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The growth and metastatic potential of most solid and hematological tumors are angiogenesis-dependent. Antiangiogenic therapies have demonstrated clinical advantages in the treatment of numerous tumor types. Nevertheless, resistance to antiangiogenic therapy has emerged over time. This study aimed to review physiological blood vessel growth, angiogenesis, tumor vasculature, the role of vascular endothelial growth factor and its receptor in tumor angiogenesis, antiangiogenesis, resistance to antiangiogenic therapy, and mechanisms of resistance to antiangiogenic treatment while also providing guidance for the development of antiangiogenic therapies. We reviewed Google Scholar and PubMed for studies examining antiangiogenesis therapy, resistance to antiangiogenic agents, and strategies for overcoming them, thereby creating a guidelines-based approach. This review discusses a novel adaptive resistance mechanism involving metabolic adaptability of tumor cells. We found that personalized medicine may enhance the angiogenic mechanisms utilized by tumors. Thus, antiangiogenic therapy should be personalized by incorporating insights into tumor-specific vascularization and metabolism along with biomarker-guided treatment strategies. In addition to developing new pharmaceuticals, we must prioritize the identification of reliable markers for pathway activation and response. Addressing these challenges enables the optimization of antiangiogenic treatments within a precision oncology framework, thereby enhancing the prediction of therapeutic benefits and minimizing the risk of resistance in pediatric malignancies. In addition to conventional or salvage chemotherapy, antiangiogenic agents may serve as adjunctive chemotherapeutic agents, particularly for solid tumors. We also provide a guidelines-based approach to pediatric cancer therapy using antiangiogenic agents in countries with limited resources.

Little is known about the clinical significance of the peripheral blood CD4+ CD25+ FOXP3+ regulatory T cells (Tregs) and T helper-17 (Th17) cells in lymphoma patients. In this study, the prognostic and clinical significance of peripheral blood Tregs and Th17 cells were evaluated in lymphoma patients during different phases. The frequency of Tregs and Th17 lymphocytes was measured by flow cytometry method in 47 classical Hodgkin’s lymphoma (cHL) and 48 diffuse large B cell lymphoma (DLBCL) patients. Our results showed that the frequency of Tregs and absolute Treg count was significantly reduced in relapsed patients compared to patients at the remission phase, as well as with newly diagnosed untreated patients in both groups. Patients who reached complete remission had elevated frequency of CD4+ FOXP3+ lymphocytes, Tregs, absolute Treg count, Treg/CD4 and Treg/Th17 ratio in the cHL group and CD4+ CD25+ cells in DLBCL group. The frequency of Tregs, absolute Treg count and Treg/Th17 ratio in cHL patients and CD4+ FOXP3+ and CD4+ CD25+ cells in DLBCL patients positively associated with survival rate. Moreover, the percentage of Tregs and absolute Treg count positively correlated with white blood cell, platelet count and ESR level in cHL patients and with white blood cell count in DLBCL patients. The initial number of Tregs/Th17 cells and also the Treg/Th17 ratio was not associated with changes in disease-free survival (DFS) in both groups. Therefore, higher frequency of peripheral blood Tregs and Treg/Th17 ratio might be associated with a favorable outcome in lymphoma patients, better response to chemotherapy and lower rate of relapse.

Tumor infiltrating lymphocytes (TILs) usually become exhausted and dysfunctional owing to chronic contact with tumor cells and overexpression of multiple inhibitor receptors. Activation of TILs by targeting the inhibitory and stimulatory checkpoints has emerged as one of the most promising immunotherapy prospectively. We investigated whether triggering of CD28, 4-1BB, and PD-1 checkpoints simultaneously or alone could enhance the immune response capacity of lymphocytes. In this regard, anti-PD-1, CD80-Fc, and 4-1BBL-Fc proteins were designed and produced in CHO-K1 cells as an expression host. Following confirmation of the Fc fusion proteins’ ability to bind to native targets expressed on engineered CHO-K1 cells (CHO-K1/hPD-1, CHO-K1/hCD28, CHO-K1/hCTLA4, and CHO-K1/h4-1BB), the effects of each protein, on its own and in various combinations, were assessed in vitro on T cell proliferation, cytotoxicity, and cytokines secretion using the Mixed lymphocyte reaction (MLR) assay, 7-AAD/CFSE cell-mediated cytotoxicity assay, and a LEGENDplex™ Human Th Cytokine Panel, respectively. MLR results demonstrated that T cell proliferation in the presence of the combinations of anti-PD-1/CD80-Fc, CD80-Fc/4-1BBL-Fc, and anti-PD-1/CD80-Fc/4-1BBL-Fc proteins was significantly higher than in the untreated condition (1.83-, 1.91-, and 2.02-fold respectively). Furthermore, anti-PD-1 (17%), 4-1BBL-Fc (19.2%), anti-PD-1/CD80-Fc (18.6%), anti-PD-1/4-1BBL-Fc (21%), CD80-Fc/4-1BBL-Fc (18.5%), and anti-PD-1/CD80-Fc/4-1BBL-Fc (17.3%) significantly enhanced cytotoxicity activity compared to untreated condition (7.8%). However, concerning the cytokine production, CD80-Fc and 4-1BBL-Fc alone or in combination significantly increased the secretion of IFN‐γ, TNF-α, and IL-2 compared with the untreated conditions. In conclusion, this research establishes that the various combinations of produced anti-PD-1, CD80-Fc, and 4-1BBL-Fc proteins can noticeably induce the immune response in vitro . Each of these combinations may be effective in killing or destroying cancer cells depending on the type and stage of cancer.

Tumor infiltrating lymphocytes (TILs) usually become exhausted and dysfunctional owing to chronic contact with tumor cells and overexpression of multiple inhibitor receptors. Activation of TILs by targeting the inhibitory and stimulatory checkpoints has emerged as one of the most promising immunotherapy prospectively. We investigated whether triggering of CD28, 4-1BB, and PD-1 checkpoints simultaneously or alone could enhance the immune response capacity of lymphocytes. In this regard, anti-PD-1, CD80-Fc, and 4-1BBL-Fc proteins were designed and produced in CHO-K1 cells as an expression host. Following confirmation of the Fc fusion proteins’ ability to bind to native targets expressed on engineered CHO-K1 cells (CHO-K1/hPD-1, CHO-K1/hCD28, CHO-K1/hCTLA4, and CHO-K1/h4-1BB), the effects of each protein, on its own and in various combinations, were assessed in vitro on T cell proliferation, cytotoxicity, and cytokines secretion using the Mixed lymphocyte reaction (MLR) assay, 7-AAD/CFSE cell-mediated cytotoxicity assay, and a LEGENDplex™ Human Th Cytokine Panel, respectively. MLR results demonstrated that T cell proliferation in the presence of the combinations of anti-PD-1/CD80-Fc, CD80-Fc/4-1BBL-Fc, and anti-PD-1/CD80-Fc/4-1BBL-Fc proteins was significantly higher than in the untreated condition (1.83-, 1.91-, and 2.02-fold respectively). Furthermore, anti-PD-1 (17%), 4-1BBL-Fc (19.2%), anti-PD-1/CD80-Fc (18.6%), anti-PD-1/4-1BBL-Fc (21%), CD80-Fc/4-1BBL-Fc (18.5%), and anti-PD-1/CD80-Fc/4-1BBL-Fc (17.3%) significantly enhanced cytotoxicity activity compared to untreated condition (7.8%). However, concerning the cytokine production, CD80-Fc and 4-1BBL-Fc alone or in combination significantly increased the secretion of IFN‐γ, TNF-α, and IL-2 compared with the untreated conditions. In conclusion, this research establishes that the various combinations of produced anti-PD-1, CD80-Fc, and 4-1BBL-Fc proteins can noticeably induce the immune response in vitro. Each of these combinations may be effective in killing or destroying cancer cells depending on the type and stage of cancer.

Acute myeloid leukemia (AML) is one of the most prevalent leukemia in adults. Among the various NK receptors, killer immunoglobulin-like receptors (KIRs) carry out indispensable roles in NK cell development and function through engaging with class I human leukocyte antigens (HLA-I) as their ligands. Besides divergent KIR and HLA loci, KIR / HLA-I combinations have a significant effect on NK cell response. In this case–control study, we aimed to verify the association of KIR / HLA-I combinations with susceptibility to AML in the Southwestern Iranian population. KIR and HLA genotyping was performed with PCR-SSP by some novel primers for 181 patients with AML and 181 healthy controls. According to our results, the frequencies of KIR3DS1 ( p  = 0.0001, OR = 2.32, 95% CI 1.51–3.58), KIR2DS4fl ( p  = 0.02, OR = 1.53, 95% CI 1.05–2.21), CxT4 genotypes ( p  = 0.03, OR = 2.0, 95% CI 1.05–3.82), and T4 gene cluster ( p  = 0.01, OR = 1.99, 95% CI 1.17–3.41) were significantly higher in patients than controls, while C1/C2 genotype ( p  = 0.00002, OR = 0.39, 95% CI 0.25–0.61), HLA-A Bw4 ( p  = 0.02, OR = 0.6, 95% CI 0.38–0.94), and HLA-A*11 ( p  = 0.03, OR = 0.57, 95% CI 0.34–0.95) alleles were more frequent in controls. In addition, inhibitory (i)KIR / HLA-I combinations analysis revealed higher frequencies of KIR2DL1( +) / HLA-C2( +), KIR2DL2/3( +) / HLA-C1( +), KIR3DL1( +) / HLA-A Bw4( +), and KIR3DL2( +) / HLA-A*03/11( +) in the control group ( p  = 0.002, OR = 0.49, 95% CI 0.3–0.78; p  = 0.04, OR = 0.62, 95% CI 0.39–0.99; p  = 0.04, OR = 0.63, 95% CI 0.4–0.99; and p  = 0.03, OR = 0.62, 95% CI 0.4–0.95, respectively). Overall, the number of iKIR / HLA-I combinations was more in the control group. Moreover, KIR3DS1( +) / HLA-B Bw4 Ile80 ( +) and the sum of HLA-B Bw4/A Bw4 combined with KIR3DS1 as activating KIR / HLA-I combinations were more frequent among patients than controls ( p  = 0.01, OR = 1.99, 95% CI 1.14–3.49 and p  = 0.005, OR = 1.97, 95% CI 1.22–3.19, respectively). In conclusion, our results postulate that inhibitory combinations play a protective role against AML by developing potent NK cells during education. It is noteworthy that KIR / HLA-I combination studies can be applicable in donor selection for allogeneic NK cell therapy in hematological malignancies.

Background Mesenchymal stromal cell (MSC) transplantation can improve the left ventricular ejection fraction (LVEF) after an acute myocardial infarction (AMI). Transplanted MSCs exert a paracrine effect, which might be augmented if repeated doses are administered. This study aimed to compare the effects of single versus double transplantation of Wharton’s jelly MSCs (WJ-MSCs) on LVEF post-AMI. Methods We conducted a single-blind, randomized, multicenter trial. After 3–7 days of an AMI treated successfully by primary PCI, 70 patients younger than 65 with LVEF < 40% on baseline echocardiography were randomized to receive conventional care, a single intracoronary infusion of WJ-MSCs, or a repeated infusion 10 days later. The primary endpoint was the 6-month LVEF improvement as per cardiac magnetic resonance (CMR) imaging. Results The mean baseline EF measured by CMR was similar (~ 40%) in all three groups. By the end of the trial, while all patients experienced a rise in EF, the most significant change was seen in the repeated intervention group. Compared to the control group ( n  = 25), single MSC transplantation ( n  = 20) improved the EF by 4.54 ± 2%, and repeated intervention ( n  = 20) did so by 7.45 ± 2% when measured by CMR imaging ( P  < 0.001); when evaluated by echocardiography, these values were 6.71 ± 2.4 and 10.71 ± 2.5%, respectively ( P  < 0.001). Conclusions Intracoronary transplantation of WJ-MSCs 3–7 days after AMI in selected patients significantly improves LVEF, with the infusion of a booster dose 10 days later augmenting this effect. Trial registration : Trial registration: Iranian Registry of Clinical Trials, IRCT20201116049408N1. Retrospectively Registered 20 Nov. 2020, https://en.irct.ir/trial/52357

Background The overall incidence of breast cancer is different all over the world and even within a nation. The present study aims to investigate the stratum-specific incidence trends of breast cancer in southern Iran. Methods In this retrospective cohort study, the data of Fars Population-Based Cancer Registry was used during 2001–2018. New cancer cases with ICD-O-3 codes C50.0 to C50.9 were categorized based on age group, morphology, and topography. Age-specific incidence rates of breast cancer were calculated during 2001–2018. Annual overall and truncated age-standardized incidence rates and their 95% Confidence Intervals (CIs) were also calculated. Afterward, the Annual Percentage Changes (APCs) of the age-specific and age-standardized incidence rates of breast cancer during 2001–2018 were calculated using Joinpoint regression software. Results An increasing trend was observed in the incidence of breast cancer among women during 2001–2018 (APC of age-standardized incidence rates: 9.5 (95% CI: 7.5, 11.5)).However, the trend was increasing less during the recent years. The APC of age-standardized rates decreased from 15.03 (95% CI: 10.4, 19.8) in 2007 to 6.15(95% CI: 4.0, 8.4) in 2018. The most common morphology of breast cancer was invasive ductal carcinoma (77.3% in females and 75.1% in males) and its trend was similar to the general trend of different types of breast cancer. The most common site of breast cancer was the upper outer quadrant. Most breast cancer cases were female and males accounted for 2.45% of the cases. Among females, 40–55 was the most prevalent age group. Conclusion The incidence of breast cancer among women living in southern Iran showed an increasing trend from 2001 to 2018. However, the rate of increase exhibited a milder slope during the more recent years. Based on the higher prevalence of breast cancer in the 40–55 age group observed in the present study, it offers valuable insight into the potential reduction of the breast cancer screening age from 50 to 40 years for healthy Iranian women. However, before implementing such a policy change, it is crucial to conduct additional studies that specifically examine the cost-effectiveness, as well as the potential benefits and risks associated with this alteration.

Introduction Bio-psychological factors may affect the relationship between pain and sleep, but they are understudied in hematopoietic stem cell transplantation (HSCT) patients. This study investigated the mediating role of health anxiety, resilience, and body image in the relationship between pain and sleep in HSCT patients. Methods In this cross-sectional study, 210 HSCT patients from Motahari clinic, Shiraz University of Medical Sciences were recruited using convenience sampling. Demographic and clinical characteristics, Pittsburgh Sleep Quality Index, Numeric Rating Scale of Pain, Health Anxiety Inventory, Body Image Scale, and Connor-Davidson’s Resilience were used. Data were analyzed using SPSS Macro process and structural equation model. Results Approximately half of the participants reported good sleep quality. Mean resilience and health anxiety scores were 66.02 (SD = 14.85), 23.88 (SD = 10.30), respectively, indicating moderate levels. The mean of body image (5.90; SD = 4.26) indicated low negative body image. Sleep was correlated with pain ( r  = 0.31, p  < 0.001), resilience ( r =˗0.39, p  < 0.001), health anxiety ( r  = 0.45, p  < 0.001), and body image ( r  = 0.42, p  < 0.001). Poorer sleep was associated with higher pain, health anxiety, body image concerns, and lower resilience. Resilience (β = 0.16, CI = 0.03 to 0.31), health anxiety (β = 0.17, CI = 0.04 to 0.32), and body image (β = 0.25, CI = 0.10 to 0.43) mediated the pain-sleep relationship, explaining 31% of the total effect. Conclusion Poorer sleep quality was associated with higher pain, health anxiety, lower resilience, and negative body image. These factors mediated the pain-sleep relationship in HSCT patients, highlighting the need for nursing interventions targeting resilience, body image, and health anxiety to improve pain and sleep outcomes.

Background The present study aimed to explore the changes in the expressions of six tumor‐related genes in myeloproliferative neoplasms (MPNs). The study population included 130 patients with MPNs (52 with chronic myeloid leukemia (CML), 49 with essential thrombocythemia (ET), 20 with polycythemia vera (PV), and 9 with primary myelofibrosis (PMF)) and 51 healthy individuals. Methods The expression profiling of six genes (ADAMTS18, CMTM5, CDKN2B, DCC, FHIT, and WNT5B) in the peripheral blood granulocyte cells was explored by real‐time quantitative reverse transcription polymerase chain reaction. Results The patients with MPNs showed significant downregulation of CMTM5 (EFC = 0.66) and DCC (EFC = 0.65) genes in contrast to a non‐significant upregulation of ADAMTS18, CDKN2B, FHIT, and WNT5B genes. Downregulation of DCC was consistent in all subtypes of MPN (EFC range: 0.591–0.860). However, CMTM5 had a 1.22‐fold upregulation in PMF in contrast to downregulation in other MPN subtypes (EFC range: 0.599–0.775). The results revealed a significant downregulation in CMTM5 and DCC at below 60‐years of age. Furthermore, female patients showed a clear‐cut downregulation in both CMTM5 and DCC (EFC DCC: 0.436 and CMTM5: 0.570), while male patients presented a less prominent downregulation with a borderline p‐value only in DCC (EFC: 0.69; p = 0.05). Conclusions Chronic myeloid leukemia cases showed a significant upregulation of WNT5B, as a known oncogenesis gene. Two tumor suppressor genes, namely DCC and CMTM5, were downregulated in the patients with MPNs, especially in females and patients below 60 years of age. The presence of the Philadelphia chromosome led to a significant upregulation of WNT5B with non‐significant changes in other genes. Two tumor suppressor genes, DCC and CMTM5, were downregulated in MPN patients especially in females and patients younger than 60 years old. WNT5B, a known oncogenesis gene, was upregulated in CML patients.

Organ transplantation has been linked to certain gene polymorphisms. The effect of gene polymorphisms–associated organ transplantation gene on infection, on the other hand, is yet unknown. The research studying the link between the CTLA-4 rs5742909, rs733618, rs4553808, rs231775, and polymorphisms of the organ transplantation gene and infection were found in PubMed, Web of Science, Scopus, and Embase, and the published articles from 2012 to 2020 were gathered. For the best estimation of the intended results, a random-effects model was used in this meta-analysis. In this study, 1,567 studies were initially included and 9 eligible studies were eligible for further analyses. A significant correlation between CTLA4+49 [A/G-231775 odds ratio (OR) = 077, 0.59–0.95] and CTLA4 [rs5742909TT OR: 0.09, 0.27–0.45] gene polymorphism with infection in organ transplantation was observed. Also, no significant association was found between other CTLA4 gene polymorphisms with infection in organ transplantation. Further studies involving gene–gene and gene–diet interactions should be conducted to investigate this association with infection.