On That Heart-Knotting Feeling: An Outline

The following feeling is what inspired this thesis and what this thesis aims to outline: the human heart is a knot, formed by a string, tying a human being to the divine. Simone Weil’s notion of affliction will broach the topic of the heart-knotting feeling. In the first chapter of the thesis, five qualities of affliction will be identified. In the second chapter, we will make a connection between Weilian affliction and the heart, understood by Dietrich von Hildebrand as an organ of affectivity and by the author as a transcendent souvenir. In the third chapter, we will discuss Christian biblical accounts of circumcision and circumcision of the heart. With the building blocks laid down, we will finally speak of the heart-knotting feeling in chapter four, more specifically, the formation and resolution of the heart-knotting feeling

Classical gonadoblastoma: its relationship to the “dissecting” variant and undifferentiated gonadal tissue

Classical gonadoblastoma occurs almost entirely in the dysgenetic gonads of an individual who has a disorder of sex development. Approximately 40% of such neoplasms are bilateral. Almost all gonadoblastomas occur in patients who have a Y chromosome or part thereof; testis specific protein Y-encoded 1 (TSPY1) is the putative gene. If a gonad in a patient who has a disorder of sex development contains germ cells with delayed maturation and also harbors the TSPY1 gene, the cells can undergo transformation to classical gonadoblastoma. The latter consists of rounded islands composed of germ cells, sex cord elements, and hyaline basement membrane material surrounded by a variably cellular gonadal stroma that sometimes contains steroid cells. Classical gonadoblastoma can be interpreted as a noninvasive neoplasm that is the precursor of germinoma, and, indirectly, other more aggressive germ cell neoplasms. Undifferentiated gonadal tissue is the precursor of classical gonadoblastoma and contains germ cells with delayed maturation that express octamer-binding transcription factor 4 (OCT4); however, other germ cells show normal maturation and express TSPY1. If all germ cells in a patient with undifferentiated gonadal tissue involute, the result is a secondary streak. Undifferentiated gonadal tissue is a non-neoplastic condition that should be clearly distinguished from “dissecting gonadoblastoma,” a neoplasm derived from classical gonadoblastoma that is the precursor of some germinomas. “Dissecting gonadoblastoma” is a variant of classical gonadoblastoma that has unusual growth patterns and contains both sex cord and germ cell elements. Clonal expansion of germ cells is a characteristic of the late stage of “dissecting gonadoblastoma”

Perspectives on testicular sex cord-stromal tumors and those composed of both germ cells and sex cord-stromal derivatives with a comparison to corresponding ovarian neoplasms

Sex cord-stromal tumors (SCSTs) are the second most frequent category of testicular neoplasms, accounting for approximately 2–5% of cases. Both genetic and epigenetic factors account for the differences in frequency and histologic composition between testicular and ovarian SCSTs. For example, large cell calcifying Sertoli cell tumor and intratubular large cell hyalinizing Sertoli cell neoplasia occur in the testis but have not been described in the ovary. In this article, we discuss recently described diagnostic entities as well as inconsistencies in nomenclature used in the recent World Health Organization classifications of SCSTs in the testis and ovary. We also thoroughly review the topic of neoplasms composed of both germ cells and sex cord derivatives with an emphasis on controversial aspects. These include “dissecting gonadoblastoma” and testicular mixed germ cell-sex cord stromal tumor (MGC-SCST). The former is a recently described variant of gonadoblastoma that sometimes is an immediate precursor of germinoma in the dysgenetic gonads of patients with a disorder of sex development. Although the relationship of “dissecting gonadoblastoma” to the previously described undifferentiated gonadal tissue is complex and not entirely resolved, we believe that it is preferable to continue to use the term undifferentiated gonadal tissue for those cases that are not neoplastic and are considered to be the precursor of classical gonadoblastoma. Although the existence of testicular MGC-SCST has been challenged, the most recent evidence supports its existence; however, testicular MGC-SCST differs significantly from ovarian examples due to both genetic and epigenetic factors

Overcoming cancer therapy resistance by targeting inhibitors of apoptosis proteins and nuclear factor-kappa B

This is the published version, also available here: http://www.ajtr.org/810001A.html.Chemo- or radioresistance markedly impairs the efficacy of cancer therapy and involves anti-apoptotic signal transduction pathways that prevent cell death. In resistant cancer cells, both inhibitors of apoptosis proteins (IAPs) and nuclear factor-kappa B (NF-κB) play a pivotal role in preventing apoptosis triggered by a variety of stresses, facilitating them as potential targets in cancer treatment. Furthermore, mounting evidences have established the crosstalks between IAPs (eg. XIAP, cIAP-1, cIAP-2) and proteins involved in NF-κB signaling (eg. TRAF2, RIP1, TAB1). Second mitochondria-derived activator of caspases (Smac) is a mitochondrial protein that released into cytoplasm upon apoptotic stimuli. As Smac functions as an endogenous IAP inhibitor, small molecule Smac-mimetics are believed to neutralize IAPs function that results in liberating caspase activity and promoting apoptosis. Moreover, recent studies show that Smac-mimetics may kill cancer cells in a different manner, which involves inducing ubiquitination of cIAPs, regulating NF-κB signaling and facilitating TNFα- triggered, caspase-8-mediated apoptosis in a certain cancer cell types. In other cancer cells that are resistant to TNFα or chemo/radiotherapy, Smac-mimetic IAP-inhibitors can enhance ionizing radiation or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, indicating the potential role of Smac- mimetics in overcoming acquired therapy-resistance. Such findings provide important impetus for utilizing IAP- inhibitors as novel adjuvant therapy for the TNFα–resistant, NF-κB constitutively active cancers that account for the majority of patients who are refractory to current therapeutic approaches. (AJTR810001)