Keloid-Specific Gene Expression Profiling for Accurate Diagnostic and Therapeutic Applications

Scars are a heterogeneous disease including normotrophic scars, hypertrophic scars, and keloids. Of these lesions, keloids are a distinct subtype from any other type of scar. Clinically, it causes pain, itching, or tenderness, causing life discomfort and characteristically irreversible. Despite various treatment modalities, restoring keloids to normal tissues is difficult, and frequent recurrences have been reported. Therefore, it is essential to identify keloid-specific genes for accurate diagnosis and treatment of keloids. In an effort to find out keloid-specific genes, several studies compared keloids with scar-free normal skin, which leading general scar-related genes to be chosen rather than keloid-specific genes. To select for highly accurate keloid-specific genes and pathways, we compared the transcriptome profile of keloids with those of normotrophic scars and hypertrophic scars, which acquired from formalin-fixed paraffin-embedded human skin samples using high-throughput RNA-sequencing techniques. Differential expression analyses and over-representation analyses revealed that genes related to nervous system process were upregulated in keloids, whereas genes related with immune responses were downregulated in keloids. Additionally, the extracellular matrix related processes were highlighted in both hypertrophic scars and keloids. Finally, we highlight potential keloid-specific biomarkers and expression changes that can be employed for future therapeutics of keloids.

Origin and evolution of HIV-1 subtype A6

Background HIV outbreaks in the Former Soviet Union (FSU) countries were characterized by repeated transmission of the HIV variant AFSU, which is now classified as a distinct subtype A sub-subtype called A6. The current study used phylogenetic/phylodynamic and signature mutation analyses to determine likely evolutionary relationship between subtype A6 and other subtype A sub-subtypes. Methods For this study, an initial Maximum Likelihood phylogenetic analysis was performed using a total of 553 full-length, publicly available, reverse transcriptase sequences, from A1, A2, A3, A4, A5, and A6 sub-subtypes of subtype A. For phylogenetic clustering and signature mutation analysis, a total of 5961 and 3959 pol and env sequences, respectively, were used. Results Phylogenetic and signature mutation analysis showed that HIV-1 sub-subtype A6 likely originated from sub-subtype A1 of African origin. A6 and A1 pol and env genes shared several signature mutations that indicate genetic similarity between the two subtypes. For A6, tMRCA dated to 1975, 15 years later than that of A1. Conclusion The current study provides insights into the evolution and diversification of A6 in the backdrop of FSU countries and indicates that A6 in FSU countries evolved from A1 of African origin and is getting bridged outside the FSU region.

Inside the biology of early T-cell precursor acute lymphoblastic leukemia: the perfect trick

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a rare, distinct subtype of T-ALL characterized by genomic instability, a dismal prognosis and refractoriness to standard chemotherapy. Since its first description in 2009, the expanding knowledge of its intricate biology has led to the definition of a stem cell leukemia with a combined lymphoid-myeloid potential: the perfect trick. Several studies in the last decade aimed to better characterize this new disease, but it was recognized as a distinct entity only in 2016. We review current insights into the biology of ETP-ALL and discuss the pathogenesis, genomic features and their impact on the clinical course in the precision medicine era today.

Hairy Cell Leukemia: Morphological and Immunophenotypic Characteristics of Seven Cases and Cyclin D1 Expression

Aberrant immunophenotypic expression in hairy cell leukemia (HCL), both at medullary and extramedullary sites, is not uncommonly reported in literature. Cyclin D1 positivity in HCL may mimic mantle cell lymphoma (MCL) morphologically, especially in the presence of aberrant CD5 immunopositivity, requiring BRAFV600E mutation and/or CCND1 gene testing for confirmation. Here, we describe seven cases of HCL with clinicomorphological and immunophenotypic characteristics with an emphasis on cyclin D1 expression using immunohistochemistry (IHC) with a brief comprehensive literature review. We suggest that cyclin D1 positive HCL may be a distinct subtype which requires further immunophenotypic and molecular characterization for accurate diagnosis and planning of definitive therapy.

Co-occurrence of Relapsing Polychondoritis and Autoimmune Thyroid Diseases

Background: Relapsing polychondritis (RP) is a rare inflammatory disease characterized by recurrent inflammation and destruction of cartilageous tissues. RP has characteristics of autoimmune disease and some reports have noted co-occurrence with autoimmune thyroid disease (AITD), consisting of Graves’ disease (GD) and Hashimoto thyroiditis (HT). However there have been no detailed studies on the co-occurrence of RP and AITD. In this study, we aimed to determine whether patients with RP tend to be complicated with AITD. We also analyzed clinical and genetic profiles of patients in whom these diseases co-occur.Methods: We recruited 117 patients with RP and reviewed their medical records. Furthermore, we genotyped Human Leucocyte Antigen (HLA)-A, B Cw, DRB1, DQB1 and DPB1 alleles for 93 of the 117 patients. The prevalence of AITD among the patients with RP was compared with that among the general Japanese population. We also analyzed the clinical and genetic features of the patients with both RP and AITD.Results: The prevalence of GD among the patients with RP was 4.3% (5 among 117 patients), significantly higher than that among Japanese (0.11%) (p=2.44×10-7, binomial test). RP patients with GD tended to have nasal involvement (p=0.023) (odds ratio (OR) 2.58) and HLA-DPB1*02:02 (p=0.035, OR 10.41). We did not find significant enrichment of HT in patients with RP.Conclusions: Patients with RP appear to be at elevated risk of GD. Nasal involvement and HLA-DPB1*02:02 may characterize the subset of RP patients with GD, which may guide attempts to characterize distinct subtype of RP for precision medicine.

Identifying the Phenotypic and Temporal Heterogeneity of Knee Osteoarthritis: Data From the Osteoarthritis Initiative

Objective: Previous studies discussing phenotypic and temporal heterogeneity of knee osteoarthritis (KOA) separately have fatal limitations that either clustering patients with similar severity or assuming all knees have a single common progression pattern, which are unreliable. This study tried to uncover more reliable information on phenotypic and temporal heterogeneity of KOA.Design: Data were from Osteoarthritis Initiative database. Six hundred and seventy-eight unilateral knees that have greater Kellgren and Lawrence (KL) grade than the contralateral knees at baseline and in all follow-up 48 months were included. Measurements of biomarkers at baseline were chosen. Subtype and Stage Inference model (SuStaIn) was applied as a subtype-progression model to identify subtypes, subtype biomarker progress sequences and stages of KOA.Results: This study identified three subtypes which account for 15, 61, and 24% of knees, respectively. Each subtype has distinct subtype biomarker progress sequence. For knees with KL grade 0/1, 2, 3, and 4, they have different distributions on stage and 26, 53, 89, and 95% of them are strongly assigned to subtypes. When assessing whether a knee has KL (grade ≥ 2), subtypes and stages from subtypes-progression model (SuStaIn) are significantly better fitting than those from subtypes-only (mixture of Gaussians) (likelihood ratio = 105.59, p = 2.2 × 10−16) or stages-only (SuStaIn where setting c = 1) (likelihood ratio = 58.04, p = 2.57 × 10−14) model. Stages in subtypes-progression model has greater β than stages-only model. Subtypes from subtypes-progression model have no statistical significance.Conclusions: For subtypes-progression model, stages contain more complete temporal information and subtypes are closer to real OA subtypes.

Solitary fibrous tumor: molecular hallmarks and treatment for a rare sarcoma

Solitary fibrous tumor (SFT) is a rare soft tissue sarcoma subtype which mainly affects adults in the fifth and sixth decades of life. Originally part of a spectrum of tumors called hemangiopericytomas, classification has been refined such that SFTs now represent a distinct subtype. The identification of NAB2-STAT6 fusion in virtually all SFTs has further aided to define this rare subgroup. SFTs have a spectrum of behavior from benign to malignant, with evidence suggesting risk of metastases related to age at diagnosis, extent of necrosis, mitotic rate and tumor size. The standard treatment for localized disease is surgical excision with or without radiotherapy. Retrospective and prospective evidence suggests antiangiogenic treatment is effective for unresectable disease. Further translational work is required to understand the biology driving the differential behavior and identify more effective treatments for patients with metastatic disease.

Leukemia With TCF3-ZNF384 Rearrangement as a Distinct Subtype of Disease With Distinct Treatments: Perspectives From A Case Report and Literature Review

BackgroundZNF384 rearrangements are found in 5-10% of B-cell acute lymphoblastic leukemia (B-ALL) and 48% of B cell/myeloid mixed phenotype acute leukemia (B/M MPAL). ZNF384-rearranged B-ALL is prone to lineage conversion after chemotherapy. TCF3 is the second most common rearrangement partner of ZNF384 in B-ALL (27.5%) and the most common partner in B/M MPAL (53.3%). TCF3-ZNF384 fusion is related to a poor steroid response and a high frequency of relapse. It is mostly reported in children and adolescents but rarely seen in adults.Patients and MethodsHere, we report a rare case of adult common B-ALL with TCF3-ZNF384 fusion in which the patient relapsed after one cycle of consolidation chemotherapy. Relapsed leukemia cells from the bone marrow were cultured for 72 hours ex vivo, and a panel of 156 kinds of cytotoxic drugs, targeted therapy drugs, combination chemotherapy drugs, etc., was used for sensitivity screening. The literature on TCF3-ZNF384 fusion was reviewed, and reported cases with TCF3-ZNF384 fusion were summarized. Clinical characteristics were compared between B-ALL and MPAL with TCF3-ZNF384 fusion.ResultsThe relapsed lymphoblasts showed moderate sensitivity to both acute myelocytic leukemia (AML) - and acute lymphoblastic leukemia (ALL)-directed combination chemotherapy schemes, as well as to multiple targeted therapeutic drugs. The hyper-CVAD (B) scheme showed synergistic effects with multiple targeted compounds and had the highest sensitivity. The patient chose the hyper-CVAD (B) scheme combined with sorafenib and achieved complete remission (CR), then consolidated with myeloid-directed homoharringtonine+cytarabine+daunorubicin (HAD) scheme and gained molecular CR. By reviewing the literature, we found that both the genomic landscapes and gene expression profiles of ZNF384-rearranged B-ALL and MPAL are similar and that both diseases have lineage plasticity. The gene expression profile in TCF3-ZNF384-positive patients shows enrichment of hematopoietic stem cell features. No significant differences in clinical characteristics were found between TCF3-ZNF384-positive ALL and MPAL.ConclusionTCF3-ZNF384-positive leukemia may be a distinct subtype of leukemia regardless of immunophenotype. Considering the frequent lineage switches and sensitivity to both ALL- and AML-directed schemes, a uniform strategy directed at both lymphoid and myeloid lineages or at hematopoietic stem cells may be better for TCF3-ZNF384-positive leukemia. Small molecule targeted therapies may be promising treatment options and deserve further investigation.