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The development of multi-functional Pt(IV) complexes as chemotherapeutic agents has gained growing attention in medical oncology. However, the design of multi-functional tumor-targeted Pt(IV) complexes with high hydrolytic stability remains challenging. Herein, we have developed a Pt(IV) prodrug conjugated with vorinostat as a multi-functional cancer therapeutic. In this design, the octahedral Pt(IV) prodrug of a DNA damaging anticancer drug cisplatin is tethered to the cancer cell targeting biotin ligand through one of the axial sites and the other axial site of the Pt(IV) center is attached to the anticancer drug vorinostat (also known as SAHA), a histone deacetylase inhibitor (HDACi) approved by the Food and Drug Administration (FDA) for treatment of cutaneous T-cell lymphoma. The designed biotinylated Pt(IV)-SAHA (Biotin-Pt(IV)-SAHA) conjugate is hydrolytically stable but reduced to Pt(II) species under intracellularly relevant conditions and concomitantly releases cisplatin and two of its axial ligands such as SAHA and biotin. The anticancer activity of the conjugate is investigated against a panel of cisplatin-sensitive human cancer cells, including cisplatin-resistant cells. Interestingly, the conjugate exhibited significantly higher cytotoxicity than the clinically approved anticancer drug cisplatin and slightly more cytotoxicity than the HDACi SAHA in all the tested cell lines. By combining the Pt(IV) prodrug of cisplatin with SAHA in the conjugate, synergistic cytotoxicity is achieved. The imaging studies revealed that the conjugate is taken up by cancer cells and shows dose-dependent cell death. The studies on our designed multi-pronged conjugate can be further optimized to enhance its efficacy, paving the way for developing a new class of clinically relevant chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

In this paper, we bring hope to patients with mycosis fungoides (MF) with CD30+ large‐cell transformation (LCT), which is often a histological marker of poor prognosis and is associated with a mean 5‐year survival of <20%. Although skin biopsy is a painful procedure, it is the only test for early diagnosis of LCT. Stage IIB has a significantly worse 5‐year survival rate compared with stage IB/IIA, which often plagues clinicians regarding appropriate treatment selection. In this case, the discovery of LCT by skin biopsy prompted treatment with BV. Thus, proactive rebiopsy is important so that CD30+ LCT is not overlooked in the early stage of MF. [ABSTRACT FROM AUTHOR]

Patients with primary immunodeficiency are at increased risk for malignancy, especially hematologic neoplasms. This paper reports a unique case of a 47‐year‐old man with X‐linked agammaglobulinemia who presented with progressive asymptomatic violaceous papules and plaques on his face, hands, and trunk for 1 year. Skin biopsies revealed deep, nodular infiltrates of histiocytes and CD8‐positive lymphocytes, with a CD4:CD8 ratio of 1:10. Laboratory studies showed cytopenias. Flow cytometry in the skin, blood, and bone marrow (BM) showed a CD3+/CD8+/CD57+ large granular lymphocyte population. BM biopsy showed 30% involvement with these atypical T‐cells. T‐cell gene rearrangement studies of skin, blood, and BM revealed identical T‐cell clones. He was diagnosed with T‐large granular lymphocyte leukemia (T‐LGLL) with an associated CD8+ cutaneous lymphoproliferation. Skin involvement was suspected to represent infiltration by T‐LGLL. However, co‐existence of two lymphoproliferative disorders (LPDs), T‐LGLL and CD8+ granulomatous LPD, remains a possibility. In general, cutaneous infiltrates associated with LGLL are rare and poorly understood. It has been suggested that they are markers of poor prognosis. Our case report describes skin, blood, and BM findings in an immunosuppressed patient with T‐LGLL in detail. These findings have not yet been reported and their significance requires further investigation. [ABSTRACT FROM AUTHOR]

Methotrexate (MTX) is an anti-metabolic cytotoxic drug. High-dose methotrexate (HD-MTX) supplemented with calcium leucovorin is a profile for clinical treatment of acute lymphoblastic leukemia, osteosarcoma, malignant lymphoma and other cancers. However, HD-MTX may produce serious toxicity and significant differences may exist individually. Serious adverse drug reactions may occur, should there be delayed metabolic excretion. This paper is a comprehensive review on the pharmacokinetics, influential factors and detection methods of plasma concentration of HD-MTX, and will provide reference for clinicians and pharmacists and safe and rational use of HD-MTX will be ensured clinically. [ABSTRACT FROM AUTHOR]

Introduction: It has been suggested that soluble immune receptors (SIRs) such as sCD25 and sCD30 may serve as potential biomarkers in evaluation of atopic dermatitis (AD). Previous studies clearly indicated that serum levels of interleukin (IL)-13 and total IgE (tIgE) might be potentially useful in the evaluation of patents with AD. Aim: To evaluate whether serum levels of sCD25 and sCD30 are suitable biomarkers of AD. Moreover, we have decided to estimate the usefulness of tIgE and IL-13 serum level determination in the evaluated population. Material and methods: A group of 102 AD patients was investigated. Serum concentrations of sCD30, sCD25, IL-13 and tIgE were measured. The clinical phenotype of AD was classified as extrinsic (ADe) or intrinsic (ADi) based on the presence of IgE. Statistical analysis was performed to estimate correlations between obtained results and clinical features of the population such as AD phenotype, age, disease extent and severity. Results: Extrinsic AD was diagnosed in 71% of patients, while ADi phenotype was observed in 29% of the investigated population. A negative correlation between serum levels of sCD25 and sCD30 and disease severity as well patients' age was established. Serum levels of IL-13 did not reach the cut-off point set by the manufacturer. A positive correlation between serum levels of total IgE and disease severity and patients' age was observed. Conclusions: This paper shows that serum levels of sCD25 and sCD30 as well as tIgE are age dependent. Determination of serum levels of sCD25, sCD30 and IL-13 is not useful in everyday practice. [ABSTRACT FROM AUTHOR]

During viral infection, the innate immune system utilizes a variety of specific intracellular sensors to detect virus-derived nucleic acids and activate a series of cellular signaling cascades that produce type I IFNs and proinflammatory cytokines and chemokines. Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus that has been associated with a variety of human malignancies, including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease. Infection with KSHV activates various DNA sensors, including cGAS, STING, IFI16, and DExD/H-box helicases. Activation of these DNA sensors induces the innate immune response to antagonize the virus. To counteract this, KSHV has developed countless strategies to evade or inhibit DNA sensing and facilitate its own infection. This review summarizes the major DNA-triggered sensing signaling pathways and details the current knowledge of DNA-sensing mechanisms involved in KSHV infection, as well as how KSHV evades antiviral signaling pathways to successfully establish latent infection and undergo lytic reactivation. [ABSTRACT FROM AUTHOR]

Intravascular lymphomas are rare disease conditions that exhibit neoplastic lymphoid cells that are confined mainly to the lumens of small capillaries and medium-sized vessels. The majority of the intravascular lymphomas are of B-cell origin, but they can include NK/T-cell and CD30+ immunophenotypes. In the histologic differential diagnosis are benign proliferations such as intralymphatic histiocytosis and intravascular atypical CD30+ T-cell proliferation. In this review, we discuss the clinical, histopathologic, and molecular findings of intravascular B-cell lymphoma, intravascular NK/T-cell lymphoma, intralymphatic histiocytosis, and benign atypical intravascular CD30+ T-cell proliferation. [ABSTRACT FROM AUTHOR]

This research study compares two methods for evaluating fat accumulation in donor liver biopsies. The study found that the simpler Average of Fields (AF) method can be used as an alternative to the more complex Banff method for assessing large droplet fat (LDF) in the biopsies. The authors emphasize the need for standardized methods in this area of research and recommend further validation of the Banff method before it is recommended for clinical use. The study also mentions the assessment of small droplet fat (SDF) and the need for correlation with graft outcomes to determine if a change in the prevailing LDF definition is warranted. [Extracted from the article]

Fatty acid and central carbon metabolism are crucial energy metabolism reactions. However, to date, few studies have examined their distribution characteristics within the alfalfa–rhizobia symbiotic system. To clarify the distributional differences and accumulation rates of fatty acids and central carbon with this system, we measured the plant phenotype, nodule formation, nitrogen fixation capacity, and key nitrogen metabolism enzyme activities of Medicago sativa 'Gannong No. 9' 35 days post-inoculation (dpi) with Sinorhizobia meliloti LL11. Additionally, we employed targeted metabolomics to analyze central carbon and fatty acid metabolites in various tissue samples of symbiotic and control (C.K.) plants, as well as in S. meliloti LL11. We found that plant height; root length; aboveground fresh and dry weights; underground fresh and dry weights; and nitrate reductase, nitrogen reductase, glutamine synthetase, and glutamate synthase activities were significantly higher in the leaves and roots of symbiotic plants than in those of C.K. plants. Compared to symbiotic plants, C.K. plants exhibited higher total central carbon and fatty acid metabolite content, accounting for 38.61% and 48.17% of C.K. plants, respectively. We detected 32 central carbon and 40 fatty acid metabolites in S. meliloti LL11, with succinate (343,180.8603 ng·mL−1) and hexadecanoic acid (4889.7783 ng·mL−1) being the most. In both symbiotic and C.K. plants, central carbon metabolite was considerably higher than the fatty acid metabolite central. Moreover, the carbon metabolites found in symbiotic plants were primarily distributed in pink nodule roots (PNRs), with malate exhibiting the highest content (4,800,612.3450 ng·g−1), accounting for 53.09% of total central carbon metabolite content. Fatty acid metabolites were mainly found in pink root nodules (P.N.s), which are sites of nitrogen fixation. Trans-10-nonadecenoic acid and hexadecanoic acid exhibited the highest contents, comprising >15% of the total fatty acid metabolite content. We found that petroselaidic acid is only present in P.N., which seems to be closely related to the nitrogen fixation reaction in P.N. In general, symbiotic plants transfer central carbon metabolites to nodules via PNRs to drive nitrogen fixation. However, in P.N.s, these metabolites are limited, leading to accumulation in PNRs. Fatty acid metabolites, crucial for nitrogen fixation, are prevalent in P.N.s. Conversely, C.K. plants without nitrogen fixation distribute these metabolites primarily to the stems, emphasizing growth. This study provides new insights into the energy metabolism of symbiotic nitrogen fixation. [ABSTRACT FROM AUTHOR]

This article discusses a case of primary cutaneous anaplastic large cell lymphoma (ALCL) with DUSP22-rearrangement that presented as a mimicker of mycosis fungoides (MF). The DUSP22 gene on chromosome 6p25 encodes a dual-specific phosphatase that regulates mitogen-activated protein kinases. The presence of DUSP22 translocation has been associated with a favorable prognosis in systemic ALCL. The case described in the article expands the spectrum and morphological variability of primary cutaneous CD30+ T-cell lymphoproliferations with DUSP22-rearrangement. The article emphasizes the importance of clinical history and evolution in the differential diagnosis of CD30+ cutaneous T-cell lymphoproliferations and lymphomas. [Extracted from the article]

The author comments on a paper by Xuan J. Wang et al. on a study of the clinicopathological features of a retrospective series of 98 patients diagnosed as de novo EBV-negative Diffuse Large B-cell Lymphoma (DLBCL). He notes that CD30 expression in large B-cell lymphomas can be found in multiple B-cell lymphoma entities with variable prevalence and concludes that the availability of new drugs against CD30 molecule should foster the development of clinical trials to test its efficacy.

CD30, also known as TNFRSF8 (tumor necrosis factor receptor superfamily member 8), is a protein receptor that is heavily glycosylated inside the Golgi apparatus, as well as a tumor marker that is found on the surface of specific cells in the body, including certain immune cells and cancer ones. This review aims to shed light on the critical importance of CD30, from its emergence in the cell to its position in diagnosing various diseases, including Hodgkin lymphoma, where it is expressed on Hodgkin and Reed–Sternberg cells, as well as embryonal carcinoma, anaplastic large cell lymphoma (ALCL), and cutaneous T-cell lymphoma (CTCL). In addition to its role in positive diagnosis, targeting CD30 has been a promising approach treating CD30-positive lymphomas, and there is ongoing research into the potential use of CD30-targeted therapies for autoimmune disorders. We aim to elaborate on CD30's roles as a tumor marker, supporting thus the hypothesis that this receptor might be the aim of cytostatic treatment. [ABSTRACT FROM AUTHOR]

Summary: CD30 is a transmembrane protein from the tumour necrosis factor receptor superfamily. It is expressed on a small subset of activated T and B lymphocytes, and various lymphoid neoplasms. CD30 is a particularly interesting treatment target because its levels are high in tumours but low in healthy tissues. Several therapeutic strategies targeting CD30 have been developed, including monoclonal antibodies, conjugated antibodies (combination of brentuximab vedotin with chemotherapy or immunotherapy), bispecific antibodies and cell and gene therapies, such as anti‐CD30 CAR‐T cells in particular. We briefly review the biology of CD30 which makes it a good therapeutic target, and we describe all of the anti‐CD30 therapies that have emerged to date. [ABSTRACT FROM AUTHOR]

Furthermore, chimeric antigen receptor (CAR) T cell therapies have recently joined the list of approved cancer immunotherapies as treatments for mantle cell lymphoma or certain types of large B-cell lymphoma. The second topic, (ii) biomarkers to predict the efficacies of current immunotherapies, is one of the hottest issues in the field of cancer immunotherapy research. The strategy to use the immune system to fight cancer is not a novel concept; in 1891, Coley reported the treatment of three cases of sarcoma by inoculation with erysipelas [[1]]. [Extracted from the article]

The proinflammatory cascade that is activated at the time of brain death plays a crucial role in organ procurement. Our aim of this study was to explore the relationship between the clinical outcome of orthotopic heart transplantation, as well as cytokine and apolipoprotein profiles of the pericardial fluid obtained at donation. Interleukin, adipokine and lipoprotein levels in the pericardial fluid, as well as clinical data of twenty donors after brain death, were investigated. Outcome variables included primary graft dysfunction, the need for posttransplantation mechanical cardiac support and International Society for Heart and Lung Transplantation grade ≥ 2R rejection. Hormone management and donor risk scores were also investigated. Lower levels of IL-6 were observed in primary graft dysfunction (median: 36.72 [IQR: 19.47–62.90] versus 183.67 [41.21–452.56]; p = 0.029) and in the need for mechanical cardiac support (44.12 [20.12–85.70] versus 247.13 [38.51–510.38]; p = 0.043). Rejection was associated with lower ApoAII (p = 0.021), ApoB100 (p = 0.032) and ApoM levels (p = 0.025). Lower adipsin levels were detected in those patients receiving desmopressin (p = 0.037); moreover, lower leptin levels were found in those patients receiving glucocorticoid therapy (p = 0.045), and higher T3 levels were found in those patients treated with L-thyroxine (p = 0.047) compared to those patients not receiving these hormone replacement therapies. IL-5 levels were significantly associated with UNOS-D score (p = 0.004), Heart Donor Score (HDS) and Adapted HDS (p < 0.001). The monitoring of immunological and metabolic changes in donors after brain death may help in the prediction of potential complications after heart transplantation, thus potentially optimizing donor heart allocation. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) remains still inconclusive. Recent studies identified an increased expression of BAFF (a B cell-activating factor) and its receptor TACI (Transmembrane Activator and cAML Interactor) in nasal polyp samples, while TNFRSF13B/TACI mutations have been found in patients with benign lymphoproliferative disorders and primary antibody deficiencies. Objective: The aim of our study was to evaluate the possible contribution of TNFRSF13B/TACI mutations in CRSwNP pathogenesis. Methods: Forty-four (44) patients with CRSwNP (male/female: 33/11, mean age: 52.5 years, range: 16-83) were analyzed for TNFRSF13B/TACI mutations by PCR-sequencing. Results: No pathogenic TNFRSF13B/TACI mutations were identified in our cohort study of CRSwNP patients. We detected two common missense mutations (p.P251L and p.V220A), along with other common silent mutations and intronic polymorphisms in an identical prevalence to healthy control population. Conclusion: TNFRSF13B/TACI mutations might not play a role in the pathogenesis of CRSwNP. [ABSTRACT FROM AUTHOR]

The prognosis for patients with CD30+ lymphomas (Hodgkin lymphoma and various T-cell lymphomas) relapsing after autologous stem cell transplantation (ASCT) is critical. Brentuximab vedotin (BV), an ADC targeting CD30, is an obvious candidate for inclusion into high-dose chemotherapy (HDCT) regimens to improve outcomes. This single center phase I trial investigated 12 patients with CD30+ lymphoma (AITL: n = 5; relapsed HL: n = 7; median of two previous treatment lines) undergoing ASCT. In a 3 + 3 dose escalation design, 12 patients received a single BV dose at three dose levels (DL) (0.9/1.2/1.8 mg/kg b.w.) prior to standard BeEAM. All patients were treated as planned; no dose limiting toxicities (DLTs) occurred at DL 1 and 2. At DL 3, one DLT (paralytic ileus, fully recovering) occurred. Grade III febrile neutropenia occurred in one patient, and two others had septic complications, all fully recovering. Median hospitalization was 23 days. Hematologic recovery was normal. Six of twelve (50%) patients achieved CR. PFS and OS at 1 year were 67% (n = 8/12) and 83% (n = 10/12), respectively. The addition of brentuximab to standard BeEAM HDCT seems to be safe. We observed a CR rate of 75% post-ASCT in a highly pretreated population. The efficacy of this novel HDCT combination with BV at a 1.8 mg/kg dose level needs to be explored in larger studies. [ABSTRACT FROM AUTHOR]

Background: Mastocytosis is characterized by the accumulation of mast cells (MCs) in the skin or other organs, and can manifest at any age. A significant number of paediatric mastocytosis cases persist after puberty. In particular, monomorphic maculopapular cutaneous mastocytosis (mMPCM) is often persistent and associated with systemic mastocytosis. However, clinical differentiation of MPCM from polymorphic (p)MPCM can be difficult. Aim: To identify histopathological features that can help to distinguish mMPCM from other subtypes of paediatric mastocytosis. Methods: This was a retrospective study using skin biopsies from patients with any subtype of mastocytosis. The localization and density of the MC infiltrate, MC morphology and expression of aberrant markers were evaluated and correlated with clinical characteristics. Results: In total, 33 biopsies were available for evaluation from 26 children [(10 with mMPCM, 5 with mastocytoma, 3 with diffuse cutaneous mastocytosis (DCM), 8 with pMPCM)] and 7 adults with MPCM. The MC number was increased in all patients, but was higher in children than adults (P < 0.01). The presence of mMPCM was associated with sparing of the papillary dermis from MC infiltration, whereas MC density in the papillary dermis was highest in pMPCM and DCM (P < 0.01). The positive predictive value of the presence of a reticular MC infiltrate for mMPCM was 72.7% (95% CI 51.4–87.0), and the negative predictive value was 83.3% (95% CI 42.2–97.2). There were no relevant differences in the expression of CD2, CD25 or CD30 between the different subtypes. Conclusion: Skin histopathology might enhance the phenotypical differentiation of mMPCM from other subtypes in children, thereby increasing the accuracy of one's prognosis. [ABSTRACT FROM AUTHOR]

Our aim was to investigate the role of left atrial longitudinal strain (LALS) in the non-invasive diagnosis of acute cellular rejection (ACR) episodes in heart transplant (HTx) recipients. Methods: We performed successive echocardiographic exams in 18 consecutive adult HTx recipients in their first year after HTx within 3 h of the routine surveillance endomyocardial biopsies (EMB) in a single center. LALS parameters were analyzed with two different software. We investigated LALS association with ACR presence, as well as inter-vendor variability in comparable LALS values. Results: A total of 147 pairs of EMB and echo exams were carried out. Lower values of LALS were significantly associated with any grade of ACR presence. Peak atrial longitudinal strain (PALS) offered the best diagnostic value for any grade of ACR, with a C statistic of 0.77 using one software (95% CI 0.68–0.84, p < 0.0005) and 0.64 with the other (95% CI 0.54–0.73, p = 0.013) (p = 0.02 for comparison between both curves). Reproducibility between comparable LALS parameters was poor (intraclass correlation coefficients were 0.60 for PALS, 95% CI 0.42–0.73, p < 0.0005; and 0.42 for PALS rate, 95% CI −0.13–0.68, p < 0.0005). Conclusions: LALS variables might be a sensitive marker of ACR in HTx recipients, principally discriminating between those studies without rejection and those with any grade of ACR. Inter-vendor variability was significant. [ABSTRACT FROM AUTHOR]

Background: Cutaneous lesions of mastocytosis (CLM) are often subtle and may require biopsy. However, dermatohistopathological criteria for CLM remain undefined. Objectives: To establish criteria for CLM by validating histological and molecular parameters. Methods: In skin samples from Caucasian patients with CLM and controls (atopic dermatitis, chronic urticaria, pruritus, tissue from tumor safety margin excisions), mast cell (MC) numbers, size, shape, distribution, immunostainability with a large panel of markers, pigmentation and presence of KIT D816V mutation were analysed. Results: Forty‐seven CLM patients (32 maculopapular cutaneous mastocytosis (MPCM), 15 mastocytomas) and 36 controls were included. Mastocytomas were easily identified by densely packed cuboidal MCs. In MPCM, skin MC density in CD117 stains was higher in CLM patients than in controls (P < 0.0001) and values correlated closely (r = 0.65, P < 0.0001) to results in tryptase stains. The optimized upper dermis cut‐off number of 62 MC/mm2 had a sensitivity and specificity of 92% in both stainings, corresponding to approximately 12 MC/high power field (HPF). MC size was larger in MPCM than in controls (P = 0.01). Interstitial (= not perivascular or periadnexal) MCs and stronger basal pigmentation of the epidermis were indicative of MPCM (P < 0.0001 each) and clusters of >3 nucleated MC/HPF exclusively found in MCPM. Surface markers CD2, CD25 and CD30 stained T‐lymphocytes, but only negligibly CLM MC. The KIT D816V mutation in formalin fixed paraffin embedded (FFPE) skin was evaluable in 87.5% of MCPM patients and had both 100% sensitivity and specificity. Conclusions: MPCM can be predicted by major and minor criteria combined in a scoring model. Presence of D816V mutation in FFPE skin and MC density > 27/HPF are >95%‐specific major criteria for MPCM. MC densities 12/HPF, interstitial MC, clusters and basal pigmentation are minor criteria. [ABSTRACT FROM AUTHOR]

Background: With the unveiling of new mechanisms and the advent of new drugs, the prognosis of diffuse large B-cell lymphoma (DLBCL) becomes promising, but some patients still progress to the relapse or refractory stage. Necroptosis, as a relatively novel programmed cell death, is involved in the development of multiple tumors. There are no relevant studies on the prognostic significance of necroptosis in DLBCL to date. Methods: We identified the differential necroptosis-related genes (NRGs) by comparing the DLBCL and normal control in GSE12195 and GSE56315 datasets. TCGA DLBC and GSE10846 containing clinical information and microarray expression profiling were merged as the entire cohort. We performed consensus clusters based on NRGs and two clusters were obtained. Kaplan–Meier (K-M) survival analysis, GSVA, GO, KEGG, and ssGSEA were used to analyze the survival, function, and immune microenvironment between two clusters. With LASSO and proportional hazard model construction, we identified differentially expressed genes (DEGs) between NRG clusters, calculated the risk score, established a prognostic model, and validated its value by calibration and ROC curves. The entire cohort was divided into the training and test cohort, and GSE87371 was included as an external validation cohort. K-M, copy number variation, tumor mutation burden, and drug sensitivity were also analyzed. Results: We found significant differences in prognosis between the two NRG clusters. Cluster A with a poor prognosis had a decreased expression of NRGs and a relatively suppressed immune microenvironment. GSVA analysis indicated that cluster A was related to the downregulation of the TGF-β signaling pathway and the activation of the Notch signaling pathway. The risk score had an accurate predictive ability. The nomogram could help predict the survival probability of DLBCL patients in the entire cohort and the external validation cohort. The area under the curve (AUC) of the nomogram, risk score, and International Prognostic Index was 0.723, 0.712, and 0.537, respectively. γ/δ T cells and Macrophage 1 cells decreased while Macrophage 2 cells and Natural Killer resting cells increased in the high-risk group. In addition, the high-risk group was more sensitive to the PI3K inhibitor and the PDK inhibitor. Conclusion: We explored the potential role of necroptosis in DLBCL from multiple perspectives and provided a prognostic nomogram for the survival prediction of DLBCL. Necroptosis was downregulated and was correlated with an immunosuppressed tumor microenvironment and poor prognosis in DLBCL. Our study may deepen the understanding and facilitate the development of new therapy targets for DLBCL. [ABSTRACT FROM AUTHOR]

This paper presents an unusual case of gingival ALCL, which mimicked a benign hyperplastic lesion that occurred in a 57-year-old white man representing the first clinical manifestation of acquired immunodeficiency syndrome (AIDS).The patient was referred to the Dental Clinic of PUCPR complaining of a lobulated nodule on the gingiva of his upper central incisors. The presence of advanced chronic periodontitis and dental plaque raised suspicion for a benignancy. An excisional biopsy was performed, and large pleomorphic cellswith an abundant cytoplasm, sometimes containing prominent nucleoli and "Hallmark" cells, were observed through hematoxylin and eosin staining. Thetumor cells showed strong CD30 expression, EMA, Ki-67, and LCA, and negative stain for p80NPM/ALK, CKAE1/AE3, CD20,CD3,CD56, andCD15.The final diagnosiswas ALCL (ALK-negative). Further laboratory tests revealed positivity for human immunodeficiency virus (HIV).The patient was submitted to chemotherapy, but four months after diagnosis, the patient died due to pneumonia and respiratory failure. Oral anaplastic large-cell lymphoma (ALCL) is a rare disorder. Only 5 cases involving the gingiva have been reported, and to our knowledge, this is the first case reported of the ALCL, which mimicked a hyperplastic benignancy as the first clinical manifestation of AIDS. [ABSTRACT FROM AUTHOR]

Keywords: CD1a; hair follicle; pseudolymphoma EN CD1a hair follicle pseudolymphoma 327 330 4 03/24/22 20220401 NES 220401 INTRODUCTION Pseudolymphomatous folliculitis (PLF) is a variant of cutaneous pseudolymphoma. Dermoscopy showed multiple follicular ostia and surface telangiectasia. gl HISTOPATHOLOGY Incisional skin biopsy revealed diffuse and dense lymphocytic infiltration from superficial to deep dermis. Histopathologically, PLF lesions show dense lymphocytic infiltrate throughout the entire dermis and may extend into the subcutaneous fat. [Extracted from the article]

Canine cutaneous lymphoma is an uncommon lymphoma in dogs. Most canine cutaneous lymphoma cases have a T‐cell origin. Canine cutaneous T‐cell lymphoma (CTCL) is classified into epitheliotropic and nonepitheliotropic cutaneous lymphomas, and each type of lymphoma is subclassified into several histological subtypes. Limited information is available regarding the prognostic significance of clinical variables and histopathological subtypes in dogs with CTCL. This retrospective study aimed to investigate the influence of clinical variables and histopathological subtypes on the prognosis of dogs with CTCL. Forty‐six dogs diagnosed with CTCL by histopathological examination were included. Histopathological specimens were reexamined and classified into CTCL subtypes. The influence of the type of skin lesion, histopathological subtype, haematological examination results and treatment response on the overall survival time (OS) was examined. Thirty‐one dogs were diagnosed with epitheliotropic CTCL (mycosis fungoides in 28 dogs; pagetoid reticulosis in 3 dogs) and 15 dogs were diagnosed with nonepitheliotropic CTCL (anaplastic large T‐cell lymphoma in 6 dogs; peripheral T‐cell lymphoma, not otherwise specified, in 9 dogs). The OS of dogs diagnosed with epitheliotropic CTCL (141 days) was significantly shorter than that of dogs diagnosed with nonepitheliotropic CTCL (374 days). As clinical variables, the presence of neoplastic lymphocytes in peripheral blood, thrombocytopenia and initial chemotherapeutic response was related to prognosis. Our results demonstrated that histopathological subtype and several clinical variables were found to influence the prognosis of dogs with CTCL. [ABSTRACT FROM AUTHOR]

Based on in vitro data that BV enhanced efficacy in three molecular subtypes of CD30 + DLBCL, we supposed that BV was able to kill CD30 + tumor cells of DLBCL. D Left and upper panels indicate T-cell activation score and immune escape score, respectively, stratified by 117 CD30 + DLBCL and 268 CD30-DLBCL. 1 A Prevalence of gene mutations in 55 lymphoma-associated genes, along with the P value for the difference in prevalence between 172 CD30 + DLBCL and 464 CD30-DLBCL. CD30 + DLBCL showed higher score in both T-cell activation and immune escape than CD30-DLBCL ( I P i = 0.004 and I P i < 0.001, Fig. [Extracted from the article]

A 27-year-old man underwent a deceased kidney transplant. Three days after transplantation, COVID-19 was diagnosed for our patient. Immunosuppressants were reduced and a renal biopsy was conducted, which showed acute T cell-mediated rejection. We intened to share a case to help clinicians to understand the risks that kidney transplant recipients face. [ABSTRACT FROM AUTHOR]

3 [18F]FDG PET/CT images in a patient who experienced a herpes zoster-associated erythema on the left thigh with associated ipsilateral inguinal lymphadenopathies that occurred after the second dose of COVID-19 vaccination. Images show hypermetabolic lymph nodes in the right and left axilla related to influenza and COVID-19 vaccinations, respectively In the last months, rare cases of autoimmune diseases that occurred or worsened after the Covid-19 vaccination were also claimed. This article is part of the Topical Collection on Infection and Inflammation The number of symptomatic and severe COVID-19 patients and deaths caused by COVID-19 were reduced by the large-scale vaccination campaign in 2021 [[1]]. [Extracted from the article]

Tumour microenvironment has an important effect on the progression of cutaneous T-cell lymphomas. Using PCR with sequence-specific primers, this study analysed single-nucleotide polymorphisms in the interleukin-17 genes of 150 patients with cutaneous T-cell lymphoma. GG homozygote rs8193036 A/G of interleukin-17A gene occurred less commonly in the cutaneous T-cell lymphoma group; however, patients with this single-nucleotide polymorphism experience significantly intense pruritus. Conversely, the rs2397084 AG heterozygote of interleukin-17F is more common in the lymphoma population. In addition, there were significant differences in the frequencies of interleukin-17 genotypes when comparing early (Ia to IIa) and advanced stages (IIb, III and IV) of this neoplasms. A similar result has been shown in comparison between Sézary syndrome and mycosis fungoides. The current data may serve as a possible explanation for the increased bacterial infection rates in the course of cutaneous T-cell lymphoma, especially caused by Staphylococcus aureus. In summary, specific single-nucleotide polymorphisms occur with different frequencies between cutaneous T-cell lymphoma and healthy patients. Moreover, genetic predisposition of several interleukin-17 single-nucleotide polymorphisms may be a factor causing impaired immune defence in cutaneous lymphomas. [ABSTRACT FROM AUTHOR]

Context: Immunohistochemistry (IHC) to differentiate germ cell tumors. Aims: The aim of the study is to differentiate seminomatous and nonseminomatous germ cell tumors (GCTs) with morphological overlap using a minimal and affordable panel of IHC markers. Settings and Design: This is a retrospective observational study. Subjects and Methods: All testicular GCTs (TGCT) which were diagnosed on biopsies and/or resection specimens (prechemotherapy) between January 2014 and June 2019. The demographic, clinical, and imaging findings were noted from the medical records. Hematoxylin and eosin (H and E)-stained sections were reviewed for morphology. The IHC markers constituted Octamer-binding transcription factor (OCT) 3/4, glypican 3 (GPC3), CD117, CD30, placental-like alkaline phosphatase, Sal-like protein 4, and β-human chorionic gonadotropin (HCG). IHC markers were performed in various combinations depending on the morphology, and a panel constituting OCT 3/4, CD117, GPC3, and CD30 was performed on cases with diagnostic dilemma and morphological overlaps. Statistical Analysis Used: Sensitivity, specificity, positive (PPV), and negative predictive value (NPV) were calculated for suggested panel of IHC OCT 3/4, CD117, GPC3, and CD30. Results: The study included 36 patients with TGCT with a mean age of 27 (15–58) years. Nonseminomatous tumors were the most common (86%). The concise panel was performed in 20/36 (56%) tumors to resolve the diagnosis. The sensitivity, specificity, PPV, and NPV for OCT3/4 were 80%, 55%, 31%, and 92% in seminomas and 65%, 100%, 100%, and 46% in embryonal carcinomas (EC), for CD117 was 89%, 82%, 73%, and 93% in seminomas and 60%, 77%, 60%, and 77% in yolk sac tumors (YST), for GPC3 was 95%, 90%, 95%, and 90% in YST, CD30 96%, 100%, 100%, and 91% in ECs, respectively. Conclusions: Designing a novel concise and affordable IHC panel constituting OCT 3/4, CD117, GPC3, and CD30 has good sensitivity and specificity in differentiating seminomas, YST, and EC, respectively. Additional markers, namely β-HCG, can be used in identifying the choriocarcinoma component. [ABSTRACT FROM AUTHOR]

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL. Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma often with poor prognosis. To identify genes defining ALCL cell state and dependencies, the authors here characterize ALCL-specific super-enhancers and describe the BATF3/IL-2R−module as a therapeutic opportunity for ALCL. [ABSTRACT FROM AUTHOR]

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare and newly recognized subtype of T cell Non-Hodgkin Lymphoma (NHLs) associated with breast implants. The mechanism involved in the development of this kind of lymphoma is still uncertain. BIA-ALCL is generally an indolent disease localized to the breast implant and its capsule and effectively treated with capsulectomy alone without chemotherapy. Clinically, BIA-ALCL may typically present a sudden-onset breast-swelling secondary to periimplant effusion. The minority of BIA-ALCL patients present a more aggressive mass-forming subtype, for which systemic therapy is mandatory. Despite the number of cases has recently increased, BIA-ALCL remains a rare disease described mainly in several case reports and small case series. Breast imaging, including mammography, ultrasound and breast MRI are routinely used in the screening of breast cancer; however, guidelines for the imaging and pathological diagnosis of this disease have only recently been proposed and included in the 2019 National Comprehensive Cancer Network (NCCN) consensus guidelines for BIA-ALCL. The main purpose of this pictorial is to illustrate the MRI signs of BIA-ALCL and correlate them with the corresponding pathology features in order to improve the knowledge of the principals MRI features of this type of lymphoma. [ABSTRACT FROM AUTHOR]

Background: Endocrine mucin‐producing sweat gland carcinoma (EMPSGC) is a rare, low‐grade, cutaneous adnexal carcinoma with neuroendocrine differentiation. It is considered to be a precursor of invasive neuroendocrine type primary cutaneous mucinous carcinoma (PCMC). Objective: To review clinicopathological literature summary of EMPSGC and associated neuroendocrine PCMC from all reported cases and compare its behavior vs non‐neuroendocrine PCMC data reported in the literature. Methods: A review of English literature of all EMPSGC cases with and without associated PCMC was carried out. Results: EMPSGC was associated with invasive neuroendocrine type PCMC in 35.7% of cases. We found the recurrence rate of PCMC associated with EMPSGC of about 12.3%, which is much less than the 30% recurrence rate reported for the non‐neuroendocrine subtype of PCMC. The non‐neuroendocrine subtype of PCMC shows a 4% and 11% rate of distant and lymph node metastasis, respectively, vs EMPSGC‐associated neuroendocrine type of PCMC, which is very indolent and only one recent case of locoregional metastasis out of 190 EMPSGC cases has been reported so far. Limitation: Limitation of our study includes data derivation from case reports and case series in the literature. Conclusion: The prognostic benefits for this cohort of patients may be considered in their overall management. [ABSTRACT FROM AUTHOR]

Ultraviolet radiation (UVR) damages the dermis and fibroblasts; and increases melanoma incidence. Fibroblasts and their matrix contribute to cancer, so we studied how UVR modifies dermal fibroblast function, the extracellular matrix (ECM) and melanoma invasion. We confirmed UVR-damaged fibroblasts persistently upregulate collagen-cleaving matrix metalloprotein-1 (MMP1) expression, reducing local collagen (COL1A1), and COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, inhibiting ECM degradation and MMP1 expression restored melanoma invasion. Primary cutaneous melanomas of aged humans show more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen, and collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. Thus, primary melanomas arising over collagen-degraded skin are less invasive, and reduced invasion improves survival. However, melanoma-associated fibroblasts can restore invasion by increasing collagen synthesis. Finally, high COL1A1 gene expression is a biomarker of poor outcome across a range of primary cancers. Ultraviolet radiation (UVR) increases melanoma incidence. Here, the authors report that UVR-damaged dermal fibroblasts upregulate MMP1 to degrade collagen which inhibits melanoma invasion and that aged primary melanomas in skin with degraded collagen have a better prognosis, while new collagen synthesis restores invasion and leads to death. [ABSTRACT FROM AUTHOR]

The treatment of patients with advanced melanoma has undergone a dramatic change over the past decade. Apart from refining the radiotherapy techniques, the repertoire of systemic treatments expanded from largely futile cytotoxic chemotherapy to substantially more effective MAP kinase and immune checkpoint inhibitors (Immunotargets Ther, 7, 2018)1. We report a case which exemplifies the improved efficacy as well as increased complexity of therapeutic decision‐making. A 71‐year‐old man presented with neglected fungating and bleeding malignant melanoma, which resulted in severe anaemia with consequent cardiac dysfunction. There was limited distant spread. Patient was treated with combined radiotherapy and immunotherapy: 55 Gray in 20 fractions over four weeks using 3D‐conformal technique followed by an anti‐PD1 antibody (pembrolizumab, Keytruda® Merck/MSD, Kenilworth N.J.; 2 mg/kg 3‐weekly). A surgical approach to provide haemostasis and cosmesis was considered, but would be associated with significant morbidity, prolonged recovery and functional impairment and would not have altered patient survival. The sequential radioimmunotherapy resulted in a complete response. Radiotherapy was completed with only mild skin toxicity. Immunotherapy was complicated by diarrhoea, which necessitated withdrawal of the medication but was controlled with steroids. The non‐operative treatment resulted in excellent oncological, functional and cosmetic outcome, with acceptable toxicity. Due to increasing complexity of melanoma therapy, a multidisciplinary approach is of paramount importance. [ABSTRACT FROM AUTHOR]

Six years after diagnosis, the patient underwent bone marrow (BM) trephine biopsy to investigate worsening cytopaenias. However, a variety of lymphomas have been reported, including T-cell lymphoma and T-cell histiocyte-rich large B-cell lymphoma.2 In essence, a lymphoma rich in T cells is quite feasible in an ALPS patient. In our case, there was down-regulation of CD7, which is a feature that may be observed in some normal and reactive T cells, and has been reported in the double-negative T cells in ALPS.7 The distribution of a lymphoid infiltrate within BM is a recognised diagnostic clue to the underlying aetiology. [Extracted from the article]

Background: Familial clustering of lymphoid and/or hematological malignancies (FHM) provides an opportunity to study the responsible genes. The data is limited in patients with lymphoid and hematological malignancies. Methods: The lymphoma database was used to identify patients seen in our institution from 1998 to 2019 with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). We studied FHM by collecting detailed history of any malignancy in the family (FM). Results: Two hundred NLPHL patients were identified. Contacting was not possible in 30 patients due to no response to the phone calls (22) and death [1]. 170/200 patients were interviewed; represented 167 families (3 patients with a family member with NLPHL). These 170 patients provided information about 8225 family members. These 167 families had a total of 329 family members with 334 malignancies (including 167 NLPHL patients and 5 members with 2 malignancies each). Of these 167 patients, 77 (46.1%) had no FM while 90 (53.9%) patients had a positive FM; 162 family members with 167 malignancies. Among these 167 families, 31 families (18.6%) had members with FHM +/− solid cancers. These 31 families had 35 family members (25 males:10 females) with 16 lymphomas: diffuse large B cell lymphoma [2], follicular center cell lymphoma [3], chronic lymphocytic leukemia/small lymphocytic lymphoma [3], non-Hodgkin lymphoma [2], classical HL [2], and NLPHL [4]. Total of 8 leukemia: acute lymphoblastic leukemia [4], acute myeloid leukemia [3], and leukemia - no subtyping [5]. These 35 FHM members are 1st [6], 2nd (16), and 3rd [7] degree relatives of 31 NLPHL patients. There are 4 families with NLPHL in family members; all these 8 NLPHL patients are male and are alive. The median total number of 1st + 2nd +3rd degree members are 81. The decrease in the age of diagnosis from 1st generation to the 2nd generation (anticipation) was noted in 13/17 patients; 2nd generation median age at diagnosis was 29.7 years vs 1st generation age 53 years (developed malignancy 23.3 years earlier). Conclusion: FHM is frequent in NLPHL. This study provided us many important insights for planning future studies in terms of interviewing technique, time, and resource allocation and genetic testing. [ABSTRACT FROM AUTHOR]

Lymphomatoid papulosis mimicking relapsed angioimmunoblastic T-cell lymphoma on histology: the importance of clinicopathological correlation Keywords: angioimmunoblastic T-cell lymphoma; lymphomatoid papulosis; CD30 positive EN angioimmunoblastic T-cell lymphoma lymphomatoid papulosis CD30 positive 470 473 4 02/01/21 20210201 NES 210201 Case summary Angioimmunoblastic T-cell lymphoma (AITL) is one of the commonest subtypes of peripheral T-cell lymphoma (PTCL) worldwide and the most common non-cutaneous PTCL in western Europe. The diagnosis was reviewed and revised to primary cutaneous CD30-positive LPD, LyP, type C. Primary cutaneous CD30-positive LPDs include LyP, primary cutaneous anaplastic large-cell lymphoma (PC-ALCL), and borderline lesions. [Extracted from the article]

Background: Anaplastic large cell lymphoma (ALCL) with uniform CD56 expression is a rare condition, that has been described in limited literature, and its clinicopathological features have not yet been well illustrated. The aim of our study was to fully investigate the clinical, histological, immunohistochemical and molecular features of CD56+ ALCL. Methods: The clinical and histological characteristics of CD56+ ALCL cases were retrospectively evaluated. The immunohistochemical phenotype, status of Epstein-Barr virus (EBV) and T-cell receptor (TCR) gene rearrangement were examined. Overall survival was also analyzed. Results: Eighteen (5.8%) cases with diffuse CD56 expression were identified out of 313 archived ALCL cases with CD56 test. CD56 expression was significantly higher in ALK+ systemic ALCLs (sALCLs) (13/64, 20.3%) than in ALK- sALCLs (3/101, 3.0%) (p < 0.001) as well as primary cutaneous ALCLs (2/148, 1.4%) (p < 0.001). Regarding the CD56+ ALK+ sALCLs, the median age was 20 years (range, 8–60 years) with a male-to-female ratio of 2.3:1, and these cases more frequently affected extranodal sites (11/38, 28.9%) rather than lymph nodes (2/26, 7.7%) (p = 0.038). Eleven (84.6%) cases presented with stage I-II diseases, which was significantly more than their CD56- ALK+ counterparts (45.5%) (p = 0.015). Histologically, 2 ALK+ cases were of small cell variant and all the others displayed characteristic morphology of classic ALCL. Regarding the immunophenotype, both CD30 and CD56 were diffusely positive in all cases. CD3, CD43, anaplastic lymphoma kinase-1 (ALK1), TIA-1, EMA expression was observed in 30.8% (4/13), 90.9% (10/11), 100% (13/13), 100% (9/9), and 80.0% (8/10) cases, respectively. EBV infection was consistently absent. Monoclonal TCR gene rearrangement was found in 100% (5/5) of investigated ALK+ cases. Chemotherapy with a CHOP regimen was most frequently employed. The 3-year overall survival (OS) rate for CD56+ ALK+ patients was 92.0%, compared with 73.0% for their CD56- counterparts, but there was no significant difference in OS between the two groups (p = 0.264). Conclusions: Uniform CD56 expression is an unexpected condition in ALCL. Of ALK+ ALCLs, CD56 expression correlated with a high frequency of early stage and an extranodal predominance. It is of great importance to raise awareness of this condition and familiarity with its characteristic features to avoid diagnostic and therapeutic pitfalls. Further investigations are warranted for a better understanding of this unusual phenotype and the significance of CD56 expression in ALCL. [ABSTRACT FROM AUTHOR]

Comparative genomic analyses have enormous potential for identifying key genes central to human health phenotypes, including those that promote cancers. In particular, the successful development of novel therapeutics using model species requires phylogenetic analyses to determine molecular homology. Accordingly, we investigate the evolutionary histories of anaplastic lymphoma kinase (ALK)—which can underlie tumorigenesis in neuroblastoma, nonsmall cell lung cancer, and anaplastic large-cell lymphoma—its close relative leukocyte tyrosine kinase (LTK) and their candidate ligands. Homology of ligands identified in model organisms to those functioning in humans remains unclear. Therefore, we searched for homologs of the human genes across metazoan genomes, finding that the candidate ligands Jeb and Hen-1 were restricted to nonvertebrate species. In contrast, the ligand augmentor (AUG) was only identified in vertebrates. We found two ALK -like and four AUG -like protein-coding genes in lamprey. Of these six genes, only one ALK -like and two AUG -like genes exhibited early embryonic expression that parallels model mammal systems. Two copies of AUG are present in nearly all jawed vertebrates. Our phylogenetic analysis strongly supports the presence of previously unrecognized functional convergences of ALK and LTK between actinopterygians and sarcopterygians—despite contemporaneous, highly conserved synteny of ALK and LTK. These findings provide critical guidance regarding the propriety of fish and mammal models with regard to model organism-based investigation of these medically important genes. In sum, our results provide the phylogenetic context necessary for effective investigations of the functional roles and biology of these critically important receptors. [ABSTRACT FROM AUTHOR]

Aftiphilin (AFTPH) plays an important role in regulating intracellular trafficking, exocytosis, and the pro‐inflammatory response. However, the potential prognostic role of AFTPH in cancers remains unclear. Here, we examined the expression profiles and prognostic significance of AFTPH in breast invasive carcinoma (BRCA), diffuse large B‐cell lymphoma (DLBC), lung squamous cell carcinoma (LUSC), and pancreatic adenocarcinoma (PADD) using the GEPIA and UALCAN databases. AFTPH expression was observed to be higher in cancer tissues than in normal tissues, but expression did not differ significantly between tumor stages for the four cancer types. AFTPH expression in cancer cell lines was investigated using the CCLE database; AFTPH was found to be highly expressed in four cancer cell lines. The relationship between AFTPH expression and patient prognosis was analyzed using GEPIA, LinkedOmics, and Kaplan–Meier plotter databases. Low expression of AFTPH was associated with improved prognosis for BRCA, DLBC, LUSC, and PAAD. Genetic alterations of AFTPH in cancers were explored using the cBioPortal website, revealing that gene copy number gains and amplification are common in BRCA, DLBC, LUSC, and PAAD. Related genes and markers associated with AFTPH were discovered using the LinkedOmics database. Furthermore, transfection of cells with AFTPH siRNA demonstrated that AFTPH exerts positive effects on cell proliferation in BRCA, LUSC, and PAAD cells. In conclusion, AFTPH may be a potential therapeutic target and prognostic biomarker for BRCA, DLBC, LUSC, and/or PAAD. [ABSTRACT FROM AUTHOR]

Over the last two decades, the development of chemical biology and the need for more defined protein conjugates have fostered active research on new bioconjugation techniques. In particular, a wide range of biorthogonal labelling strategies have been reported to functionalise the phenol side chain of tyrosines (Tyr). Tyr occur at medium frequency and are partially buried at the protein surface, offering interesting opportunities for site‐selective labelling of the most reactive residues. Tyr‐targeting has proved effective for designing a wide range of important biomolecules including antibody–drug conjugates, fluorescent or radioactive protein probes, glycovaccines, protein aggregates, and PEG conjugates. Innovative methods have also been reported for site‐specific labelling with ligand‐directed anchors and for the specific affinity capture of proteins. This review will present and discuss these promising alternatives to the conventional labelling of the nucleophilic lysine and cysteine residues. [ABSTRACT FROM AUTHOR]

DAB389IL‐2 (Denileukin diftitox) is considered an immunotoxin, and it is the first immunotoxin approved by Food and Drug Administration. It is used for the treatment of a cutaneous form of T‐cell lymphoma. This fusion protein has two disulfide bonds in its structure that play an essential role in toxicity and functionality of the immunotoxin. Escherichia coli (E. coli) strain BL21 (DE3) is not capable of making disulfide bonds in its reductive cytoplasm, but the E. coli strain Rosetta‐gami (DE3) is a proper strain for the correct expression of the protein due to mutations in glutaredoxin reductase and thioredoxin reductase. In this study, a pET21a vector with the His6‐tag fused at the N‐terminus of DAB389IL‐2 was used to express the soluble immunotoxin in E. coli Rosetta‐gami (DE3). After the purification of the soluble protein by two‐step column chromatographies, the structure of DAB389IL‐2 was analyzed using the Native‐PAGE and circular dichroism methods. In the following, the nuclease activity of soluble DAB389IL‐2 and its cytotoxicity activity were determined. It is concluded that the soluble recombinant protein expressed in the E. coli Rosetta‐gami (DE3) has an intact structure and also functional; hence, this form of immunotoxin could be competitive with its commercial counterparts. [ABSTRACT FROM AUTHOR]

Expanding the number of nucleotides in DNA increases the information density of functional DNA molecules, creating nanoassemblies that cannot be invaded by natural DNA/RNA in complex biological systems. Here, we show how six‐letter GACTZP DNA contributes this property in two parts of a nanoassembly: 1) in an aptamer evolved from a six‐letter DNA library to selectively bind liver cancer cells; and 2) in a six‐letter self‐assembling GACTZP nanotrain that carries the drug doxorubicin. The aptamer‐nanotrain assembly, charged with doxorubicin, selectively kills liver cancer cells in culture, as the selectivity of the aptamer binding directs doxorubicin into the aptamer‐targeted cells. The assembly does not kill untransformed cells that the aptamer does not bind. This architecture, built with an expanded genetic alphabet, is reminiscent of antibodies conjugated to drugs, which presumably act by this mechanism as well, but with the antibody replaced by an aptamer. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor receptor 2 (TNFR2) is expressed on some tumor cells, such as myeloma, Hodgkin lymphoma, colon cancer and ovarian cancer, as well as immunosuppressive cells. There is increasingly evidence that TNFR2 expression in cancer microenvironment has significant implications in cancer progression, metastasis and immune evasion. Although nanomedicine has been extensively studied as a carrier of cancer immunotherapeutic agents, no study to date has investigated TNFR2-targeting nanomedicine in cancer treatment. From an epigenetic perspective, previous studies indicate that DNA demethylation might be responsible for high expressions of TNFR2 in cancer models. This perspective review discusses a novel therapeutic strategy based on nanomedicine that has the capacity to target TNFR2 along with inhibition of DNA demethylation. This approach may maximize the anti-cancer potential of nanomedicine-based immunotherapy and, consequently, markedly improve the outcomes of the management of patients with malignancy. [ABSTRACT FROM AUTHOR]

Background: Cutaneous microcystic lymphatic malformations (CMLMs) are rare conditions in children and adults. They present as clusters of vesicles full of lymph and blood to various extents, inducing maceration, esthetic impairment, pain, and impaired quality of life. The treatment is challenging. Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) involved in angio-lymphangiogenesis. Topical sirolimus has recently been reported as effective in a few reports of patients with CMLMs. The objective is to compare the efficacy and safety of a 12-week application of 0.1% topical sirolimus versus topical vehicle in CMLMs in children and adults.Methods: This French blinded multicenter within-person randomized controlled phase 2 trial aims to include 55 patients aged ≥ 6 years who have a primary CMLM. The CMLM will be divided into two equal areas that will be randomly allocated to 0.1% topical sirolimus or topical vehicle applied for 12 weeks. At the end of the 12-week period, the patient/parent will treat the whole area of CMLM with 0.1% topical sirolimus on remaining lesions, for eight more weeks. Patients will be seen at week 20 (treatment will be stopped) and at month 12 to evaluate long-term efficacy. The primary outcome will be improvement of the CMLM in the area treated with topical sirolimus compared to the area treated with topical vehicle by the investigator physician (blinded to the treatment) with the Physician Global Assessment score at week 12. Secondary outcomes will include: assessment of efficacy by independent experts on the basis of standardized photographs; impact on quality of life; efficacy for oozing, bleeding, erythema, and thickness evaluated by the investigators; and global efficacy as well as efficacy for functional and aesthetic impairment evaluated by the patient. Systemic passage of sirolimus will be measured at weeks 6, 12, and 20, and at week 16 for CMLMs ≥ 900 cm2.Discussion: For patients with CMLMs, topical sirolimus could be a non-invasive and well-tolerated therapeutic option. If the trial demonstrates efficacy and safety of this treatment, this result will lead to a real change in the management of this condition, and 0.1% sirolimus cream would become the first-line treatment.Trial Registration: ClinicalTrials.gov, NCT03972592. Registered on 3 June 2019. EU Clinical Trials Register EudraCT, 2018-001359-11. [ABSTRACT FROM AUTHOR]