| 1. |
- Lucero-Prisno III, Don Eliseo, et al.
(författare)
-
Drug shortage crisis in Sudan in times of COVID-19
- 2020
-
Ingår i: Public Health in Practice. - : Elsevier. - 2666-5352. ; 1
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Sudan is witnessing severe drugs, medicines, and medical supplies shortages, which present a major impediment to the provision of emergency healthcare services. Drug insecurity in Sudan is as a result of several accumulated factors, primarily due to worsening economic condition, inappropriate pricing policy, privatization of the pharmaceutical sector, poor manufacturing and weak weak weregulatory system. These could threaten patient health through replacement of highly efficacious medicines with less effective alternatives and by impacting the scheduling of urgent medical operations and procedures. Drug and medicine shortages are of catastrophic impact especially amid the current epidemic of COVID-19 where these are salient needs. Efforts should be quickly directed to ensure immediate access to pharmaceutical products and other essential health commodities. Effective policies on drug importation, production, pricing, and distribution should be established to avoid the consequences of an impending crisis.
|
|
| 2. |
- Backman, Max, et al.
(författare)
-
Extending the immune phenotypes of lung cancer: Oasis in the desert
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Tumor infiltrating immune cells are key elements of the tumor microenvironment and mediate the anti-tumor effects of immunotherapy. The aim of the study was to characterize patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to tumor mutations and clinicopathological parameters. Methods: Lymphocytes (CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+) and PD-L1+ were annotated on a tissue microarray including 357 operated NSCLC cases. Somatic mutations and tumor mutational burden were analyzed by targeted sequencing for 82 genes, and transcriptomic immune patterns were established in 197 patients based on RNAseq data. Results: We identified somatic mutations (TP53, NF1, KEAP1, CSMD3, LRP1B) that correlated with specific immune cell infiltrates. Hierarchical clustering revealed four immune classes: with (1) high immune cell infiltration (“inflamed”), (2) low immune cell infiltration (“desert”), (3) a mixed phenotype, and (4) a new phenotype with an overall muted inflammatory cell pattern but with an imprint of NK and plasma cells. This latter class exhibited low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, TGFB1), but was linked to better survival and therefore designated “oasis”. Otherwise, the four immune classes were not related to the presence of specific mutations (EGFR, KRAS, TP53) or histologic subtypes. Conclusion: We present a compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC and identified the novel immune class “oasis”. The immune classification helps to better define the immunogenic potency of NSCLC in the era of immunotherapy.
|
|
| 3. |
- Backman, Max, et al.
(författare)
-
Infiltration of NK and plasma cells is associated with a distinct immune subset in non‐small cell lung cancer
- 2021
-
Ingår i: Journal of Pathology. - : John Wiley & Sons. - 0022-3417 .- 1096-9896. ; 255:3, s. 243-256
-
Tidskriftsartikel (refereegranskat)abstract
- Immune cells of the tumor microenvironment are central but erratic targets for immunotherapy. The aim of this study was to characterize novel patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to its molecular and clinicopathologic characteristics. Lymphocytes (CD3+, CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+), PD1+, and PD-L1+ were annotated on a tissue microarray including 357 NSCLC cases. Somatic mutations were analyzed by targeted sequencing for 82 genes and a tumor mutational load score was estimated. Transcriptomic immune patterns were established in 197 patients based on RNA sequencing data. The immune cell infiltration was variable and showed only poor association with specific mutations. The previously defined immune phenotypic patterns, desert, inflamed, and immune excluded, comprised 30, 13, and 57% of cases, respectively. Notably, mRNA immune activation and high estimated tumor mutational load were unique only for the inflamed pattern. However, in the unsupervised cluster analysis, including all immune cell markers, these conceptual patterns were only weakly reproduced. Instead, four immune classes were identified: (1) high immune cell infiltration, (2) high immune cell infiltration with abundance of CD20+ B cells, (3) low immune cell infiltration, and (4) a phenotype with an imprint of plasma cells and NK cells. This latter class was linked to better survival despite exhibiting low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, CTLA4). This compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC reveals two previously unrecognized immune classes. A refined immune classification, including traits of the humoral and innate immune response, is important to define the immunogenic potency of NSCLC in the era of immunotherapy. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
|
|
| 4. |
|
|
| 5. |
- Eltahir, Mohamed, et al.
(författare)
-
An Adaptable Antibody-Based Platform for Flexible Synthetic Peptide Delivery Built on Agonistic CD40 Antibodies
- 2022
-
Ingår i: Advanced Therapeutics. - : Wiley. - 2366-3987. ; 5:7
-
Tidskriftsartikel (refereegranskat)abstract
- The agonistic potentials of therapeutic anti-CD40 antibodies have been profiled in relation to antibody isotype and epitope specificity. Still, clinical impact relies on a well-balanced clinical efficacy versus target-mediated toxicity. As CD40-mediated immune activation must rely on a combination of stimulation of antigen-presenting cells (APCs) alongside antigen presentation, for efficient T cell priming, alternative approaches to improve the therapeutic outcome of CD40-targeting strategies should focus on providing optimal antigen presentation together with CD40 stimulation. Herein, a bispecific antibody targeting CD40 as a means to deliver cargo (i.e., synthetic peptides) into APCs through a non-covalent, high-affinity interaction between the antibody and the cargo peptide, further referred to as the Adaptable Drug Affinity Conjugate (ADAC) technology, has been developed. The ADAC platform demonstrated a target-specific CD4+ and CD8+ T cell expansion in vitro and significantly improved peptide-specific CD8+ T cell proliferation in vivo. In addition, the strategy dramatically improved the in vitro and in vivo half-life of the synthetic peptides. Future applications of ADAC involve pandemic preparedness to viral genetic drift as well as neoepitope vaccination strategies where the bispecific antibody is an off-the-shelf product, and the peptide antigen is synthesized based on next-generation sequencing data mining.
|
|
| 6. |
- Eltahir, Mohamed
(författare)
-
Antibody-based Cancer Immunotherapy : Personalization, response prediction and safety considerations
- 2021
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Antibody-based therapeutics have remarkably improved the field of immuno-oncology. Multiple monoclonal antibodies (mAbs) are approved for clinical use, and numerous antibodies are under clinical development. The scope of this thesis is to study the personalization of antibody-based immunotherapeutics and tools to predict their efficacy and safety.In paper I, we investigated a new method for predicting immune toxicity related to mAbs infusion, the whole blood loop assay (WBLA). The assay recapitulates the in vivo setting and harmonizes well with clinically validated cytokine release assays (CRAs) following agonistic mAbs infusion. We also demonstrated the robustness of the assay in studying complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC).Rituximab, the first approved mAb for an oncology indication, is known to induce CRS occasionally. In paper II, the WBLA was used to profile the chronic lymphocytic leukemia (CLL) patients’ specific responses to rituximab infusion. We demonstrated rituximab-induced CRS profile and complement activation in blood from CLL patients but not in blood from healthy donors. We also noted that NK cells were a significant source of the rituximab-induced cytokine release. Using Fc mutant versions of rituximab, the mode-of-action of rituximab in whole blood with respect to CDC and ADCC was elaborated.In paper III, we presented a novel flexible peptide cancer vaccine platform based on an anti-CD40 agonistic antibody. The platform consists of a bispecific antibody targeting CD40 and peptide-tagged antigens. The bispecific antibody retained the agonistic activity of anti-CD40 and was superior to parental anti-CD40 mAb in targeting antigen cross-presentation and stimulating both CD8+ and CD4+ T cell responses.In paper IV, we investigated the feasibility of proximity-extension assay (PEA) plasma proteomic analysis in predicting response to checkpoint inhibitors (CPIs) in non-small cell lung cancer patients. CPIs show great success in the clinic. However, not all patients benefit from CPIs. Using an immuno-oncology protein panel, we demonstrated that high plasma levels of T cell activation proteins were associated with better survival. We also identified an association between the pre-CPI plasma levels of CXCL9, CXCL10, IL-15, ADA and Casp8 and the response to CPI therapy. In conclusion, this thesis demonstrates the feasibility of using the WBLA to assess antibody infusion efficacy and safety, as well as PEA plasma proteomics to predict response to CPI therapy. Additionally, it presents a novel approach for personalized therapeutic cancer vaccine delivery.
|
|
| 7. |
- Eltahir, Mohamed, et al.
(författare)
-
Plasma Proteomic Analysis in Non-Small Cell Lung Cancer Patients Treated with PD-1/PD-L1 Blockade
- 2021
-
Ingår i: Cancers. - : MDPI. - 2072-6694. ; 13:13
-
Tidskriftsartikel (refereegranskat)abstract
- Simple Summary Immunotherapy leads to highly variable responses in lung cancer patients. We assessed the value of a blood-based test to predict which patients would benefit from this new treatment modality. We determined that some patients have higher and lower levels of immune markers in their blood samples, and that this is related to better survival without tumor growth. The blood test has the potential to help select the optimal therapy for lung cancer patients. Checkpoint inhibitors have been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of patients demonstrate a durable clinical response. PD-L1 scoring is currently the only biomarker measure routinely used to select patients for immunotherapy, but its predictive accuracy is modest. The aim of our study was to evaluate a proteomic assay for the analysis of patient plasma in the context of immunotherapy. Pretreatment plasma samples from 43 NSCLC patients who received anti-PD-(L)1 therapy were analyzed using a proximity extension assay (PEA) to quantify 92 different immune oncology-related proteins. The plasma protein levels were associated with clinical and histopathological parameters, as well as therapy response and survival. Unsupervised hierarchical cluster analysis revealed two patient groups with distinct protein profiles associated with high and low immune protein levels, designated as "hot" and "cold". Further supervised cluster analysis based on T-cell activation markers showed that higher levels of T-cell activation markers were associated with longer progression-free survival (PFS) (p < 0.01). The analysis of single proteins revealed that high plasma levels of CXCL9 and CXCL10 and low ADA levels were associated with better response and prolonged PFS (p < 0.05). Moreover, in an explorative response prediction model, the combination of protein markers (CXCL9, CXCL10, IL-15, CASP8, and ADA) resulted in higher accuracy in predicting response than tumor PD-L1 expression or each protein assayed individually. Our findings demonstrate a proof of concept for the use of multiplex plasma protein levels as a tool for anti-PD-(L)1 response prediction in NSCLC. Additionally, we identified protein signatures that could predict the response to anti-PD-(L)1 therapy.
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Eltayeb-Elsheikh, Nezar, et al.
(författare)
-
Association of HLA-DR-DQ alleles, haplotypes, and diplotypes with type 1 diabetes in Saudis
- 2020
-
Ingår i: Diabetes/Metabolism Research Reviews. - : John Wiley & Sons. - 1520-7552 .- 1520-7560. ; 36:8
-
Tidskriftsartikel (refereegranskat)abstract
- Aims: Type 1 diabetes (T1D) is an autoimmune disease that affects many children worldwide. Genetic factors and environmental triggers play crucial interacting roles in the aetiology. This study aimed to assess the contribution of HLA-DRB1-DQA1-DQB1 alleles, haplotypes, and genotypes to the risk of T1D among Saudis.Methods: A total of 222 children with T1D and 342 controls were genotyped for HLA-DRB1, -DQA1, and -DQB1 using reverse sequence-specific oligonucleotide (rSSO) Lab Type high definition (HD) kits. Alleles, haplotypes, and diplotypes were compared between cases and controls using the SAS statistical package.Results: DRB1*03:01-DQA1*05:01-DQB1*02:01 (32.4%; OR = 3.68; P-c < .0001), DRB1*04:05-DQA1*03:02-DQB1*03:02 (6.6%; OR = 6.76; P-c < .0001), DRB1*04:02-DQA1*03:01-DQB1*03:02 (6.0%; OR = 3.10; P-c = .0194), DRB1*04:01-DQA1*03:01-DQB1*03:02 (3.7%; OR = 4.22; P-c = .0335), and DRB1*04:05-DQA1*03:02-DQB1*02:02 (2.7%; OR = 6.31; P-c = .0326) haplotypes were significantly increased in cases compared to controls, whereas DRB1*07:01-DQA1*02:01-DQB1*02:02 (OR = 0.41; P-c = .0001), DRB1*13:01-DQA1*01:03-DQB1*06:03 (OR = 0.05; P-c < .0001), DRB1*15:01-DQA1*01:02-DQB1*06:02 (OR = 0.03; P-c < .0001), and DRB1*11:01-DQA1*05:05-DQB1*03:01 (OR = 0.07; P-c = .0291) were significantly decreased. Homozygous DRB1*03:01-DQA1*05:01-DQB1*02:01 genotypes and combinations of DRB1*03:01-DQA1*05:01-DQB1*02:01 with DRB1*04:05-DQA1*03:02-DQB1*03:02, DRB1*04:02-DQA1*03:01-DQB1*03:02, and DRB1*04:01-DQA1*03:01-DQB1*03:02 were significantly increased in cases than controls. Combinations of DRB1*03:01-DQA1*05:01-DQB1*02:01 with DRB1*07:01-DQA1*02:01-DQB1*02:02 and DRB1*13:02-DQA1*01:02-DQB1*06:04 showed low OR values but did not remain significantly decreased after Bonferroni correction.Conclusions: HLA-DRB1-DQA1-DQB1 alleles, haplotypes, and diplotypes in Saudis with T1D are not markedly different from those observed in Western and Middle-Eastern populations but are quite different than those of East Asians.
|
|
| 11. |
- Eriksson, Jenny, et al.
(författare)
-
The 434(G>C) polymorphism within the coding sequence of Eosinophil Cationic Protein (ECP) correlates with the natural course of Schistosoma mansoni infection
- 2007
-
Ingår i: International Journal of Parasitology. - : Elsevier BV. - 0020-7519 .- 1879-0135. ; 37:12, s. 1359-1366
-
Tidskriftsartikel (refereegranskat)abstract
- Schistosomiasis is a chronic parasitic infection with over 200 million people infected worldwide. In Schistosoma mansoni infections, parasite-derived eggs get trapped in the liver, causing the formation of granulomas, which may develop into periportal fibrosis and portal hypertension, and thus severe morbidity. Eosinophil cationic protein (ECP) is a secretory protein of eosinophil granulocytes that efficiently kills the larval stage of S. mansoni, but also affects fibroblast functions. We have investigated the prevalence of the ECP gene polymorphism 434(G>C) in two African populations, from an S. mansoni endemic area in Uganda (n = 297) and from a non-endemic area in Sudan (n - 78), and also compared these with a Swedish population (n = 209). The genotype frequencies in the Ugandan population differed significantly from both the Sudanese and Swedish populations (P < 0.001). In the Ugandan population there was a significant association between genotype and prevalence of infection (P = 0.03), with lower prevalence in subjects with the GG genotype compared with GC (P = 0.02) and CC (P = 0.03). There was also a trend towards an association with periportal fibrosis (P = 0.08) in the Ugandan population. This suggested association was confirmed when the predominant tribe (n = 212) was analysed separately (P = 0.004). Our results suggest that ECP may be an important protein, both in the immune response against S. mansoni and in the development of periportal fibrosis. The results also suggest genetic selection towards the ECP 434CC genotype in populations living in S. mansoni endemic areas.
|
|
| 12. |
- Fletcher, Erika A. K., et al.
(författare)
-
Extracorporeal human whole blood in motion, as a tool to predict first-infusion reactions and mechanism-of-action of immunotherapeutics
- 2018
-
Ingår i: International Immunopharmacology. - : Elsevier BV. - 1567-5769 .- 1878-1705. ; 54, s. 1-11
-
Tidskriftsartikel (refereegranskat)abstract
- First infusion reactions along with severe anaphylactic responses can occur as a result of systemic administration of therapeutic antibodies. The underlying mechanisms by which monoclonal antibodies induce cytokine release syndrome (CRS) can involve direct agonistic effects via the drug target, or a combination of target-engagement along with innate receptor interactions. Despite the wide variety of pathways and cells that can play a role in CRS, many currently used assays are devoid of one or more components that must be present for these responses to occur. One assay that has not been assessed for its capacity to predict CRS is the modified Chandler loop model. Herein we evaluate a plethora of commercially available monoclonal antibodies to evaluate the modified Chandler loop model's potential in CRS prediction. We demonstrate that in a 4-hour loop assay, both the superagonistic antibodies, anti-CD3 (OKT3) and anti-CD28 (ANC28.1), display a clear cytokine response with a mixed adaptive/innate cytokine source. OKT3 induce TNFα and IFN-γ release in 20 out of 23 donors tested, whereas ANC28.1 induce TNF-α, IL-2 and IFN-γ release in all donors tested (n = 18–22). On the other hand, non-agonistic antibodies associated with no or low infusion reactions in the clinic, namely cetuximab and natalizumab, neither induce cytokine release nor cause false positive responses. A TGN1412-like antibody also display a clear cytokine release with an adaptive cytokine profile (IFN-γ and IL-2) and all donors (n = 9) induce a distinct IL-2 response. Additionally, the value of an intact complement system in the assay is highlighted by the possibility to dissect out the mechanism-of-action of alemtuzumab and rituximab. The loop assay can either complement lymph node-like assays or stand-alone to investigate drug/blood interactions during preclinical development, or for individual safety screening prior to first-in-man clinical trial.
|
|
| 13. |
- Fletcher, Erika, et al.
(författare)
-
Extracorporeal human whole blood in motion, as a tool to predict first-infusion reactions and mechanisms-of-action of immunotherapeutics : CRS prediction in human whole blood
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- First infusion reactions along with severeanaphylactic responses can occur as a result of systemic administration oftherapeutic antibodies. The underlying mechanisms by which monoclonal antibodiesinduce cytokine release syndrome (CRS) can involve direct agonistic effects viathe drug target, or a combination of target-engagement along with innatereceptor interactions. Despite the wide variety of pathways and cells that canplay a role in CRS, many currently used assays are devoid of one or morecomponents that must be present for these responses to occur. To date, oneassay that has not been used for studying CRS is the Chandler loop model. Thismodel is commonly used to study surface/blood interface interactions and has alsobeen used to study the instant blood-mediated inflammatory reaction (IBMIR). Herein we use a modified Chandler loopmodel with a heparin conjugate lining the inner surface of the loops to studyCRS. This allows for an assay harboring immune cells, intact cascade systemsalong with endogenous antibodies. Here, we evaluated a plethora of commerciallyavailable monoclonal antibodies to assess the capacity of the Chandler loopmodel for CRS prediction. We demonstrated that in a 4-hour loop assay both thesuperagonistic antibodies, anti-CD3 (OKT3) and anti-CD28 (ANC28.1), displayed aclear cytokine response with a mixed adaptive/innate cytokine source. OKT3 induced TNFα and IFN-g release in 20 out of23 donors tested, whereas ANC28.1 induced TNF-α, IL-2 and IFN-g release in all donors tested (n=18-22). On theother hand, non-agonistic antibodies associated with no or low infusionreactions in the clinic, namely cetuximab and natalizumab, neither induced cytokinerelease nor caused false positive responses. A TGN1412-like antibody alsodisplayed a clear cytokine release with an adaptive cytokine profile (IFN-g and IL-2) and all donors (n=9) inducing adistinct IL-2 response. Additionally, the value of an intact complement systemin the assay was highlighted by the possibility to dissect out themechanism-of-action (MOA) of alemtuzumab and rituximab. The loop assay can eithercomplement lymph node-like assays or stand-alone to investigate drug/bloodinteractions during preclinical development, or for individual safety screeningprior to a first-in-man clinical trial.
|
|
| 14. |
- Kamil, Noon Abubakr Abdelrahman, et al.
(författare)
-
The impact of COVID-19 on pharmacy students in Sudan : A cross-sectional survey
- 2020
-
Ingår i: Pharmacy Education. - : International Pharmaceutical Federation (FIP). - 1560-2214 .- 1477-2701. ; 20:2, s. 276-282
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The new coronavirus disease (COVID-19) has impacted many aspects of life. Several studies have investigated the effect of this pandemic on academic activities. Yet, no studies addressed the impact of COVID-19 on students in Sudan. This study examines the impact of COVID-19 on Sudanese undergraduate pharmacy students. Methods: A cross-sectional study was conducted using an online questionnaire delivered to undergraduate pharmacy students. Results: A total of 137 students responded to the survey. The majority were female (74.5%) and were students in private colleges (60.6%). Majority of the students (95.0%) were affected by COVID-19 crisis and about half of the respondents (54.0%) were depressed and 85.4% reported a decreased level of concentration. In spite of these challenges, majority of our respondents were still motivated (85.3%) to continue their education on campus. Conclusion: Despite unprecedented challenges posed by the COVID-19 pandemic, pharmacy students in Sudan are motivated to continue their studies, and they want the traditional teaching model to resume. It is time to invest more in education and rethink delivery of pharmacy education in Sudan during public health emergencies. There is no better time than now.
|
|
| 15. |
- Lauren, Ida, et al.
(författare)
-
Long-term SARS-CoV-2-specific and cross-reactive cellular immune responses correlate with humoral responses, disease severity, and symptomatology
- 2022
-
Ingår i: Immunity, Inflammation and Disease. - : John Wiley & Sons. - 2050-4527. ; 10:4
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Cellular immune memory responses post coronavirus disease 2019 (COVID-19) have been difficult to assess due to the risks of contaminating the immune response readout with memory responses stemming from previous exposure to endemic coronaviruses. The work herein presents a large-scale long-term follow-up study investigating the correlation between symptomology and cellular immune responses four to five months post seroconversion based on a unique severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific peptide pool that contains no overlapping peptides with endemic human coronaviruses. Methods: Peptide stimulated memory T cell responses were assessed with dual interferon-gamma (IFN gamma) and interleukin (IL)-2 Fluorospot. Serological analyses were performed using a multiplex antigen bead array. Results: Our work demonstrates that long-term SARS-CoV-2-specific memory T cell responses feature dual IFN gamma and IL-2 responses, whereas cross-reactive memory T cell responses primarily generate IFN gamma in response to SARS-CoV-2 peptide stimulation. T cell responses correlated to long-term humoral immune responses. Disease severity as well as specific COVID-19 symptoms correlated with the magnitude of the SARS-CoV-2-specific memory T cell response four to five months post seroconversion. Conclusion: Using a large cohort and a SARS-CoV-2-specific peptide pool we were able to substantiate that initial disease severity and symptoms correlate with the magnitude of the SARS-CoV-2-specific memory T cell responses.
|
|
| 16. |
- Rostedt Punga, Anna, et al.
(författare)
-
Flodvåg av långtidssjuka covid-19-patienter väntar
- 2020
-
Ingår i: Dagens Nyheter. - : Dagens Nyheter. - 1101-2447. ; , s. 5-5
-
Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Hittills har sjukvård och forskning fokuserat på de som är svårt sjuka i covid-19. Samhällsspridningen i Sverige gör att även primärvården måste förbereda sig på ett stort antal patienter med komplexa och långdragna symtom. Nu publiceras en av de första vetenskapliga fallbeskrivningarna av en långtidssjuk patient, skriver forskare vid Uppsala universitet.
|
|
