Exploring the Effectiveness of Ajwain Cream in Treating Taxane-induced Peripheral Neuropathy in Cancer Patients: A Pilot, Randomised and Double-blind Clinical Trial.

Objectives: Chemotherapy-induced peripheral neuropathy is a common disorder among cancer patients receiving various chemotherapeutic protocols. The present study aimed to explore the feasibility of ajwain (Trachyspermum ammi [L.] Sprague) cream in treating peripheral neuropathy symptoms triggered by taxane chemotherapeutic agents. Materials and Methods: This was a pilot, double-blind, and randomised clinical trial on patients with peripheral neuropathy attributable to chemotherapy with taxane drugs during 2021-2022 in Tehran. Patients received ajwain or placebo cream for four weeks and filled out the chemotherapy-induced peripheral neuropathy assessment tool (CIPNAT) at the start and end finale of the trial. Side effects were also noted. Results: Thirty patients suffering from breast, lung, gastro-intestinal, or prostate cancer were allocated to each of the drug and placebo groups. The mean difference in CIPNAT score between the groups was 0.83, demonstrating the statistical ineffectiveness of the drug compared with the placebo (P = 0.372). The safety profile showed promising outcomes at the end of the trial. Conclusion: Although the effectiveness of ajwain cream was unacceptable in treating chemotherapy-induced peripheral neuropathy symptoms, multicentre controlled trials with ample sample size are mandatory for an all-inclusive inference.

PX-478, an HIF-1α inhibitor, impairs mesoCAR T cell antitumor function in cervical cancer.

Introduction: Chimeric Antigen Receptor (CAR) T cell therapy has demonstrated remarkable success in treating hematological malignancies. However, its efficacy against solid tumors, including cervical cancer, remains a challenge. Hypoxia, a common feature of the tumor microenvironment, profoundly impacts CAR T cell function, emphasizing the need to explore strategies targeting hypoxia-inducible factor-1α (HIF-1α). Methods: In this study, we evaluated the effects of the HIF-1α inhibitor PX-478 on mesoCAR T cell function through in-silico and in vitro experiments. We conducted comprehensive analyses of HIF-1α expression in cervical cancer patients and examined the impact of PX-478 on T cell proliferation, cytokine production, cytotoxicity, and exhaustion markers. Results: Our in-silico analyses revealed high expression of HIF-1α in cervical cancer patients, correlating with poor prognosis. PX-478 effectively reduced HIF-1α levels in T and HeLa cells. While PX-478 exhibited dose-dependent inhibition of antigen-nonspecific T and mesoCAR T cell proliferation, it had minimal impact on antigen-specific mesoCAR T cell proliferation. Notably, PX-478 significantly impaired the cytotoxic function of mesoCAR T cells and induced terminally exhausted T cells. Discussion: Our results underscore the significant potential and physiological relevance of the HIF-1α pathway in determining the fate and function of both T and CAR T cells. However, we recognize the imperative for further molecular investigations aimed at unraveling the intricate downstream targets associated with HIF-1α and its influence on antitumor immunity, particularly within the context of hypoxic tumors. These insights serve as a foundation for the careful development of combination therapies tailored to counter immunosuppressive pathways within hypoxic environments and fine-tune CAR T cell performance in the intricate tumor microenvironment.

Retraction notice to "The therapeutic potential of human adipose-derived mesenchymal stem cells producing CXCL10 in a mouse melanoma lung metastasis model" [Cancer Lett. 419 (2018) 30-39].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor. After publication, the Editors were contacted by a concerned reader regarding alleged image duplication. These allegations are in regard to Fig. 3a being duplicated from a previously published paper in the journal Stem Cells (Stem Cells. 2008 Sep;26 (9):2332-8. doi: 10.1634/stemcells.2008-0084) and Fig. 8a being duplicated from a previously published paper in the journal Molecular Cancer (Mol Cancer 13, 255 (2014). https://doi.org/10.1186/1476-4598-13-255). After a thorough investigation by the editorial team, the Editors determined that there are multiple identical details between Fig. 5A (Cancer Letters) and Fig. 3A (Stem Cells) and the authors did not produce satisfactory evidence that the published images in Cancer Letters were original. Due to this, the Editor does not have confidence in the results and conclusions presented and has made the decision to retract.

Sexual function index adaptation for breast cancer patients (FSFI-BC)- translation and psychometric properties of Persian version.

BACKGROUND: Effective interventions to improve sexual dysfunction in breast cancer survivors need screening of these dysfunctions with a suitable instrument. The aim of present study was translation and identifying psychometric properties of Female Sexual Function Index - Adapted for Breast Cancer (FSFI-BC) which has been specifically developed for breast cancer survivors. METHOD: This methodological study was performed between February 2017 and October 2018. 200 breast cancer survivors in stage 1 or 2 who were selected through convenience sampling method, completed the questionnaire. Reliability was assessed by Cronbach's alfa and test re-test analysis and construct validity was performed through confirmatory (CFA) and exploratory factor analysis( EFA). RESULTS: Six factors were extracted in exploratory factor analysis (EFA). These factors explained 74.6% of the total variance in in NSA group and 0.821 in SA group. Reliability evaluation indicated high internal consistency and good test re-test reliability. Cronbach's alpha coefficient in all areas of the tool was above 0.7 (the lowest and the highest measures were 0.885 and 0.945, respectively), which is a good indicator for reliability of an instrument. Confirmatory factor analysis showed an acceptable fitness for seven factors of FSFI-BC questionnaire (Normed Fit Index or NFI = 0.9 for both groups, Comparative of Fit Index or CFI = 0.93 and 0.92, χ 2/df = 1.68 and 1.71 for SA(Sexually Active) and NSA(No Sexually Active) individuals, respectively) . CONCLUSION: Study findings suggest that Persian version of FSFI-BC is a suitable instrument for sexual dysfunction screening in breast cancer survivors.

Effect of Honey-Lime Spray as Add-On Therapy on Chemotherapy-Induced Xerostomia in Breast Cancer Patients: A Pilot Randomized Double-Blinded Controlled Trial.

INTRODUCTION: Xerostomia (dry mouth) is a common side effect among patients with cancer undergoing chemotherapy. There is no standard treatment for this symptom yet, although Persian medicine textbooks suggested some products to relieve xerostomia. We aimed to assess the efficacy of honey-lime spray in treating chemotherapy-induced xerostomia in breast cancer patients through a controlled study. METHODS: In this pilot, randomized, double-blinded clinical trial conducted in Shohadaye Tajrish Hospital, Iran, the intervention group received honey-lime spray and nystatin, while the control group used distilled water plus nystatin for 2 weeks. The six-item dry mouth form and visual analog score (VAS) were used to evaluate xerostomia extent and pain, respectively. RESULTS: The standardized value of the difference between the mean scores before and after the study was -10.21 (p < 0.001), and the effect size was estimated at 55%. Also, VAS showed a significant decrease in pain for the intervention group compared with the control group (p < 0.001). There were no serious side effects. CONCLUSION: Honey-lime spray may be a good treatment choice for xerostomia in chemotherapy-induced breast cancer patients, but robust trials with larger samples and prolonged follow-ups are highly recommended.Mundtrockenheit (Xerostomie) ist eine häufige Nebenwirkung bei Krebspatienten, die sich einer Chemotherapie unterziehen. Es gibt bisher keine Standardtherapie für dieses Symptom, doch Lehrbücher der persischen Medizin schlagen einige Mittel zur Linderung von Mundtrockenheit vor. Unser Ziel war es, die Wirksamkeit von Honig-Limetten-Spray zur Behandlung von chemotherapiebedingter Mundtrockenheit bei Patientinnen mit Brustkrebs im Rahmen einer kontrollierten Studie zu untersuchen.In dieser randomisierten, doppelt verblindeten klinischen Pilotstudie, die im Shohadaye Tajrish Hospital im Iran durchgeführt wurde, erhielt die Interventionsgruppe zwei Wochen lang Honig-Limetten-Spray und Nystatin und die Kontrollgruppe destilliertes Wasser plus Nystatin. Ein Mundtrockenheits-Fragebogen mit sechs Items wurde zur Beurteilung der Schwere der Mundtrockenheit verwendet und eine visuelle Analogskala zur Beurteilung der Schmerzen.Der standardisierte Wert der Differenz zwischen den mittleren Scores vor und nach der Studie betrug −10,21 (p < 0,01), und die geschätzte Effektstärke betrug 55%. Zudem zeigte die VAS eine signifikante Abnahme der Schmerzen in der Interventionsgruppe im Vergleich zur Kontrollgruppe (p < 0,01). Es traten keine schwerwiegenden Nebenwirkungen auf.Honig-Limetten-Spray könnte eine gute Wahl für die Behandlung von Mundtrockenheit bei Brustkrebspatientinnen unter Chemotherapie sein, doch hierzu werden belastbare Studien mit größerem Probenumfang und längerer Nachbeobachtung nachdrücklich empfohlen.

Applications of single-cell omics for chimeric antigen receptor T cell therapy.

Chimeric antigen receptor (CAR) T cell therapy is a promising cancer treatment modality. The breakthroughs in CAR T cell therapy were, in part, possible with the help of cell analysis methods, such as single-cell analysis. Bulk analyses have provided invaluable information regarding the complex molecular dynamics of CAR T cells, but their results are an average of thousands of signals in CAR T or tumour cells. Since cancer is a heterogeneous disease where each minute detail of a subclone could change the outcome of the treatment, single-cell analysis could prove to be a powerful instrument in deciphering the secrets of tumour microenvironment for cancer immunotherapy. With the recent studies in all aspects of adoptive cell therapy making use of single-cell analysis, a comprehensive review of the recent preclinical and clinical findings in CAR T cell therapy was needed. Here, we categorized and summarized the key points of the studies in which single-cell analysis provided insights into the genomics, epigenomics, transcriptomics and proteomics as well as their respective multi-omics of CAR T cell therapy.

Outsmarting trogocytosis to boost CAR NK/T cell therapy.

Chimeric antigen receptor (CAR) NK and T cell therapy are promising immunotherapeutic approaches for the treatment of cancer. However, the efficacy of CAR NK/T cell therapy is often hindered by various factors, including the phenomenon of trogocytosis, which involves the bidirectional exchange of membrane fragments between cells. In this review, we explore the role of trogocytosis in CAR NK/T cell therapy and highlight potential strategies for its modulation to improve therapeutic efficacy. We provide an in-depth analysis of trogocytosis as it relates to the fate and function of NK and T cells, focusing on its effects on cell activation, cytotoxicity, and antigen presentation. We discuss how trogocytosis can mediate transient antigen loss on cancer cells, thereby negatively affecting the effector function of CAR NK/T cells. Additionally, we address the phenomenon of fratricide and trogocytosis-associated exhaustion, which can limit the persistence and effectiveness of CAR-expressing cells. Furthermore, we explore how trogocytosis can impact CAR NK/T cell functionality, including the acquisition of target molecules and the modulation of signaling pathways. To overcome the negative effects of trogocytosis on cellular immunotherapy, we propose innovative approaches to modulate trogocytosis and augment CAR NK/T cell therapy. These strategies encompass targeting trogocytosis-related molecules, engineering CAR NK/T cells to resist trogocytosis-induced exhaustion and leveraging trogocytosis to enhance the function of CAR-expressing cells. By overcoming the limitations imposed by trogocytosis, it may be possible to unleash the full potential of CAR NK/T therapy against cancer. The knowledge and strategies presented in this review will guide future research and development, leading to improved therapeutic outcomes in the field of immunotherapy.

Crosstalk between autophagy and metabolic regulation of (CAR) T cells: therapeutic implications.

Despite chimeric antigen receptor (CAR) T cell therapy's extraordinary success in subsets of B-cell lymphoma and leukemia, various barriers restrict its application in solid tumors. This has prompted investigating new approaches for producing CAR T cells with superior therapeutic potential. Emerging insights into the barriers to CAR T cell clinical success indicate that autophagy shapes the immune response via reprogramming cellular metabolism and vice versa. Autophagy, a self-cannibalization process that includes destroying and recycling intracellular components in the lysosome, influences T cell biology, including development, survival, memory formation, and cellular metabolism. In this review, we will emphasize the critical role of autophagy in regulating and rewiring metabolic circuits in CAR T cells, as well as how the metabolic status of CAR T cells and the tumor microenvironment (TME) alter autophagy regulation in CAR T cells to restore functional competence in CAR Ts traversing solid TMEs.

Development of deep eutectic solvent-based microwave-assisted extraction combined with temperature controlled ionic liquid-based liquid phase microextraction for extraction of aflatoxins from cheese samples.

In this study, for the first time, a deep eutectic solvent-based microwave-assisted extraction was combined with ionic liquid-based temperature controlled liquid phase microextraction for the extraction of several aflatoxins from cheese samples. Briefly, the analytes are extracted from cheese sample (3 g) into a mixture of 1.5 mL choline chloride:ethylene glycol deep eutectic solvent and 3.5 mL deionized water by exposing to microwave irradiations for 60 s at 180 W. The liquid phase was taken and mixed with 55 µL 1-hexyl-3-methylimidazolium hexafluorophosphate. By cooling the solution in the refrigerator centrifuge, a turbid state was obtained and the analytes were extracted into the ionic liquid droplets. The analytes were determined by high-performance liquid chromatography equipped with fluorescence detector. Low limits of detection (9-23 ng kg-1 ) and quantification (30-77 ng kg-1 ), high extraction recovery (66%-83%), acceptable enrichment factor (40-50), and good precision (relative standard deviations ≤ 5.2%) were obtained using the offered approach. These results reveal the high extraction capability of the method for determination of aflatoxins in the cheese samples. In this method, there was no need for organic solvents and it can be considered as green extraction method.

PGE2-EP2/EP4 signaling elicits mesoCAR T cell immunosuppression in pancreatic cancer.

Introduction: For many years, surgery, adjuvant and combination chemotherapy have been the cornerstone of pancreatic cancer treatment. Although these approaches have improved patient survival, relapse remains a common occurrence, necessitating the exploration of novel therapeutic strategies. CAR T cell therapies are now showing tremendous success in hematological cancers. However, the clinical efficacy of CAR T cells in solid tumors remained low, notably due to presence of an immunosuppressive tumor microenvironment (TME). Prostaglandin E2, a bioactive lipid metabolite found within the TME, plays a significant role in promoting cancer progression by increasing tumor proliferation, improving angiogenesis, and impairing immune cell's function. Despite the well-established impact of PGE2 signaling on cancer, its specific effects on CAR T cell therapy remain under investigation. Methods: To address this gap in knowledge the role of PGE2-related genes in cancer tissue and T cells of pancreatic cancer patients were evaluated in-silico. Through our in vitro study, we manufactured fully human functional mesoCAR T cells specific for pancreatic cancer and investigated the influence of PGE2-EP2/EP4 signaling on proliferation, cytotoxicity, and cytokine production of mesoCAR T cells against pancreatic cancer cells. Results: In-silico investigations uncovered a significant negative correlation between PGE2 expression and gene signature of memory T cells. Furthermore, in vitro experiments demonstrated that the activation of PGE2 signaling through EP2 and EP4 receptors suppressed the proliferation and major antitumor functions of mesoCAR T cells. Interestingly, the dual blockade of EP2 and EP4 receptors effectively reversed PGE2-mediated suppression of mesoCAR T cells, while individual receptor antagonists failed to mitigate the PGE2-induced suppression. Discussion: In summary, our findings suggest that mitigating PGE2-EP2/EP4 signaling may be a viable strategy for enhancing CAR T cell activity within the challenging TME, thereby improving the efficacy of CAR T cell therapy in clinical settings.

Apoptosis induction in cancer cell lines and anti-inflammatory and anti-pathogenic properties of proteinaceous metabolites secreted from potential probiotic Enterococcus faecalis KUMS-T48.

Potential probiotic Enterococcus faecalis KUMS-T48, isolated from a kind of Iranian traditional dairy product (Tarkhineh), was assessed for its anti-pathogenic, anti-inflammatory and anti-proliferative properties against HT-29 and AGS cancer cell lines. This strain showed strong effects on Bacillus subtilis and Listeria monocytogenes and moderate effect on Yersinia enterocolitica, while indicated weak effect on Klebsiella pneumoniae and Escherichia coli. Also, neutralizing the cell-free supernatant and treating it with catalase and proteinase K enzymes reduced the antibacterial effects. Similar to Taxol, the cell-free supernatant of E. faecalis KUMS-T48 inhibited the in vitro proliferation of both cancer cells in a dose-dependent manner, but unlike Taxol, they had no activity against normal cell line (FHs-74). Pronase-treatment of the CFS of E. faecalis KUMS-T48 abrogated its anti-proliferative capacity, thereby showing the proteinaceous nature of the cell-free supernatant. Further, induction of apoptosis-based cytotoxic mechanism by E. faecalis KUMS-T48 cell-free supernatant is related to anti-apoptotic genes ErbB-2 and ErbB-3, which is different from Taxol's apoptosis induction (intrinsic mitochondria apoptosis pathway). Also, as evidenced by a decline in interleukin 1ß inflammation-promoting gene expression and a rise in the anti-inflammatory interleukin-10 gene expression in the HT-29 cell line, probiotic E. faecalis KUMS-T48 cell-free supernatant demonstrated a significant anti-inflammatory impact.

The inhibitory receptors PD1, Tim3, and A2aR are highly expressed during mesoCAR T cell manufacturing in advanced human epithelial ovarian cancer.

BACKGROUND: Chemotherapy and surgery have been the mainstays of epithelial ovarian cancer (EOC) treatment so far. Cellular immunotherapies such as CAR T cell therapy have recently given hope of a cure for solid tumors like EOC. However, extrinsic factors associated with the CAR T cell manufacturing process and/or intrinsic dysregulation of patient-derived T cells, which could be associated with cancer itself, cancer stage, and treatment regimen, may hamper the efficacy of CAR T cell therapy and promote their exhaustion or dysfunction. METHODS: To investigate the association of these factors with CAR T cell exhaustion, the frequency of T and CAR T cells expressing three immune inhibitory receptors (i.e., TIM3, PD1, A2aR) generated from T cells of EOC patients and healthy controls was measured during each stage of CAR T cell production. RESULTS: Our findings revealed that primary T cells from EOC patients show significantly elevated expression of immune inhibitory receptors, and this increase was more prominent in patients undergoing chemotherapy and those with advanced cancer. In addition, the CAR T cell manufacturing process itself was found to upregulate the expression of these inhibitory receptors and more importantly increase the population of exhausted mesoCAR T cells. CONCLUSIONS: Our observations suggest that intrinsic characteristics of patient-derived T cells and extrinsic factors in CAR T cell production protocols should be considered and properly counteracted during CAR T cell manufacturing process. In addition, mitigating the signaling of immune inhibitory receptors through pharmacological/genetic perturbation during CAR T cell manufacturing might profoundly improve CAR T cells function and their antitumor activity in EOC and other solid tumors.

MicroRNA-124 Enhances T Cells Functions by Manipulating the Lactic Acid Metabolism of Tumor Cells.

High production of lactic acid is a common feature of various tumors. Lactic acid is an immunosuppressive molecule with crucial roles in tumor cells' immune escape, which could largely be attributed to its negative effects on the T cells present in the tumor microenvironment (TME). Strategies that decrease the glycolysis rate of tumor cells could enhance immunosurveillance and limit tumor growth. Pyruvate kinase M2 (PKM2) is a key enzyme in the glycolysis pathway, and it plays a vital role in lactic acid buildup in the TME. MicroRNA (miR)-124 has been shown to be able to decrease tumor cell lactic acid synthesis indirectly by reducing PKM2 levels. In this study, we first overexpressed miR-124 in the tumor cells and evaluated its effects on the PKM2 expression and lactic acid production of the tumor cells using quantitative real-time polymerase chain reaction (qRT-PCR) and spectrophotometry, respectively. Then, we cocultured miR-124-treated tumor cells with T cells to investigate the effects of miR-124 overexpression on T cell proliferation, cytokine production, and apoptosis. Our results demonstrated that miR-124 overexpression could significantly reduce the amount of lactic acid produced by tumor cells by manipulating their glucose metabolism, which led to the augmented proliferation and IFN-γ production of T cells. Moreover, it rescued T cells from lactic acid-induced apoptosis. Our data suggest that lactic acid is a hindering factor for T-cell-based immunotherapies; however, manipulating tumor cells' metabolism via miR-124 could be a promising way to improve antitumor responses of T cells.

Postoperative cosmetic outcome of intraoperative radiotherapy in comparison to whole breast radiotherapy in early stage breast cancer; a retrospective cohort study.

BACKGROUND: In this study, we aim to evaluate the cosmetic outcome differences between Intraoperative electron beam radiation therapy (IOERT) and whole breast radiotherapy (WBR) with further investigation of boosted IOERT. METHODS: This retrospective cohort study was conducted in two referral centers in Tehran, Iran. 116 women aged 30 to 79 with early-stage breast cancer (T0-2N0-1M0) eligible for breast conservation were divided into two groups of 58 based on the intervention they received, and further subgroups were defined based on receiving boosted IOERT. Patients in both groups underwent breast conservation surgery and those in the IOERT group received either a 21 Gy radical dose (radical IOERT) or 12 Gy boosted electron beam radiotherapy and a routine fractionated dose of 50 Gy in 25 sessions of WBR (boosted IOERT). Those in the WBR group were administered 50Gy in 32 sessions. Physician-assessed cosmetic outcome was defined as the primary result and incidence of fat necrosis and fibrosis and post-operative chronic pain were secondary outcomes. RESULTS: Post-operative cosmetic outcome scores and chronic pain, showed no significant difference between the two groups. The median cosmetic score in both groups was 9. Fat necrosis and fibrosis had significantly higher rates in the IOERT group (P. VALUE: 0.001). However, the majority (21/34 or 61.8%) of this complication was observed in the boosted IOERT subgroup and no statistical significance was recorded between the radical IOERT subgroup and the WBR group. CONCLUSIONS: In early-stage breast cancer treatment, radical IOERT has noninferiority compared to WBR in terms of cosmesis. Regarding fat necrosis and fibrosis, boosted IOERT was associated with higher rates in comparison to other groups. Therefore, radical IOERT seems to be a better treatment option for selected patients.

Molecular Characteristics of TYK2 Gene Expressions in Patients with Colorectal Cancer.

Background: TYK2 is a member of the JAK family and is known to mediate signals of multiple cytokines that play a crucial role in immune and inflammatory signaling. Activation of TYK2 in tumor cells has been linked to promote cell survival, growth, and invasion. This study aimed to investigate the expression of tyrosine kinase 2 (TYK2) in colorectal cancer (CRC) and adjacent control tissues. Materials and Methods: Quantitative Real-Time PCR (qRT-PCR) method was elaborated to examine the expression levels of TYK2 in 100 colorectal tumor tissues and adjacent tissues as a control. Furthermore, we analyzed the diagnostic power of the mentioned TYK2 by plotting the receiver operating characteristic (ROC) curve. Results: Our results revealed that the expression level of TYK2 was significantly up-regulated in CRC patients sample compared to the adjacent sample of the control group. Analysis of patient's clinic pathological features shows that expressions TYK2 were differently associated with lymph vascular invasion and TMN stage (P < 0.0001, P < 0.0006). Conclusion: These results indicated that TYK2 levels potential biomarkers for diagnosing colorectal cancer may be identified.

Bcl-2 expression in cell lines breast cancer and death program.

Breast cancer is a hormone-dependence and heterogenic disease. Drug resistance is the main reason for the failure of breast cancer treatment. Combinatory medications are methods for treatment but they are not sufficient in action. However, new approaches like molecular therapy reveal a new insight into cancer treatment. Studies show that Bcl-2 gene family inhibitors and ER blockers cause the improvement of recovery. Interfering molecules such as antisense ones can inhibit the expression of Bcl-2 and push the cancer cells to apoptosis. Our team designed a new Antisense Oligonucleotide (ASO) based on Antisense oligo G3139. MCF-7 and MDA-MB-231 cell lines were used to evaluate cellular proliferation. Liposomes and cationic nano-complex (Niosome) are used to increase the cellular delivery of ASO and Tamoxifen. We also investigated the cytotoxicity and apoptotic effects of Tamoxifen, naked ASO and Nano-packed ASO. The results indicated significant down-regulation of the Bcl-2 gene and inhibition of MCF-7 and MDA-MB-231 cellular proliferation. Flow-cytometry showed early apoptosis in all cell groups. The newly designed ASO reduced the expression of the Bcl-2 gene. It also had a synergistic effect with the Tamoxifen. The cationic nano-complex (Niosome) was more efficient than the liposome in delivering designed oligo antisense Bcl-2 in the cancer cells.

CD8+ chimeric antigen receptor T cells manufactured in absence of CD4+ cells exhibit hypofunctional phenotype.

BACKGROUND: Cell culture conditions during manufacturing can impact the clinical efficacy of chimeric antigen receptor (CAR) T cell products. Production methods have not been standardized because the optimal approach remains unknown. Separate CD4+ and CD8+ cultures offer a potential advantage but complicate manufacturing and may affect cell expansion and function. In a phase 1/2 clinical trial, we observed poor expansion of separate CD8+ cell cultures and hypothesized that coculture of CD4+ cells and CD8+ cells at a defined ratio at culture initiation would enhance CD8+ cell expansion and simplify manufacturing. METHODS: We generated CAR T cells either as separate CD4+ and CD8+ cells, or as combined cultures mixed in defined CD4:CD8 ratios at culture initiation. We assessed CAR T cell expansion, phenotype, function, gene expression, and in vivo activity of CAR T cells and compared these between separately expanded or mixed CAR T cell cultures. RESULTS: We found that the coculture of CD8+ CAR T cells with CD4+ cells markedly improves CD8+ cell expansion, and further discovered that CD8+ cells cultured in isolation exhibit a hypofunctional phenotype and transcriptional signature compared with those in mixed cultures with CD4+ cells. Cocultured CAR T cells also confer superior antitumor activity in vivo compared with separately expanded cells. The positive impact of CD4+ cells on CD8+ cells was mediated through both cytokines and direct cell contact, including CD40L-CD40 and CD70-CD27 interactions. CONCLUSIONS: Our data indicate that CD4+ cell help during cell culture maintains robust CD8+ CAR T cell function, with implications for clinical cell manufacturing.

Metabolic and epigenetic orchestration of (CAR) T cell fate and function.

Longevity, functionality, and metabolic fitness are key determinants of chimeric antigen receptor (CAR) T cell efficacy. Activated T cells follow an ordered differentiation program which is facilitated by metabolic adaptations. In response to antigen, T cells undergo a highly-regulated shift to glycolysis. Committing to, and engaging in, glycolysis supports T cell expansion and effector function. Inside tumors, heightened tumor cell metabolism and dysregulated perfusion create a competition for nutrients. As local metabolism supports the differentiation of T cells into functionally-competent progeny, nutrient depletion coupled with persisting antigen can trigger T cell exhaustion. Emerging insights into the barriers impeding CAR T cell function in hostile tumor microenvironments (TME) reveal that metabolic intermediates shape the immune response by influencing epigenetic programs and the control of gene expression. In this review, we discuss recent progress connecting cellular metabolism with epigenetic states in CAR T cells. Given that CAR T cell metabolism can be dynamically regulated, we introduce the concepts of "metabolic-based epigenetic altering" and "epigenetic-based metabolism altering" to restore functional competence in CARTs traversing solid TMEs.

Comparing Dermolina-Henna Cream with Mometasone Cream in Improving Radiodermatitis Among Patients with Breast Cancer: A Randomized Active-Control Double-Blind Clinical Trial.

Objectives: Radiotherapy is one of the treatments used for different types of cancer. Acute radiodermatitis is one of its most common complications. Despite the high prevalence of radiodermatitis, few studies investigated how to prevent or treat this complication. Hence, a standard treatment has not been introduced so far. We sought to evaluate the efficacy of Dermolina-Henna cream, a new polyherbal formulation, compared to Mometasone cream for alleviating acute radiodermatitis among breast cancer patients. Design: Randomized active-control double-blind clinical trial. Setting/Location: The oncology clinic of Shohaday-e Tajrish Hospital (Tehran, Iran). Subjects: Women older than 18 years with breast cancer undergoing radiotherapy. Interventions: Patients were instructed to apply a thin layer of Dermolina-Henna or Mometasone cream once daily on their lesions at least 3 h after radiotherapy for 4 weeks, and if grade I or II radiodermatitis developed, also afterward. Patients were visited weekly until end of study at after 4 weeks. Radiation Therapy Oncology Group standard questionnaires were evaluated and recorded every week as the primary outcome. Outcome measures: Primary outcome was defined as evaluating the efficacy of Dermolina-Henna cream to change the radiodermatitis grade, while the level of patients' satisfaction and the rate of adverse events recorded by patients were secondary outcomes. Results: The trends on decrease in number of lesions, erythema, radiodermatitis grade, burning sensation, pain, and itchiness were statistically significant for each treatment, separately (p < 0.001), except for radiodermatitis grade in Mometasone group (p = 0.4). Dermolina-Henna was significantly better than Mometasone in alleviating burning sensation (p < 0.001) and itchiness (p = 0.041). Approximately 3.7% of patients showed adverse events and 3.7% declared dissatisfaction in both groups. Conclusions: In summary, we showed that Dermolina-Henna cream and Mometasone cream were significantly effective in decreasing severity of radiodermatitis symptoms among patients with breast cancer. Dermolina-Henna cream was significantly superior to Mometasone cream in alleviating burning and itchiness. Clinical Trial Registration Number: IRCT20200115046144N1.

Association between serum Vitamin D levels and prognostic factors in nonmetastatic breast cancer patients.

Background: Breast cancer is among the most common malignancies in women around the world. There is evidence of high prevalence of serum/blood Vitamin D deficiency in Iranian women. Considering the multitude of factors that may be involved in the prognosis and lifespan of breast cancer patients, this study investigated the level of Vitamin D in Iranian patients with nonmetastatic breast cancer. Materials and Methods: This cross-sectional study was carried out on 214 women diagnosed with breast cancer, who were referred to the radio-oncology department. Serum Vitamin D level of the patients was measured. Prognostic factors were determined based on demographic and pathological characteristics. The results were analyzed using descriptive statistics tests, Chi-square, one-way analysis of variance, Kaplan-Meier, and Cox regression model in SPSS v22. For all cases, the significance level was considered to be P < 0.05. Results: The total mean of 25-hydroxyvitamin D serum level was 25.15 ± 17.68 ng/ml. There was no significant relationship between levels of Vitamin D with disease stage, tumor size, tumor grade, estrogen receptor, progesterone receptor, and Human epidermal growth factor receptor 2 (P > 0.05). The mean survival time was 5 years and 45 days. Conclusion: No relationship was found between serum Vitamin D levels and the factors affecting the prognosis of nonmetastatic breast cancer. The Cox analysis showed that the survival time was not influenced by Vitamin D as a prognosis factor.