Adult-Onset Hemophagocytic Lymphohistiocytosis Associated With Epstein-Barr Virus, Lyme Disease, and Anaplasmosis.

Adult-onset hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by dysregulated immune activation. Diagnosing HLH poses significant challenges due to its nonspecific clinical presentation, which often mimics infections, malignancies, and autoimmune diseases. Early recognition and prompt initiation of immunosuppressive therapy are crucial, as delayed treatment is associated with a high risk of mortality.

Predicting the Diagnosis of Prostate Cancer with a Novel Blood-Based Biomarker: Comparison of Its Performance with Prostate-Specific Antigen.

The purpose of this study was to assess the efficacy, specificity, and predictive value of a newly discovered biomarker, Zinc finger-like1 protein (referred to as neuroendocrine marker, NEM) for the detection of prostate cancer (PCa). We retrospectively analyzed banked plasma samples from 508 men, with a median age of 67 years (range 48-97), to compare the performance of NEM and PSA in predicting subsequent histologic PCa. The cohort consisted of four groups of patients visiting a urology clinic: (1) patients not diagnosed with either benign prostatic disease or prostate cancer (PCa) were defined as normal; (2) patients diagnosed with benign hyperplasia (BPH) but not PCa; (3) patients with confirmed PCa; and (4) patients with cancer other than PCa.

Poly (ADP-ribose) Polymerase-1 modulations in the genesis of thrombosis.

Thrombosis, a coagulation disorder, occurs due to altered levels of coagulation, fibrinolytic and immune factors, which are otherwise known to maintain hemostasis in normal physiological conditions. Here, we review the direct and indirect participation of a multifunctional nuclear enzyme poly (ADP-ribose) polymerase-1 (PARP1) in the expression of key genes and cellular processes involved in thrombotic pathogenesis. PARP1 biological activities range from maintenance of genomic integrity, chromatin remodeling, base excision DNA repair, stress responses to cell death, angiogenesis and cell cycle pathways.

Human C1q Tumor Necrosis Factor 8 (CTRP8) defines a novel tryptase+ mast cell subpopulation in the prostate cancer microenvironment.

The adipokine C1q Tumor Necrosis Factor 8 (CTRP8) is the least known member of the 15 CTRP proteins and a ligand of the relaxin receptor RXFP1. We previously demonstrated the ability of the CTRP8-RXFP1 interaction to promote motility, matrix invasion, and drug resistance. The lack of specific tools to detect CTRP8 protein severely limits our knowledge on CTRP8 biological functions in normal and tumor tissues.

Zinc finger protein‑like 1 is a novel neuroendocrine biomarker for prostate cancer.

Prostate‑derived calcitonin (CT) and its receptor induce tumorigenicity and increase metastatic potential of prostate cancer (PC). CT‑inducible genes in human prostate were identified by subtraction hybridization. Among these genes, zinc finger protein like 1 (ZFPL1) protein was interesting since it was abundantly expressed in malignant prostates but was almost absent in benign prostates.

Role of poly(ADP-ribose) polymerase-1 in regulating human islet cell differentiation.

Poly(ADP-ribose) polymerase-1 (PARP1), a fundamental DNA repair enzyme, is known to regulate β cell death, replication, and insulin secretion. PARP1 knockout (KO) mice are resistant to diabetes, while PARP1 overactivation contributes to β cell death. Additionally, PARP1 inhibition (PARPi) improves diabetes complications in patients with type-2 diabetes.

XPC-PARP complexes engage the chromatin remodeler ALC1 to catalyze global genome DNA damage repair.

Cells employ global genome nucleotide excision repair (GGR) to eliminate a broad spectrum of DNA lesions, including those induced by UV light. The lesion-recognition factor XPC initiates repair of helix-destabilizing DNA lesions, but binds poorly to lesions such as CPDs that do not destabilize DNA. How difficult-to-repair lesions are detected in chromatin is unknown.

Deubiquitinating enzymes and the proteasome regulate preferential sets of ubiquitin substrates.

The ubiquitin-proteasome axis has been extensively explored at a system-wide level, but the impact of deubiquitinating enzymes (DUBs) on the ubiquitinome remains largely unknown. Here, we compare the contributions of the proteasome and DUBs on the global ubiquitinome, using UbiSite technology, inhibitors and mass spectrometry. We uncover large dynamic ubiquitin signalling networks with substrates and sites preferentially regulated by DUBs or by the proteasome, highlighting the role of DUBs in degradation-independent ubiquitination.

Poly (ADP-ribose) polymerase (PARP) inhibition in cancer: Potential impact in cancer stem cells and therapeutic implications.

Inhibitors of poly(ADP-ribose) polymerase (PARP) are used in mono- or combination therapies for several malignancies. They are also used as maintenance therapy for some cancers after initial treatment. While the focus of this therapeutic approach is on the effect of PARP inhibition on the bulk tumour cells, in this review, we discuss their effect on the cancer stem cells.

Chemotherapy-Induced Upregulation of Somatostatin Receptor-2 Increases the Uptake and Efficacy of Lu-DOTA-Octreotate in Neuroendocrine Tumor Cells.

The peptide receptor radionuclide therapy (PRRT) with Lu-DOTA-octreotate (LuTate) is recommended for different types of neuroendocrine tumors (NETs) which overexpress somatostatin receptors (SSTR). A combination with chemotherapy improves objective response to LuTate in NET patients and here we characterized chemotherapy-induced upregulation of SSTR2 receptors as a cause for this improved response to LuTate. The NET cell lines with low (BON-1) or relatively high (NCI-H727) SSTR2-expression levels, and non-NET cancer and normal cells were treated with chemotherapeutic drugs and assessed for upregulation of SSTR2.

Poly(ADP-ribosyl)ation temporally confines SUMO-dependent ataxin-3 recruitment to control DNA double-strand break repair.

DNA damage-induced SUMOylation serves as a signal for two antagonizing proteins that both stimulate repair of DNA double-strand breaks (DSBs). Here, we demonstrate that the SUMO-dependent recruitment of the deubiquitylating enzyme ataxin-3 to DSBs, unlike recruitment of the ubiquitin ligase RNF4, additionally depends on poly [ADP-ribose] polymerase 1 (PARP1)-mediated poly(ADP-ribosyl)ation (PARylation). The co-dependence of ataxin-3 recruitment on PARylation and SUMOylation temporally confines ataxin-3 to DSBs immediately after occurrence of DNA damage.

Methods to Study Intracellular Movement and Localization of the Nucleotide Excision Repair Proteins at the DNA Lesions in Mammalian Cells.

Nucleotide excision repair (NER) is the most versatile DNA repair pathway that removes a wide variety of DNA lesions caused by different types of physical and chemical agents, such as ultraviolet radiation (UV), environmental carcinogen benzo[a]pyrene and anti-cancer drug carboplatin. The mammalian NER utilizes more than 30 proteins, in a multi-step process that begins with the lesion recognition within seconds of DNA damage to completion of repair after few hours to several days. The core proteins and their biochemical reactions are known from in vitro DNA repair assays using purified proteins, but challenge was to understand the dynamics of their rapid recruitment and departure from the lesion site and their coordination with other proteins and post-translational modifications to execute the sequential steps of repair.

Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome.

The autosomal recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite the identification of the underlying gene defects, it is unclear how mutations in any of the four known ICF genes cause a primary immunodeficiency. Here we demonstrate that loss of ZBTB24 in B cells from mice and ICF2 patients affects nonhomologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and isotype balance.

Calcitonin receptor is required for T-antigen-induced prostate carcinogenesis.

Expression of calcitonin (CT) and its receptor (CTR) is frequently elevated in prostate cancer (PC) and activation of CT-CTR axis in non- invasive PC cells induces an invasive phenotype. However, the role of CT-CTR axis in prostate carcinogenesis has not been investigated. We employed a transgenic mouse prostate cancer model that uses long probasin promoter to target the expression of T-antigen in the prostate gland (LPB-Tag) along with CTR knock-out mice (CTRKO) to address this question.

A panel of criteria for comprehensive assessment of severity of ultraviolet B radiation-induced non-melanoma skin cancers in SKH-1 mice.

The study of causes and cures for ultraviolet B radiation (UVB)-induced non-melanoma skin cancers (NMSC) has been greatly facilitated by use of the albino SKH-1 hairless mice. These mice develop multiple tumors of different sizes and the severity of cancer is often measured by one or more of the four criteria, namely the prevalence, multiplicity, area and volume of tumors. However, there are inherent limitations of each criterion: the prevalence and number do not account for size differences among tumors, area measurement ignores the tumor height, and volume measurement overcompensates for the height at the cost of planar dimensions.

Calcitonin induces stem cell-like phenotype in prostate cancer cells.

Stem cell-like-cancer cells are key drivers of tumor growth, metastasis, and relapse of cancer following remission. Prostate stem cell-like cancer cells isolated from human prostate cancer (PC) biopsies express CD44+/α2β1 hi/CD133+ cell surface markers and can self-renew in vitro. Expression of calcitonin (CT) and its receptor (CTR) is frequently elevated in PCs and activation of CT-CTR axis in non-invasive PC cells induces an invasive phenotype.

Combination treatments to enhance peptide receptor radionuclide therapy of neuroendocrine tumours.

The incidence of neuroendocrine tumours (NETs) is increasing, but curative therapeutic options are limited because diagnosis is often delayed until the tumour has metastasized. Peptide receptor radionuclide therapy (PRRT) is among the most effective therapeutic options for metastatic NETs because of targeted delivery of radioactivity to the tumour via the somatostatin receptor (SSTR) and relatively low systemic toxicity. However, current PRRT regimes result in palliation rather than cure, and higher doses of PRRT that might achieve remission would also be too toxic to the patients.

Potentiation of Lu-octreotate peptide receptor radionuclide therapy of human neuroendocrine tumor cells by PARP inhibitor.

For patients with inoperable neuroendocrine tumors (NETs) expressing somatostatin receptors, peptide receptor radionuclide therapy (PRRT) with Lu-[DOTA0-Tyr3]-octreotate (Lu-octreotate) is one of the most promising targeted therapeutic options but it rarely achieves cure. Therefore, different approaches are being tested to increase the efficacy of Lu-octreotate PRRT in NET patients. Using the gastroenteropancreatic BON-1 and the bronchopulmonary NCI-H727 as NET cell models, here we report that pharmacological inhibitors of DNA repair-associated enzyme poly(ADP-ribose) polymerase-1 (PARPi) potentiate the cytotoxic effect of Lu-octreotate on 2D monolayer and 3D spheroid models of these two types of NET cells.

Characterization of prostate cancer cell progression in zebrafish xenograft model.

Early diagnosis of prostate cancer (PCa) is critical for the application of efficient treatment to PCa patients. However, the majority of PCas remains indolent from several months to several years before malignancy. Current diagnosis methods have limitations in their reliability and are inefficient in time cost.

Poly(ADP-ribose) polymerase 1 escorts XPC to UV-induced DNA lesions during nucleotide excision repair.

Xeroderma pigmentosum C (XPC) protein initiates the global genomic subpathway of nucleotide excision repair (GG-NER) for removal of UV-induced direct photolesions from genomic DNA. The XPC has an inherent capacity to identify and stabilize at the DNA lesion sites, and this function is facilitated in the genomic context by UV-damaged DNA-binding protein 2 (DDB2), which is part of a multiprotein UV-DDB ubiquitin ligase complex. The nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP1) has been shown to facilitate the lesion recognition step of GG-NER via its interaction with DDB2 at the lesion site.

Calcitonin receptor increases invasion of prostate cancer cells by recruiting zonula occludens-1 and promoting PKA-mediated TJ disassembly.

Almost all primary prostate cancers (PCs) and PC cell lines express calcitonin (CT) and/or its receptor (CTR), and their co-expression positively correlates with their invasiveness. Activation of the CT-CTR axis in non-invasive LNCaP cells induces an invasive phenotype. In contrast, silencing of CT/CTR expression in highly metastatic PC-3M cells markedly reduces their tumorigenicity and abolishes their ability to form distant metastases in nude mice.

Comprehensive measurement of UVB-induced non-melanoma skin cancer burden in mice using photographic images as a substitute for the caliper method.

The vernier caliper has been used as a gold standard to measure the length, width and height of skin tumors to calculate their total area and volume. It is a simple method for collecting data on a few tumors at a time, but becomes tedious, time-consuming and stressful for the animals and the operator when used for measuring multiple tumors in a large number of animals in protocols such as UVB-induced non-melanoma skin cancer (NMSC) in SKH-1 mice. Here, we show that photographic images of these mice taken within a few minutes under optimized conditions can be subjected to computerized analyses to determine tumor volume and area as accurately and precisely as the caliper method.