To overcome challenges associated with adoptive cell therapy (ACT), we developed a personalized autologous T-cell therapy program. Patients with advanced cancer with HLA-A *02:01 allele and tumor ...expression of PRAME, MAGEA1, MAGEA4, MAGEA8, NY-ESO-1, COL6A3 exon 6, MXRA5, and/or MMP1 underwent leukapheresis and T-cell product manufacturing. Patients received lymphodepletion, IMA101 infusion and interleukin 2 for 14 days. Of 214 screened patients, 14 were treated (6, IMA101; 8, IMA101 and atezolizumab). The most common adverse events were cytokine release syndrome (G1, n = 6; G2, n = 4) and cytopenia. At 6 weeks, 12 (85.7%) patients had stable disease. Three patients had prolonged disease stabilization for 12.9, 7.3, and 13.7 months, respectively. The median progression-free survival and overall survival were 3.4 months and 9.4 months, respectively. Target-specific T cells expanded to constitute up to 78.7% of CD8+ cells. In conclusion, IMA101 was feasible and well tolerated, leveraging the potential of multi-targeted ACT that warrants further investigation.
The anti-CD19 chimeric antigen receptor (CAR)–T cell therapy tisagenlecleucel was evaluated in the global, phase 2 JULIET study in adult patients with relapsed/refractory diffuse large B-cell ...lymphoma (DLBCL). We correlated tisagenlecleucel cellular kinetics with clinical/product parameters in 111 patients treated in JULIET. Tisagenlecleucel persistence in responders and nonresponders, respectively, was demonstrated for 554 and 400 days maximum by flow cytometry and for 693 and 374 days maximum by quantitative polymerase chain reaction (qPCR). No relationships were identified between cellular kinetics (qPCR) and product characteristics, intrinsic/extrinsic factors, dose, or immunogenicity. Most patients with 3-month response had detectable transgene at time of response and continued persistence for ≥6 months. Expansion (maximal expansion of transgene/CAR-positive T-cell levels in vivo postinfusion Cmax) was potentially associated with response duration but this did not reach statistical significance (hazard ratio for a twofold increase in Cmax, 0.79; 95% confidence interval, 0.61-1.01). Tisagenlecleucel expansion was associated with cytokine-release syndrome (CRS) severity and tocilizumab use; no relationships were observed with neurologic events. Transgene levels were associated with B-cell levels. Dose was associated with CRS severity, but this was not statistically significant after adjusting for baseline tumor burden. In contrast to the results from B-cell precursor acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia, similar exposure was observed in DLBCL in this study regardless of response and expansion was lower in DLBCL than B-ALL, likely from differences in cancer location and/or T-cell intrinsic factors. Relationships between expansion and CRS severity, and lack of relationships between dose and exposure, were similar between DLBCL and B-ALL. Tisagenlecleucel cellular kinetics in adult relapsed/refractory DLBCL improve current understanding of in vivo expansion and its relationships with safety/efficacy endpoints. This trial was registered at www.clinicaltrials.gov as #NCT02445248.
•Tisagenlecleucel mean expansion (lower vs B-ALL; not related to response) and baseline tumor burden in DLBCL correlated with CRS severity.•Impact of dose on estimated probability of severe CRS was not statistically significant after adjusting for baseline tumor burden.
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Changes in the three-dimensional (3D) structure of the genome are an emerging hallmark of cancer. Cancer-associated copy number variants and single nucleotide polymorphisms promote rewiring of ...chromatin loops, disruption of topologically associating domains (TADs), active/inactive chromatin state switching, leading to oncogene expression and silencing of tumor suppressors. However, little is known about 3D changes during cancer progression to a chemotherapy-resistant state. We integrated chromatin conformation capture (Hi-C), RNA-seq, and whole-genome sequencing obtained from triple-negative breast cancer patient-derived xenograft primary tumors (UCD52) and carboplatin-resistant samples and found increased short-range (< 2 Mb) interactions, chromatin looping, formation of TAD, chromatin state switching into a more active state, and amplification of ATP-binding cassette transporters. Transcriptome changes suggested the role of long-noncoding RNAs in carboplatin resistance. Rewiring of the 3D genome was associated with TP53, TP63, BATF, FOS-JUN family of transcription factors and led to activation of aggressiveness-, metastasis- and other cancer-related pathways. Integrative analysis highlighted increased ribosome biogenesis and oxidative phosphorylation, suggesting the role of mitochondrial energy metabolism. Our results suggest that 3D genome remodeling may be a key mechanism underlying carboplatin resistance.
To study efficacy and safety of escalating doses of canakinumab, a fully human anti-IL-1β monoclonal antibody in the severe cryopyrin-associated periodic syndrome, neonatal-onset multisystem ...inflammatory disease (NOMID).
6 patients were enrolled in this 24-month, open-label phase I/II study. All underwent anakinra withdrawal. The initial subcutaneous canakinumab dose was 150 mg (or 2 mg/kg in patients ≤40 kg) or 300 mg (or 4 mg/kg) with escalation up to 600 mg (or 8 mg/kg) every 4 weeks. Full remission was remission of patient-reported clinical components and measures of systemic inflammation and CNS inflammation. Hearing, vision and safety were assessed. Primary endpoint was full remission at month 6.
All patients flared after anakinra withdrawal, and symptoms and serum inflammatory markers improved with canakinumab. All patients required dose escalation to the maximum dose. At month 6, none had full remission, although 4/6 achieved inflammatory remission, based on disease activity diary scores and normal C-reactive proteins. None had CNS remission; 5/6 due to persistent CNS leucocytosis. At the last study visit, 5/6 patients achieved inflammatory remission and 4/6 had continued CNS leucocytosis. Visual acuity and field were stable in all patients, progressive hearing loss occurred in 1/10 ears. Adverse events (AEs) were rare. One serious AE (abscess due to a methicillin-resistant Staphylococcus aureus infection) occurred.
Canakinumab at the studied doses improves symptoms and serum inflammatory features of NOMID, although low-grade CNS leukocytosis in four patients and headaches in one additional patient persisted. Whether further dose intensifications are beneficial in these cases remains to be assessed.
NCT00770601.
Background: Dental implant treatment is an excellent option for prosthetic restoration that is associated with high success rates. Implant stability is essential for a good outcome. The basal bone ...implants are usually placed in poorly atrophied basal bone areas. Aims: To determine the stability during insertion in bones by measuring the torque using a wrench. To obtain the number of cortical engagements via stimulating concerned anatomical location in jaws. Settings and Design: The study was designed as an ex vivo study. In case of basal implants, the integration of the implants is in stable cortex. Such a stable engagement is achieved by stimulation of certain areas in anterior maxilla such as anterior nasal spine, nasal floor, canine fossa, while posteriorly, maxillary tuberosity and pterygoid. In mandible the symphysis, parasymphysis, lingual cortex and retromolar pad areas were engaged. Materials and Methods: In this study, the above-mentioned areas were stimulated for the engagement of cortical bones using cortical implantology. Cortical implants of various sizes and tapers were inserted and analyzed for its bone quality and quantity. The stability of such implants was tested during insertion by measuring the torque with the use of a torque wrench instrument. Statistical Analysis Used: Comparative observational study using standards of deviation. Results and Conclusions: Within the limitations of this study, it may be concluded that there was a significant correlation between insertion force and diameter of implants when placed in jaws in a dried human skull model. The present study needs to be further conducted to establish the observational results completely and hence correlate the results with human studies.
Cardiovascular diseases (CVD) remain a major global health challenge, with an escalating impact on mortality despite advancements in managing conventional risk factors. This review investigates the ...intricate relationship between human papillomavirus (HPV) and CVD, shedding light on a novel aspect of cardiovascular health. Despite significant progress in understanding and managing traditional CVD risk factors, a substantial proportion of CVD cases lack these conventional markers. Recent research has unveiled HPV, a prevalent sexually transmitted infection, as a potential unconventional risk factor for CVD.
This review delves into the underlying mechanisms linking HPV to CVD pathogenesis. HPV's influence on vascular endothelium and induction of systemic inflammation are key contributors. Additionally, HPV disrupts host lipid metabolism, further exacerbating the development of atherosclerosis. The link between HPV and CAD is not merely correlative; it encompasses a complex interplay of virological, immunological, and metabolic factors. Understanding the connection between HPV and CVD holds transformative potential. Insights from this review not only underscore the significance of considering HPV as a crucial risk factor but also advocate for targeted HPV screening and vaccination strategies to mitigate CVD risks. This multidisciplinary exploration bridges the gap between infectious diseases and cardiovascular health, emphasizing the need for a comprehensive approach to combating the global burden of cardiovascular disease. Further research and clinical guidelines in this realm are essential to harness the full scope of preventive and therapeutic interventions, ultimately shaping a healthier cardiovascular landscape.
In the global economy, the intermediate companies owned by multinational corporations (MNCs) have become important players in policy issue, influencing the international profit shifting and diversion ...of foreign direct investment (FDI). The purpose of this analysis is to identify and analyze high-risk intermediate companies used for international profit shifting. To achieve this aim, we propose a model that focuses on the structure of MNC’s ownership of each affiliate. On the basis of the information in the Orbis database, we constructed the Global Ownership Network (GON) to reflect the relationship between MNCs and intermediate companies. Moreover, we analyzed large MNCs listed in Fortune Global 500. In this analysis, we confirmed the validity of this model by identifying affiliates playing an important role in international tax avoidance. We found that intermediate companies are mainly based in the Netherlands and the United Kingdom, etc., and these companies are located in the jurisdictions favorably to treaty shopping. And it was found that such key companies are concentrated in the IN component of the bow-tie structure, which is the giant weakly connected component with the GON. Therefore, this clarifies that the key companies are geographically located in specific jurisdictions and concentrates on the specific GON components. The key companies are located in the areas that facilitate treaty shopping. Depending on the location of the MNCs, a difference is remarked in the jurisdiction where key companies are located.
Background: With an increasing life expectancy, the population of geriatric age group is increasing in India and all around the world. The population aged above 60 years is 8% as per census 2011 and ...likely to be 21% of the total population by 2050. People from older age group suffer from mental problems more than their younger counterparts. Few studies have targeted the mental health of elderly in community level, especially in Bengal.
Aims and Objectives: This study aims to estimate the prevalence of mental illness among older age group of urban area in Kolkata, West Bengal.
Materials and Methods: This cross-sectional, descriptive, epidemiological community-based study was conducted in the Chetla area of Kolkata Municipal Corporation, West Bengal. The General Health Questionnaire-12 (GHQ-12) and Mini-Mental State Examination were administered to 341 participants.
Results: We found 36.95% of old age people having mental illness based on GHQ-12. Females have more prevalence of having a psychiatric illness than males. The most common psychiatric disorder was mood disorder followed by dementia. The prevalence of mental illness increased with advancement of age. About 64.7% of people never sought any kind of treatment for their illness.
Conclusion: Mental illness is common among elderly people, but they are not well documented. A very significant number of patients do no seek any kind of treatment for their ailments. A comprehensive health-care system to be developed to reduce this treatment gap.
An active immune surveillance and a range of barriers to infection allow the host to effectively eliminate microbial pathogens. However, pathogens may use diverse strategies to subdue such host ...defences. For instance, one such mechanism is the use of leucine-rich repeat (LRR) proteins by pathogens (microbial) to cause infection. In this study, we aimed at identifying novel virulence factor(s) in Leishmania donovani, based on the possibility of lateral gene transfers of bacterial virulence factor(s) to L. donovani.
Rigorous homology searching protocols including Hidden Markov Model (HMM) and BLASTp based searches were employed to detect remote but significant similarities between L. donovani proteins and bacterial virulence factors.
We found that some L. donovani proteins are similar to internalin-A (Inl-A) protein of Listeria monocytogenes, a surface LRR protein that helps mediate host cell invasion by interacting with E-cadherin on the cell membrane. However, to date, no such invasion mechanism has been reported in Leishmania donovani, the causative agent of visceral leishmaniasis. Moreover, a comparative LRR motif analysis of L. donovani Inl-A-like proteins against the Inl-A protein of L. monocytogenes revealed existence of characteristic consensus LRR regions, suggesting a reliable evolutionary relationship between them. Further, through rigorous three dimensional (3D) modeling of L. donovani Inl-A-like proteins and subsequent molecular docking studies we suggest the probability of human E-cadherin binding with the L. donovani Inl-A-like proteins.
We have identified three potential candidates (UniProt ID: E9B7L9, E9BMT7 and E9BUL5) of Inl-A-like LRR containing proteins in L. donovani with the help of systematic whole genome sequence analysis. Thus, herein we propose the existence of a novel class of Inl-A-like virulence factor proteins in L. donovani and other Leishmania species based on sequence similarity, phylogenetic analysis and molecular modelling studies in L. donovani.
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