A Newly Diagnosed Patient With Human Immunodeficiency Virus (HIV)-Associated Epstein-Barr Virus (EBV)-Positive Diffuse Large B-cell Lymphoma and Esophageal Candidiasis: A Case Report.

The link between the Epstein-Barr virus (EBV) and the development of certain types of lymphomas in patients with human immunodeficiency virus (HIV) is of noteworthy clinical importance. Their immunocompromised state increases the risk of cancers such as lymphomas. Gastrointestinal (GI) lymphomas, though, can occur due to the immunosuppression caused by HIV, with diffuse large B-cell lymphoma (DLBCL) being common in this group. This case report describes a case of a patient with a newly diagnosed HIV who initially presented with symptoms associated with EBV-associated DLBCL and with esophageal candidiasis. This case report highlights the need for increased awareness of HIV-related complications and the importance of close follow-up. In addition, despite advancements in highly active antiretroviral therapy (HAART), acquired immunodeficiency syndrome (AIDS)-related lymphomas continue to be a concern requiring treatment approaches.

Primary Splenic Angiosarcoma Presenting as Idiopathic Thrombocytopenic Purpura: A Case Report and Review of the Literature.

Angiosarcoma of the spleen is a rare malignancy that arises from vascular endothelial origin. This neoplasm is highly malignant and diagnosis is often delayed due to the vague presentation of clinical symptoms. A case report and concise review of the current diagnostic criteria and surgical treatment are provided to aid in the detection and treatment of this malignancy. We present a case of a 56-year-old female who presented with massive splenomegaly secondary to angiosarcoma of the spleen. The patient suffered from longstanding symptomatic anemia and thrombocytopenia. Diagnosis of a splenic angiosarcoma can be difficult due to the vague presentation and lack of concrete risk factors. Early identification and splenectomy are paramount. However, it is an aggressive malignancy with poor prognosis. We reviewed the literature of the current diagnostic and surgical treatment of primary splenic angiosarcoma.

Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases.

Leukemias expressing constitutively activated mutants of ABL1 tyrosine kinase (BCR-ABL1, TEL-ABL1, NUP214-ABL1) usually contain at least 1 normal ABL1 allele. Because oncogenic and normal ABL1 kinases may exert opposite effects on cell behavior, we examined the role of normal ABL1 in leukemias induced by oncogenic ABL1 kinases. BCR-ABL1-Abl1(-/-) cells generated highly aggressive chronic myeloid leukemia (CML)-blast phase-like disease in mice compared with less malignant CML-chronic phase-like disease from BCR-ABL1-Abl1(+/+) cells. Additionally, loss of ABL1 stimulated proliferation and expansion of BCR-ABL1 murine leukemia stem cells, arrested myeloid differentiation, inhibited genotoxic stress-induced apoptosis, and facilitated accumulation of chromosomal aberrations. Conversely, allosteric stimulation of ABL1 kinase activity enhanced the antileukemia effect of ABL1 tyrosine kinase inhibitors (imatinib and ponatinib) in human and murine leukemias expressing BCR-ABL1, TEL-ABL1, and NUP214-ABL1. Therefore, we postulate that normal ABL1 kinase behaves like a tumor suppressor and therapeutic target in leukemias expressing oncogenic forms of the kinase.

Primary Peritoneal Mesothelioma Resulting in Small Bowel Obstruction: A Case Report and Review of Literature.

BACKGROUND: Peritoneal mesothelioma is a rare malignancy that affects the serosal surfaces of the peritoneum. The peritoneum is the second most common site of mesothelium affected following the pleura. The aggressive nature and vague presentation pose many obstacles in not only diagnosis but also the treatment of patients with this disease. CASE REPORT: We present a case of a 76-year-old woman who presented with small bowel obstruction secondary to carcinomatosis secondary to primary peritoneal mesothelioma. The patient had multiple risk factors with asbestos exposure and prior therapeutic radiation. CONCLUSIONS: We discuss the highly varied and elusive presentation of peritoneal mesothelioma. Cumulative asbestos exposure, either directly or indirectly, remains the leading cause of mesothelioma. However, there are other non-asbestos etiologies. Small bowel obstruction often is a late-presenting symptom of widespread tumor burden. A concise review of the current diagnostic and surgical treatment of primary peritoneal mesothelioma demonstrates that early diagnosis and implementation remains vital.

Cutaneous T cell lymphoma expresses immunosuppressive CD80 (B7-1) cell surface protein in a STAT5-dependent manner.

In this article, we report that cutaneous T cell lymphoma (CTCL) cells and tissues ubiquitously express the immunosuppressive cell surface protein CD80 (B7-1). CD80 expression in CTCL cells is strictly dependent on the expression of both members of the STAT5 family, STAT5a and STAT5b, as well as their joint ability to transcriptionally activate the CD80 gene. In IL-2-dependent CTCL cells, CD80 expression is induced by the cytokine in a Jak1/3- and STAT5a/b-dependent manner, whereas in the CTCL cells with constitutive STAT5 activation, CD80 expression is also STAT5a/b dependent but is independent of Jak activity. Although depletion of CD80 expression does not affect the proliferation rate and viability of CTCL cells, induced expression of the cell-inhibitory receptor of CD80, CD152 (CTLA-4), impairs growth of the cells. Coculture of CTCL cells with normal T lymphocytes consisting of both CD4(+) and CD8(+) populations or the CD4(+) subset alone, transfected with CD152 mRNA, inhibits proliferation of normal T cells in a CD152- and CD80-dependent manner. These data identify a new mechanism of immune evasion in CTCL and suggest that the CD80-CD152 axis may become a therapeutic target in this type of lymphoma.

Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile.

Homologous recombination repair (HRR) protects cells from the lethal effect of spontaneous and therapy-induced DNA double-stand breaks. HRR usually depends on BRCA1/2-RAD51, and RAD52-RAD51 serves as back-up. To target HRR in tumor cells, a phenomenon called "synthetic lethality" was applied, which relies on the addiction of cancer cells to a single DNA repair pathway, whereas normal cells operate 2 or more mechanisms. Using mutagenesis and a peptide aptamer approach, we pinpointed phenylalanine 79 in RAD52 DNA binding domain I (RAD52-phenylalanine 79 [F79]) as a valid target to induce synthetic lethality in BRCA1- and/or BRCA2-deficient leukemias and carcinomas without affecting normal cells and tissues. Targeting RAD52-F79 disrupts the RAD52-DNA interaction, resulting in the accumulation of toxic DNA double-stand breaks in malignant cells, but not in normal counterparts. In addition, abrogation of RAD52-DNA interaction enhanced the antileukemia effect of already-approved drugs. BRCA-deficient status predisposing to RAD52-dependent synthetic lethality could be predicted by genetic abnormalities such as oncogenes BCR-ABL1 and PML-RAR, mutations in BRCA1 and/or BRCA2 genes, and gene expression profiles identifying leukemias displaying low levels of BRCA1 and/or BRCA2. We believe this work may initiate a personalized therapeutic approach in numerous patients with tumors displaying encoded and functional BRCA deficiency.

The potent oncogene NPM-ALK mediates malignant transformation of normal human CD4(+) T lymphocytes.

With this study we have demonstrated that in vitro transduction of normal human CD4(+) T lymphocytes with NPM-ALK results in their malignant transformation. The transformed cells become immortalized and display morphology and immunophenotype characteristic of patient-derived anaplastic large-cell lymphomas. These unique features, which are strictly dependent on NPM-ALK activity and expression, include perpetual cell growth, proliferation, and survival; activation of the key signal transduction pathways STAT3 and mTORC1; and expression of CD30 (the hallmark of anaplastic large-cell lymphoma) and of immunosuppressive cytokine IL-10 and cell-surface protein PD-L1/CD274. Implantation of NPM-ALK-transformed CD4(+) T lymphocytes into immunodeficient mice resulted in formation of tumors indistinguishable from patients' anaplastic large-cell lymphomas. Our findings demonstrate that the key aspects of human carcinogenesis closely recapitulating the features of the native tumors can be faithfully reproduced in vitro when an appropriate oncogene is used to transform its natural target cells; this in turn points to the fundamental role in malignant cell transformation of potent oncogenes expressed in the relevant target cells. Such transformed cells should permit study of the early stages of carcinogenesis, and in particular the initial oncogene-host cell interactions. This experimental design could also be useful for studies of the effects of early therapeutic intervention and likely also the mechanisms of malignant progression.

The Fbx4 tumor suppressor regulates cyclin D1 accumulation and prevents neoplastic transformation.

Skp1-Cul1-F-box (SCF) E3 ubiquitin ligase complexes modulate the accumulation of key cell cycle regulatory proteins. Following the G(1)/S transition, SCF(Fbx4) targets cyclin D1 for proteasomal degradation, a critical event necessary for DNA replication fidelity. Deregulated cyclin D1 drives tumorigenesis, and inactivating mutations in Fbx4 have been identified in human cancer, suggesting that Fbx4 may function as a tumor suppressor. Fbx4(+/-) and Fbx4(-/-) mice succumb to multiple tumor phenotypes, including lymphomas, histiocytic sarcomas and, less frequently, mammary and hepatocellular carcinomas. Tumors and premalignant tissue from Fbx4(+/-) and Fbx4(-/-) mice exhibit elevated cyclin D1, an observation consistent with cyclin D1 as a target of Fbx4. Molecular dissection of the Fbx4 regulatory network in murine embryonic fibroblasts (MEFs) revealed that loss of Fbx4 results in cyclin D1 stabilization and nuclear accumulation throughout cell division. Increased proliferation in early passage primary MEFs is antagonized by DNA damage checkpoint activation, consistent with nuclear cyclin D1-driven genomic instability. Furthermore, Fbx4(-/-) MEFs exhibited increased susceptibility to Ras-dependent transformation in vitro, analogous to tumorigenesis observed in mice. Collectively, these data reveal a requisite role for the SCF(Fbx4) E3 ubiquitin ligase in regulating cyclin D1 accumulation, consistent with tumor suppressive function in vivo.

Ovarian preservation in a young patient with Gorlin syndrome and multiple bilateral ovarian masses.

OBJECTIVE: To report a case of bilateral ovarian fibromas and ovarian leiomyomas in a young patient with Gorlin syndrome and to highlight issues of fertility preservation, ovarian conservation, and preimplantation genetic diagnosis in this population. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 15-year-old female patient with Gorlin syndrome and bilateral ovarian masses. INTERVENTION(S): Ultrasound, magnetic resonance imaging, hormone analysis, and laparotomy with resection of ovarian fibromas. MAIN OUTCOME MEASURE(S): Preservation of ovarian function, pathologic diagnosis. RESULT(S): Our patient represented an adolescent case of bilateral ovarian fibromas and leiomyomas in Gorlin syndrome presenting with menstrual irregularities. She was managed surgically with resection of the lesions and conservation of normal ovarian tissue. CONCLUSION(S): In Gorlin syndrome, ovarian fibromas are a common clinical manifestation. Patients with ovarian involvement may present with complex gynecologic needs and may have decreased fertility potential. Careful surgical management, follow-up, and counseling on options for future fertility should be offered to all patients.

The dynamic behavior of bacterial macrofibers growing with one end prevented from rotating: variation in shaft rotation along the fiber's length, and supercoil movement on a solid surface toward the constrained end.

BACKGROUND: Bacterial macrofibers twist as they grow, writhe, supercoil and wind up into plectonemic structures (helical forms the individual filaments of which cannot be taken apart without unwinding) that eventually carry loops at both of their ends. Terminal loops rotate about the axis of a fiber's shaft in contrary directions at increasing rate as the shaft elongates. Theory suggests that rotation rates should vary linearly along the length of a fiber ranging from maxima at the loop ends to zero at an intermediate point. Blocking rotation at one end of a fiber should lead to a single gradient: zero at the blocked end to maximum at the free end. We tested this conclusion by measuring directly the rotation at various distances along fiber length from the blocked end. The movement of supercoils over a solid surface was also measured in tethered macrofibers. RESULTS: Macrofibers that hung down from a floating wire inserted through a terminal loop grew vertically and produced small plectonemic structures by supercoiling along their length. Using these as markers for shaft rotation we observed a uniform gradient of initial rotation rates with slopes of 25.6 degrees /min. mm. and 36.2 degrees /min. mm. in two different fibers. Measurements of the distal tip rotation in a third fiber as a function of length showed increases proportional to increases in length with constant of proportionality 79.2 rad/mm. Another fiber tethered to the floor grew horizontally with a length-doubling time of 74 min, made contact periodically with the floor and supercoiled repeatedly. The supercoils moved over the floor toward the tether at approximately 0.06 mm/min, 4 times faster than the fiber growth rate. Over a period of 800 minutes the fiber grew to 23 mm in length and was entirely retracted back to the tether by a process involving 29 supercoils. CONCLUSIONS: The rate at which growing bacterial macrofibers rotated about the axis of the fiber shaft measured at various locations along fibers in structures prevented from rotating at one end reveal that the rate varied linearly from zero at the blocked end to maximum at the distal end. The increasing number of twisting cells in growing fibers caused the distal end to continuously rotate faster. When the free end was intermittently prevented from rotating a torque developed which was relieved by supercoiling. On a solid surface the supercoils moved toward the end permanently blocked from rotating as a result of supercoil rolling over the surface and the formation of new supercoils that reduced fiber length between the initial supercoil and the wire tether. All of the motions are ramifications of cell growth with twist and the highly ordered multicellular state of macrofibers.