CRLF2-rearranged B-cell ALL with extramedullary lineage switch to AML following CD19-targeted therapy.

Lineage switch (LS) refers to the immunophenotypic transformation of one leukemia lineage to another (ie, lymphoid to myeloid) with retention of baseline genetics. This phenomenon was originally observed in infants with B-lymphoblastic leukemia (B-ALL) with KMT2A rearrangements following chemotherapy, but is now increasingly being observed as a form of immune escape following targeted therapies among children and adults with B-ALL with and without KMT2A rearrangements. In this report, we present two cases of adolescents with B-ALL harboring CRLF2 rearrangements (Philadelphia-like phenotype) who developed LS to acute myeloid leukemia following CD19 targeted therapy. To our knowledge, these are the first cases of LS to be reported in patients with CRLF2 rearranged acute lymphoblastic leukemia. In addition to raising awareness that this genetic mutation may associate with lineage plasticity, our cases illustrate the importance of multi-modal disease surveillance in the diagnosis of LS.

Birth of a Social Mediatrician: Adopting Slack, Twitter, and Instagram for Residents.

Introduction Physicians have increasingly used social media platforms to review new research, expand networks, and communicate. However, few studies have evaluated how the integration of social media into residency programs affects training. This is relevant during the COVID-19 pandemic, with a shift towards virtual formats for medical education, community building, and recruitment. Objective The objective of this study was to evaluate how the integration of social media platforms, including Slack, Twitter, and Instagram, influences education, social connectedness, and recruitment within a residency program. Methods In 2020, pediatric residents at one institution were encouraged to create personal Twitter and Instagram accounts if they did not already have one and follow the residency program's Twitter and Instagram accounts. Residents were also encouraged to enroll in a private Slack network within the residency program. We surveyed residents in May and June 2020 (pre-intervention) and March 2021 (post-intervention). Analytics from the residency program's social media accounts and Slack were recorded. Data were analyzed using a mixed-methods approach. Results Response rates from residents regarding the impact of social media interventions on education, connectedness, and recruitment were 98% (100/102) pre-intervention and 74.5% (76/102) post-intervention. During the study period from May 2020 to March 2021, chief resident posts on the residency program's Twitter and Instagram accounts garnered 447,467 and 151,341 impressions, respectively. Posts with the highest average impressions were those related to advocacy. After the intervention, residents reported increased connectedness to residents in other classes and increased usage of their personal Twitter and Slack accounts for learning and education. Residents rated the program's Instagram account as a useful recruitment tool. Feasibility of posting was assessed by the number of posts by chief residents during the study period (Twitter n=806, Instagram n=67). There were no costs. Conclusion Our data shows that social media in residency is feasible, cost-effective, and valuable for education, connectedness, and recruitment. We outlined specific ways social media was feasible and useful in these domains.

Primary Ewing Sarcoma of the Testicle in an Adolescent Patient.

Extraosseous Ewing sarcoma with genitourinary tract involvement is rare. We present a case of primary Ewing sarcoma of the testis with review of the literature. While primary Ewing sarcoma of the testis is unusual, it is important to appropriately diagnose. This case emphasizes the benefits of prompt and appropriate evaluation, pathologic work-up, and treatment of testicular tumors.

The Krüppel-like factors in female reproductive system pathologies.

Female reproductive tract pathologies arise largely from dysregulation of estrogen and progesterone receptor signaling, leading to aberrant cell proliferation, survival, and differentiation. The signaling pathways orchestrated by these nuclear receptors are complex, require the participation of many nuclear proteins serving as key binding partners or targets, and involve a range of paracrine and autocrine regulatory circuits. The members of the Krüppel-like factor (KLF) family of transcription factors are ubiquitously expressed in reproductive tissues and have been increasingly implicated as critical co-regulators and integrators of steroid hormone actions. Herein, we explore the involvement of KLF family members in uterine pathology, describe their currently known molecular mechanisms, and discuss their potential as targets for therapeutic intervention.

The Effector Domain of MARCKS Is a Nuclear Localization Signal that Regulates Cellular PIP2 Levels and Nuclear PIP2 Localization.

Translocation to the nucleus of diacylglycerol kinase (DGK)- ζ is dependent on a sequence homologous to the effector domain of Myristoylated Alanine Rich C-Kinase Substrate (MARCKS). These data would suggest that MARCKS could also localize to the nucleus. A single report demonstrated immunofluorescence staining of MARCKS in the nucleus; however, further experimental evidence confirming the specific domain responsible for this localization has not been reported. Here, we report that MARCKS is present in the nucleus in GBM cell lines. We then over-expressed wild-type MARCKS (WT) and MARCKS with the effector domain deleted (ΔED), both tagged with V5-epitope in a GBM cell line with low endogenous MARCKS expression (U87). We found that MARCKS-WT localized to the nucleus, while the MARCKS construct without the effector domain remained in the cytoplasm. We also found that over-expression of MARCKS-WT resulted in a significant increase in total cellular phosphatidyl-inositol (4,5) bisphosphate (PIP2) levels, consistent with prior evidence that MARCKS can regulate PIP2 levels. We also found increased staining for PIP2 in the nucleus with MARCKS-WT over-expression compared to MARCKS ΔED by immunofluorescence. Interestingly, we observed MARCKS and PIP2 co-localization in the nucleus. Lastly, we found changes in gene expression when MARCKS was not present in the nucleus (MARCKS ΔED). These data indicate that the MARCKS effector domain can function as a nuclear localization signal and that this sequence is critical for the ability of MARCKS to regulate PIP2 levels, nuclear localization, and gene expression. These data suggests a novel role for MARCKS in regulating nuclear functions such as gene expression.

Update on celiac disease - etiology, differential diagnosis, drug targets, and management advances.

Celiac disease (CD) is an immune-mediated enteropathy triggered by exposure to wheat gluten and similar proteins found in rye and barley that affects genetically susceptible persons. This immune-mediated enteropathy is characterized by villous atrophy, intraepithelial lymphocytosis, and crypt hyperplasia. Once thought a disease that largely presented with malnourished children, the wide spectrum of disease activity is now better recognized and this has resulted in a shift in the presenting symptoms of most patients with CD. New advances in testing, both serologic and endoscopic, have dramatically increased the detection and diagnosis of CD. While the gluten-free diet is still the only treatment for CD, recent investigations have explored alternative approaches, including the use of altered nonimmunogenic wheat variants, enzymatic degradation of gluten, tissue transglutaminase inhibitors, induction of tolerance, and peptides to restore integrity to intestinal tight junctions.