcomes for PLHIV, psychosocial factors, particularly stigma and lack of social support, continue to hold back overall well-being. Physician-patient trust and employment may enhance access to supportive care environments. Conclusions Addressing stigma and strengthening social and healthcare support systems are essential to improving the QoL of PLHIV in Lebanon. Empowering patients to make informed choices about their physicians may play a key role in facilitating better access to care and reducing the burden of stigma.

Neuroblastoma, the most common type of pediatric extracranial solid tumor, causes 10% of childhood cancer deaths. Despite intensive multimodal treatment, the outcomes of high-risk neuroblastoma remain poor. We urgently need to develop new therapies with safe long-term toxicity profiles for rapid testing in clinical trials. Drug repurposing is a promising approach to meet these needs. Here, we investigated disulfiram, a safe and successful chronic alcoholism treatment with known anticancer and epigenetic effects. Disulfiram efficiently induced cell cycle arrest and decreased the viability of six human neuroblastoma cell lines at half-maximal inhibitory concentrations up to 20 times lower than its peak clinical plasma level in patients treated for chronic alcoholism. Disulfiram shifted neuroblastoma transcriptome, decreasing MYCN levels and activating neuronal differentiation. Consistently, disulfiram significantly reduced the protein level of lysine acetyltransferase 2A (KAT2A), drastically reducing acetylation of its target residues on histone H3. To investigate disulfiram’s anticancer effects in an in vivo model of high-risk neuroblastoma, we developed a disulfiram-loaded emulsion to deliver the highly liposoluble drug. Treatment with the emulsion significantly delayed neuroblastoma progression in mice. These results identify KAT2A as a novel target of disulfiram, which directly impacts neuroblastoma epigenetics and is a promising candidate for repurposing to treat pediatric neuroblastoma.

Background: Extended-spectrum β-lactamase (ESBL)–producing Escherichia coli represent an increasing therapeutic challenge. While ertapenem (ERP) is commonly used as first-line therapy, amoxicillin–clavulanic acid (AMC) achieves therapeutic concentrations in serum and ascitic fluid and may offer a narrower-spectrum alternative. This exploratory preclinical study evaluated whether AMC produces effects comparable to ERP in a rat model of ESBL E. coli peritonitis. Methods: Thirty-three male rats were allocated to four groups: untreated E. coli, AMC, ERP, and sham controls. Peritonitis was induced by intraperitoneal injection of an ESBL-producing E. coli strain. The primary outcome was peritoneal bacterial culture positivity. Secondary outcomes included plasma inflammatory cytokines (CRP, PCT, TNF-α, IL-1β, IL-6), proteomic signaling markers, and histopathological inflammation scores in the peritoneum, spleen, and lungs. Results: One death occurred in the untreated group. Both AMC and ERP were associated with lower peritoneal culture positivity compared with untreated animals, with ERP achieving statistical significance and AMC showing a similar downward trend. Inflammatory cytokines and proteomic markers demonstrated comparable reductions in both treated groups. Histopathology showed reduced inflammatory scores, with AMC exhibiting the lowest peritoneal inflammation. Lung involvement was observed in 7/10 untreated rats versus 5/10 AMC- and ERP-treated rats; these differences were not statistically significant, reflecting the limited sample size. Conclusions: AMC and ERP produced broadly comparable effects on microbiological, biochemical, and inflammatory parameters in ESBL E. coli peritonitis. These findings suggest that AMC may merit further investigation as a potential narrower-spectrum option, though definitive comparisons require larger, adequately powered studies.

Background Local anesthesia is an essential skill of pain control for most dental procedures, commonly taught through face-to-face learning (FFL). Distant learning (DL) has emerged as an alternative teaching method for many techniques in medicine. Aim To evaluate the performance scores of DL compared with FFL in teaching maxillary infiltrative local anesthesia to novice learners. Methods A prospective randomized trial included 93 students randomized into two groups for applying infiltrative local anesthesia of the maxillary arch: FFL ( n  = 47) and DL ( n  = 46). The evaluation was conducted by two examiners using a performance checklist and a global rating tool. Agreement between the examiners was calculated, and performance scores of the participants on 11 well defined tasks in the process of infiltration were compared. Participants’ satisfaction was assessed via a questionnaire. Results Levels of completion of each infiltration step were not statistically significantly different between the learning groups ( p  > 0.05). Group differences in the duration of the total infiltration procedure (76.06 ± 20.36, and 83.39 ± 24.05 s, for the FFL and DL groups, respectively) also were not statistically significantly different ( p  = 0.116). Both methods were reported as efficient by participants. While nearly all students enjoyed the learning process in both groups, all FFL participants felt confident performing the infiltration and 11% less confident in the DL group. Conclusion The results suggest that distant learning of administering infiltration local anesthesia was as effective as in-person learning by novice learners. Students appreciated the respective method of learning, with more reservations to perform the procedure by those in the DL group.