40 research outputs found
Prostate Cancer-Associated Disseminated Intravascular Coagulation with Excessive Fibrinolysis Treated with Degarelix
Disseminated intravascular coagulation (DIC) with excessive fibrinolysis (XFL) is a rare and acute life-threatening variant of DIC in patients with prostate cancer. Patients present with coagulopathy, hypofibrinogenemia, and systemic bleeding. We describe a case of DIC XFL caused by prostate cancer (PC) successfully treated with a single injection of degarelix, a gonadotropin-releasing hormone (GnRH) receptor antagonist. This led to prompt control of the patient's coagulopathy within ten days of treatment. Our case highlights features of this rare and devastating hemorrhagic complication of PC along with a fast-acting and effective therapeutic drug option. Case Description A 61-year-old Hispanic man with past medical history of benign prostatic hyperplasia (BPH) treated with transurethral resection of the prostate the preceding year presented to our emergency room with a nonhealing wound on his right thigh. He reported that he sustained a laceration to his right thigh during work with machinery one week prior to presentation and had visited the nearest urgent care. Despite suture placement at the urgent care, he continued to bleed. In addition, he reported multiple ecchymoses on his lower abdomen and extremities and severe pain in his left hip and leg. The patient had a temperature of 36.5 ∘ C, a heart rate of 101 beats per minute, a blood pressure of 138/87 mm Hg, a respiratory rate of 18 breaths per minute, and an oxygen saturation of 98% on room air. Physical exam revealed skin pallor along with diffuse ecchymoses of the abdomen, thighs, and extremities. No lymphadenopathy was noted. Labs revealed a WBC An X-ray of the left hip and femur demonstrated extensive metastatic lesions of the left ilium, ischium, and pubic bones including involvement of the acetabulum. A contrastenhanced chest CT revealed focal periosteal reaction in the left posteromedial 6th, 7th, and 8th ribs along with nonhomogenous mixed sclerotic and lytic appearance in the spine. An abdominal MRI with and without contrast demonstrated diffuse osseous metastatic disease but no evidence of primary malignancy in the abdomen. Nuclear medicine whole bod
Mangel an GM-CSF und IFN-γ verbindet Autoimmunerkrankungen und Krebs - Eine Kontroverse bezüglich der Immunüberwachung von Krebs
0\. Title Page and Table of Contents 1\. Introduction 6
2\. Materials and Methods 16
3\. Results 31
4\. Discussion 53
5\. Summary 62
6\. Abbreviations 65
7\. References 68Infection and inflammation contribute to autoimmune diseases and cancer but
the underlying mechanisms are still poorly understood. Here, I report that
aged GM-CSF and GM-CSF/IL-3-deficient mice develop a SLE-like disorder
associated with the impaired phagocytosis of apoptotic cells. Moreover, aged
GM-CSF/IL-3-deficient mice develop an autoimmune diabetes. Treatment of young
GM-CSF/IL-3-deficient mice with anti-CTLA4 antibodies induces diabetes in
these mice within one month, indicating that regulatory T cells may be
critical in the development of the disease. Since the NOD diabetes mouse shows
a defective GM-CSF signaling, and impaired GM-CSF responses are known with
patients with diabetes, my model suggests that cytokine regulation is, indeed,
an important component in the aetiology of diabetes. Concurrent deficiency of
IFN-g attenuates the SLE and prevents diabetes, but promotes the formation of
diverse hematologic and solid neoplasms on a background of a persistent severe
infection and inflammation. Whereas activated B cells, in the combined absence
of GM-CSF and IFN-g, show a resistance to fas-induced apoptosis, anti-
microbial or anti-inflammatory therapy prevents lymphomagenesis and solid
tumor development without influencing the fas-resistance. My results
contradict the theory of an IFN-g-dependent Tumor Immune Surveillance mediated
by T cells. This theory basically states that endogenously produced IFN-g
forms the basis of a Tumor Immune Surveillance System that controls the
development of both chemically induced and spontaneously arising tumors in
mice. If this theory would be accurate for my tumor model, tumor incidence
would not to be expected to dramatically decline under anti-infectious or
anti-inflammatory treatment. My findings rather indicate that tissue damage
due to chronic infection and inflammation is an important contributor to
carcinogenesis, and that GM-CSF and IFN-g synergistically protect the organism
from this damage.Infektionen und Entzuendungsprozesse tragen zur Entstehung von
Autoimmunerkrankungen und Krebs bei. Die zugrundeliegenden Mechanismen sind
jedoch wenig bekannt. In der vorliegenden Arbeit berichte ich, dass aeltere
GM-CSF- und GM-CSF/IL-3-defiziente Maeuse eine Krankheit enwickeln, die dem
systemischen Lupus erythematosus aehnlich ist, und der eine verminderte
Phagozytose von apoptotischen Zellen zugrunde liegt. Aeltere GM-
CSF/IL-3-defiziente Maeuse entwickeln zudem einen Autoimmundiabetes.
Interessanterweise fuehrt die Behandlung von jungen GM-CSF/IL-3-defizienten
Tieren mit einem nichtstimulierenden anti-CTLA-4 Antikoerper innerhalb eines
Monats ebenfalls zur Entwicklung eines Diabetes, was vermuten laesst, dass
regulatorische T Zellen an der Krankheitsentstehung wesentlich mitbeteiligt
sind. Da die diabetische NOD Maus eine gestoerte GM-CSF Signaluebertragung
aufweist und Immunzellen von Diabetespatienten eine pathologische Antwort auf
Stimulation mit GM-CSF zeigen, liegt aufgrund meiner Ergebnisse die Vermutung
nahe, dass der pathologischen Regulation von Zytokinen bei der
Diabetesentstehung eine wichtige Rolle zukommt. Der zusaetzliche Mangel an
IFN-g schwaecht die Lupus-Erkrankung ab und bringt den Diabetes zum
Verschwinden. GM-CSF/IFN-g- und GM-CSF/IL-3/IFN-g-defiziente Maeuse entwickeln
jedoch eine Reihe von verschiedenen haematologischen und soliden Tumoren. Sie
tun dies auf der Basis von schwersten infektioesen und entzuendlichen
Prozessen. Aktivierte B Zellen in diesen Tieren zeigen eine Resistenz
gegenueber Fas-induzierter Apoptose. Ueberraschenderweise vermag eine
antibiotische oder entzuendungshemmende Behandlung die Tumorentstehung nahezu
vollstaendig zu verhindern, ohne dass die Fas-Resistenz beeinflusst wird.
Diese Tatsache jedoch widerspricht der gaengigen Theorie der T Zell-
vermittelten, IFN-g-abhaengigen Tumorimmunueberwachung. Diese Theorie besagt,
dass endogen produziertes IFN-g die Basis fuer ein
Tumorimmunueberwachungssystem bildet, das die Entstehung sowohl von chemisch
induzierten als auch von spontanen Tumoren einschraenkt. Falls diese Theorie
stimmte, waere es nicht ersichtlich, dass die antibiotische oder
entzuendungshemmende Behandung meiner IFN-g-defizienten Maeuse zur nahezu
vollstaendigen Verhinderung der Tumorentstehung fuehrt. Meine Ergebnisse
deuten eher daraufhin, dass der Gewebeschaden, gesetzt durch Zytokinmangel-
bedingte, chronische Infektionen/Entzuendungen, ein wichtiger Betrag zur
Krebsentstehung leistet, und dass GM-CSF und IFN-g in synergistischer Weise
gegen diesen Schaden zu schuetzen vermoegen
Application exploration regarding a DPC like architecture
This report explores applications in the fields of multimedia, cryptography and telecommunication with regard to the Dynamically Programmable Cache (DPC) architecture proposed by Nakkar [38]. A set of applica-tions representing future systems ’ requirements are investigated in order to obtain an application base, which allows deriving a suitable DPC like architecture. The considered evaluation criteria are operations, granular-ity, parallelism and data access patterns. Our investigations show that a DPC like architecture has the potential to significantly speed-up the tar-geted application classes. We believe, however, that the proposed DPC architecture is too restrictive to fully exploit its potential, and that it is therefore worth to investigate several basic systems parameters more in depth.
Cell-Selective Inhibition of NF-kB Signaling Improves Therapeutic Index in a Melanoma Chemotherapy Model
A Comparison of Spatial and Phenotypic Immune Profiles of Pancreatic Ductal Adenocarcinoma and Its Precursor Lesions
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of 12.5%. PDAC predominantly arises from non-cystic pancreatic intraepithelial neoplasia (PanIN) and cystic intraductal papillary mucinous neoplasm (IPMN). We used multiplex immunofluorescence and computational imaging technology to characterize, map, and compare the immune microenvironments (IMEs) of PDAC and its precursor lesions. We demonstrate that the IME of IPMN was abundantly infiltrated with CD8+ T cells and PD-L1-positive antigen-presenting cells (APCs), whereas the IME of PanIN contained fewer CD8+ T cells and fewer PD-L1-positive APCs but elevated numbers of immunosuppressive regulatory T cells (Tregs). Thus, immunosuppression in IPMN and PanIN seems to be mediated by different mechanisms. While immunosuppression in IPMN is facilitated by PD-L1 expression on APCs, Tregs seem to play a key role in PanIN. Our findings suggest potential immunotherapeutic interventions for high-risk precursor lesions, namely, targeting PD-1/PD-L1 in IPMN and CTLA-4-positive Tregs in PanIN to restore immunosurveillance and prevent progression to cancer. Tregs accumulate with malignant transformation, as observed in PDAC, and to a lesser extent in IPMN-associated PDAC (IAPA). High numbers of Tregs in the microenvironment of PDAC went along with a markedly decreased interaction between CD8+ T cells and cancerous epithelial cells (ECs), highlighting the importance of Tregs as key players in immunosuppression in PDAC. We found evidence that a defect in antigen presentation, further aggravated by PD-L1 expression on APC, may contribute to immunosuppression in IAPA, suggesting a role for PD-L1/PD-1 immune checkpoint inhibitors in the treatment of IAPA
Deficiencies of GM-CSF and interferon gamma link inflammation and cancer
Chronic inflammation contributes to carcinogenesis, but the underlying mechanisms are poorly understood. We report that aged granulocyte-macrophage colony stimulating factor (GM-CSF)-deficient mice develop a systemic lupus erythematosis (SLE)-like disorder associated with the impaired phagocytosis of apoptotic cells. Concurrent deficiency of interferon (IFN)-γ attenuates the SLE, but promotes the formation of diverse hematologic and solid neoplasms within a background of persistent infection and inflammation. Whereas activated B cells show a resistance to fas-induced apoptosis, antimicrobial therapy prevents lymphomagenesis and solid tumor development. These findings demonstrate that the interplay of infectious agents with cytokine-mediated regulation of immune homeostasis is a critical determinant of cancer susceptibility
Prostate Cancer-Associated Disseminated Intravascular Coagulation with Excessive Fibrinolysis Treated with Degarelix
Disseminated intravascular coagulation (DIC) with excessive fibrinolysis (XFL) is a rare and acute life-threatening variant of DIC in patients with prostate cancer. Patients present with coagulopathy, hypofibrinogenemia, and systemic bleeding. We describe a case of DIC XFL caused by prostate cancer (PC) successfully treated with a single injection of degarelix, a gonadotropin-releasing hormone (GnRH) receptor antagonist. This led to prompt control of the patient’s coagulopathy within ten days of treatment. Our case highlights features of this rare and devastating hemorrhagic complication of PC along with a fast-acting and effective therapeutic drug option