- Poikilodermatous Mycosis Fungoides - Rare Entity, Different Treatment Modalities. [Journal Article]
- ADActa Dermatovenerol Croat 2018; 26(1):48-52
- Poikilodermatous mycosis fungoides (PMF) is a rare clinical variant of early-stage MF with peculiar histological features. Poikiloderma occurs in many different clinical conditions, which makes a dia...
Poikilodermatous mycosis fungoides (PMF) is a rare clinical variant of early-stage MF with peculiar histological features. Poikiloderma occurs in many different clinical conditions, which makes a diagnostic procedure more complicated. PMF belongs to a group of MF variants with low risk of disease progression. We report a case of a 64-year-old woman, who presented with mottled skin aspect of erythema, poikilodermatous patches (hypopigmentation, hyperpigmentation, atrophy, and telangiectasia) on more than 80% of the body. Based on clinical, histopathological, and immunohistochemical findings, we established the diagnosis of PMF. Staging procedure determined stage IIA. As skin-directed therapy was the treatment of choice, the patient was successfully treated with psoralen-UVA (PUVA), nbUVB plus retinoid (Re-nbUVB), and PUVA plus retinoid (Re-PUVA), however, with rapid recurrence.
- Life expectancy and comorbidities in patients with hereditary hemorrhagic telangiectasia. [Journal Article]
- VMVasc Med 2018 May 01; :1358863X18767761
- There are only a few published studies that demonstrate associations between life expectancy, severe comorbidities, and their complications in patients with hereditary hemorrhagic telangiectasia (HHT...
There are only a few published studies that demonstrate associations between life expectancy, severe comorbidities, and their complications in patients with hereditary hemorrhagic telangiectasia (HHT). Relatives of 73 deceased patients with suspected HHT completed a questionnaire about causes of death, and symptoms and comorbidities that the patients had developed. We compared the data for 55 cases where HHT had been clinically confirmed with the general population. Patients suffering from HHT lost, on average, 19 years (SD 11 years) of potential life compared to the general population. Among the deceased HHT patients, 35% (95% CI: 23-48%) died from sepsis, 26% (95% CI: 16-38%) from cardiac failure, 20% (95% CI: 9-28%) from a severe bleeding episode, and 13% (95% CI: 6-24%) from terminal cancer. Congestive heart failure (69%, 95% CI: 56-80%) and pulmonary hypertension (23%, 95% CI: 14-36%) were the main non-fatal comorbidities in patients with HHT. Patients with HHT appear to have a lower life expectancy than the general population. Sepsis and cardiac failure were the main causes of death. Optimized and targeted screening programs for the most frequent comorbidities followed by improved management of infectious complications may increase life expectancy.
- Dermoscopic patterns of filiform papillae of the tongue in patients with and without connective tissue autoimmune diseases. [Journal Article]
- IJInt J Dermatol 2018 May 18
- CONCLUSIONS: We have noted alterations in filiform papillae in CTADs, which emphasizes the importance of a detailed intraoral exploration and the macroscopic and dermoscopic evaluation of the dorsum of the tongue, specifically the filiform papillae.
- Camptothecin induces G2/M phase arrest through the ATM-Chk2-Cdc25C axis as a result of autophagy-induced cytoprotection: Implications of reactive oxygen species. [Journal Article]
- OOncotarget 2018 Apr 24; 9(31):21744-21757
- In the present study, we report that camptothecin (CPT) caused irreversible cell cycle arrest at the G2/M phase, and was associated with decreased levels of cell division cycle 25C (Cdc25C) and incre...
In the present study, we report that camptothecin (CPT) caused irreversible cell cycle arrest at the G2/M phase, and was associated with decreased levels of cell division cycle 25C (Cdc25C) and increased levels of cyclin B1, p21, and phospho-H3. Interestingly, the reactive oxygen species (ROS) inhibitor, glutathione, decreased CPT-induced G2/M phase arrest and moderately induced S phase arrest, indicating that the ROS is required for the regulation of CPT-induced G2/M phase arrest. Furthermore, transient knockdown of nuclear factor-erythroid 2-related factor 2 (Nrf2), in the presence of CPT, increased the ROS' level and further shifted the cell cycle from early S phase to the G2/M phase, indicating that Nrf2 delayed the S phase in response to CPT. We also found that CPT-induced G2/M phase arrest increased, along with the ataxia telangiectasia-mutated (ATM)-checkpoint kinase 2 (Chk2)-Cdc25C axis. Additionally, the proteasome inhibitor, MG132, restored the decrease in Cdc25C levels in response to CPT, and significantly downregulated CPT-induced G2/M phase arrest, suggesting that CPT enhances G2/M phase arrest through proteasome-mediated Cdc25C degradation. Our data also indicated that inhibition of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) inhibited CPT-induced p21 and cyclin B1 levels; however, inhibition of ERK blocked CPT-induced G2/M phase arrest, and inhibition of JNK enhanced apoptosis in response to CPT. Finally, we found that CPT-induced G2/M phase arrest circumvented apoptosis by activating autophagy through ATM activation. These findings suggest that CPT-induced G2/M phase arrest through the ROS-ATM-Chk2-Cdc25C axis is accompanied by the activation of autophagy.
- OCT Angiography Helps Distinguish Between Proliferative Macular Telangiectasia Type 2 and Neovascular Age-Related Macular Degeneration. [Journal Article]
- OSOphthalmic Surg Lasers Imaging Retina 2018 May 01; 49(5):303-312
- CONCLUSIONS: OCTA is an important tool for the correct diagnosis of MacTel2 in older patients with the concomitant or masquerading diagnosis of AMD. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:303-312.].
- The major tegument protein of bovine herpesvirus-1, VP8, interacts with DNA damage response proteins and induces apoptosis. [Journal Article]
- JVJ Virol 2018 May 16
- VP8, the UL47 gene product in bovine herpes virus-1 (BoHV-1), is a major tegument protein, essential for virus replication in vivo The major DNA damage response protein, ataxia telangiectasia mutated...
VP8, the UL47 gene product in bovine herpes virus-1 (BoHV-1), is a major tegument protein, essential for virus replication in vivo The major DNA damage response protein, ataxia telangiectasia mutated (ATM), phosphorylates Nijmegen breakage syndrome (NBS1) and structural maintenance of chromosome-1 (SMC1) proteins during the DNA damage response. VP8 was found to interact with ATM and NBS1 during transfection and BoHV-1 infection. However, VP8 did not interfere with phosphorylation of ATM in transfected or BoHV-1-infected cells. In contrast, VP8 inhibited phosphorylation of both NBS1 and SMC1 in transfected cells, as well as in BoHV-1-infected cells, but not in cells infected with a VP8 deletion mutant (BoHV-1ΔUL47). Inhibition of NBS1 and SMC1 phosphorylation was observed at 4 h post infection by nuclear VP8. Furthermore, ultraviolet light (UV)-induced cyclobutane pyrimidine dimer (CPD) repair was reduced in the presence of VP8, and VP8 in fact enhanced etoposide or UV-induced apoptosis. This suggests that VP8 blocks the ATM/NBS1/SMC1 pathway and inhibits DNA repair. VP8 induced apoptosis in VP8-transfected cells through caspase-3 activation. The fact that BoHV-1 is known to induce apoptosis through caspase-3 activation is in agreement with this observation. The role of VP8 was confirmed by the observation that BoHV-1 induced significantly more apoptosis than BoHV-1ΔUL47. These data reveal a potential role of VP8 in the modulation of the DNA damage response pathway and induction of apoptosis during BoHV-1 infection.IMPORTANCE To our knowledge, the effect of BoHV-1 infection on the DNA damage response has not been characterized. Since BoHV-1ΔUL47 was previously shown to be avirulent in vivo, VP8 is critical for the progression of viral infection. We demonstrated that VP8 interacts with DNA damage response proteins and disrupts the ATM-NBS1-SMC1 pathway by inhibiting phosphorylation of DNA repair proteins, NBS1 and SMC1. Furthermore, interference of VP8 with DNA repair was correlated to decreased cell viability and increased DNA damage-induced apoptosis. These data show that BoHV-1 VP8 developed a novel strategy to interrupt the ATM signaling pathway and to promote apoptosis. These results further enhance our understanding of the functions of VP8 during BoHV-1 infection and provide an additional explanation for the reduced virulence of BoHV-1ΔUL47.
- Orally bioavailable and blood-brain-barrier penetrating ATM inhibitor (AZ32) radiosensitizes intracranial gliomas in mice. [Journal Article]
- MCMol Cancer Ther 2018 May 16
- Inhibition of ataxia-telangiectasia mutated (ATM) during radiotherapy of glioblastoma multiforme (GBM) may improve tumor control by short-circuiting the response to radiation-induced DNA damage. A ma...
Inhibition of ataxia-telangiectasia mutated (ATM) during radiotherapy of glioblastoma multiforme (GBM) may improve tumor control by short-circuiting the response to radiation-induced DNA damage. A major impediment for clinical implementation is that current inhibitors have limited CNS bioavailability, thus, the goal was to identify ATM inhibitors (ATMi) with improved CNS penetration. Drug screens and refinement of lead compounds identified AZ31 and AZ32. The compounds were then tested in vivo for efficacy and impact on tumor and healthy brain. Both AZ31 and AZ32 blocked the DNA damage response (DDR) and radiosensitized GBM cells in vitro. AZ32, with enhanced blood-brain barrier (BBB) penetration, was highly efficient in vivo as radiosensitizer in syngeneic and human, orthotopic mouse glioma model compared with AZ31. Furthermore, human glioma cell lines expressing mutant p53 or having checkpoint-defective mutations were particularly sensitive to ATMi radiosensitization. The mechanism for this p53 effect involves a propensity to undergo mitotic catastrophe relative to cells with wild-type p53. In vivo, apoptosis was >6-fold higher in tumor relative to healthy brain after exposure to AZ32 and low dose radiation. AZ32 is the first ATMi with oral bioavailability shown to radiosensitize glioma and improve survival in orthotopic mouse models. These findings support the development of a clinical-grade, BBB-penetrating ATMi for the treatment of GBM. Importantly, since many GBMs have defective p53 signalling, the use of an ATMi concurrent with standard radiotherapy is expected to be cancer-specific, increase the therapeutic ratio, and maintain full therapeutic effect at lower radiation doses.
- StatPearls [BOOK]
- BOOKStatPearls Publishing: Treasure Island (FL)
- Immunodeficiency results from a failure or absence of elements of the immune system including lymphocytes, phagocytes and complement system. These immunodeficiencies can be either primary such as Bru...
Immunodeficiency results from a failure or absence of elements of the immune system including lymphocytes, phagocytes and complement system. These immunodeficiencies can be either primary such as Bruton’s disease or secondary as the one caused by HIV infection. Primary ImmunodeficiencyB-cell Deficiencies X- linked Agammaglobulinemia (Bruton’s disease): First described by Bruton. X-linked disorder. Found in male babies expressed around 5 to 6 months of age (maternal IgG disappears). In boys, pre-B cells did not differentiate into mature B lymphocytes. There is a mutation in the gene that encodes for a tyrosine kinase protein. Low level of all immunoglobulins (IgG, IgA, IgM, IgD and IgE) is present. Infants with X-linked agammaglobulinemia suffer from recurrent bacterial infections: otitis media, bronchitis, septicemia, pneumonia, and arthritis, and Giardia lamblia causes intestinal malabsorption. Intermittent injections of large amounts of IgG keep the patient alive, but a patient may die at a younger age if infection with antibiotic-resistant bacteria occurs. Selective Immunoglobulin IgA Deficiencies : IgA deficiency is more common than other deficiencies of immunoglobulins. These patients are more prone to recurrent sinus and lung infections. A malfunctioning in heavy-chain gene switching may cause this problem. Treatment should not include gammaglobulin preparations to prevent hypersensitivity reactions. T-cell Immunodeficiencies Congenital thymic Aplasia (DiGeorge Syndrome): Tetany is present. Fungal and viral infections are common. A transplant of the fetal thymus is needed to correct this deficiency. Chronic Mucocutaneous Candidasis: Selective defect in functioning of T-cells. Patient with this disorder usually have a normal T-cell mediated immunity to microorganisms other than Candida. B-cells function is normal. Disorders affect both genders, and it is inherited. Patient in addition to the above will have other disorders like parathyroid deficiencies. Antifungals are useful. Hyper-IgM syndrome: This disorder is characterized by bacterial infections including pneumonia, meningitis, otitis, among others that start in early childhood. High levels of IgM. Other immunoglobulins are defective. Lymphocytes are normal in numbers. The gene encoding the CD40 ligand on T lymphocytes is faulty. B and T lymphocyte cooperation in the immune response is compromised. The failure to interact with CD40 results in an inability of the B cell to switch from the production of IgM to the other classes of antibodies. Immunoglobulin therapy is recommended. Interleukin-12 receptor deficiency: Mycobacterial infections are frequent due to the lack of the interleukin-12 receptor. Treatment involves selective antimicrobials. T-cell and B-cell Deficiencies Severe combined immunodeficiency disease (SCID): There is a failure of early stem cells to differentiate into T and B lymphocytes. Deficiency of the interleukin-2 receptor is the most prevalent. Other problems are due to defective genes encoding ZAP-70, Janus kinase 3 and the genes involved in the DNA recombination of immune cells receptors: RAG1 and RAG2. Clinically characterized by a variety of infections, including those caused by opportunistic pathogens. Selective antibiotics, antivirals, and antifungals are available after the pathogen identification. Immunosuppressive therapy is not needed after allograft transplantation. Wiskott-Aldrich syndrome: This syndrome is associated with normal T-cell numbers with reduced functions, which get progressively worse. IgM concentrations are reduced, but IgG levels are normal. Both IgA and IgE levels are elevated. These patients have a defective WASP which is involved in actin filament assembly. Immunodeficiency with ataxia-telangiectasia: This is a deficiency of T-cells associated with a lack of coordination of movement (ataxia) and dilation of small blood vessels of the facial area (telangiectasis). T-cells and their functions are diminished to various degrees. B-cell numbers and IgM concentrations are normal to low. IgG is often reduced, and IgA is considerably reduced. There is a high incidence of malignancy, especially leukemias, in these patients. MHC deficiency (Bare leukocyte syndrome): This subjects have have fewer CD4+ or CD8+ T lymphocytes that predispose to these individuals to be prone to recurrent infections. Antibody production is affected and predispose to bacteremia. Complement Deficiencies Hereditary angioedema : This disease has an autosomal dominant genetic pattern. Caused by C1 inhibitor deficiency. Clinically characterized by generalized edema including the one leading to acute suffocation. Therapy with oxymetholone and danazol can be helpful in correcting the defect. Recurrent infections: Frequent infections by extracellular bacteria may be caused by C3 deficiency. C5 deficiency predisposes to viral infections. Patients with deficiency of the membrane attack complex (MAC) are particularly susceptible to bacteremia caused by Neisseria species. Autoimmune diseases This are caused by C2 and C4 deficiencies and mimic systemic lupus erythematosus. Phagocyte Deficiencies Chronic granulomatous disease (CGD): It is mostly an X-linked disorder. It is clinically characterized by a defective NADPH that interferes with the intracellular ability of neutrophils to kill engulfed bacteria species. NAPDH oxidase is required for the generation of peroxidase and superoxides that will kill the organisms. The intracellular survival of the organisms leads to the formation of a granuloma, an organized structure consisting of mononuclear cells. These granulomas can become large enough to obstruct the stomach, esophagus, or bladder. Patients with this disease are very susceptible to opportunistic infection by certain bacteria and fungi especially with Serratia and Burkholderia. Nitroblue tetrazolium (NBT) dye reduction test confirms the diagnosis of CGD and the dichlorofluorescein (DCF) test is also useful. Aggressive therapy with wide spectrum antibiotics and antifungal agents is required. Leukocyte adhesion deficiency syndrome: Characterized by pyogenic infections including pneumonia and otitis. It is an autosomal recessive disease, and the faulty gene encodes for an integrin. There is an impaired adhesion and defective phagocytosis of bacteria. Treatment involves the use of selective antibiotics. Secondary Immunodeficiency Use of Drugs (Steroids) : Administration of steroids has direct effects on immune cell traffic and functions. T cells are more affected than B cells. Cytokine synthesis is inhibited. Nutrient Deficiencies : They are associated with impaired immune system. Affects cell-mediated immunity, antibody production, phagocyte function, complement system and cytokine synthesis. Aggravated by infections. Multiple enzymes with important roles require zinc, iron and other micronutrients. Obesity : It may cause impaired immune responses. There is altered NK function. Cytotoxicity is compromised and the ability of phagocytes to kill microorganisms. Acquired Immune Deficiency Syndrome (AIDS) : Caused by human immunodeficiency virus (HIV), which is a retrovirus transmitted sexually, perinatally or blood products. Immune dysfunction results from the direct effects of HIV and impairment of CD4 T cells. HIV proteins may act as superantigens. There is decreased responses to antigens and mitogens. Interleukin-2 and other cytokines are decreased. Infected cells may be killed by HIV-1 specific CD8+ T cells. In HIV-1 infection neutralizing antibodies appear to be ineffective in controlling viral replication and infection.
- Distinct roles of ATM and ATR in the regulation of ARP8 phosphorylation to prevent chromosome translocations. [Journal Article]
- EElife 2018 May 08; 7
- Chromosomal translocations are hallmarks of various types of cancers and leukemias. However, the molecular mechanisms of chromosome translocations remain largely unknown. The ataxia-telangiectasia mu...
Chromosomal translocations are hallmarks of various types of cancers and leukemias. However, the molecular mechanisms of chromosome translocations remain largely unknown. The ataxia-telangiectasia mutated (ATM) protein, a DNA damage signaling regulator, facilitates DNA repair to prevent chromosome abnormalities. Previously, we showed that ATM deficiency led to the 11q23 chromosome translocation, the most frequent chromosome abnormalities in secondary leukemia. Here, we show that ARP8, a subunit of the INO80 chromatin remodeling complex, is phosphorylated after etoposide treatment. The etoposide-induced phosphorylation of ARP8 is regulated by ATM and ATR, and attenuates its interaction with INO80. The ATM-regulated phosphorylation of ARP8 reduces the excessive loading of INO80 and RAD51 onto the breakpoint cluster region. These findings suggest that the phosphorylation of ARP8, regulated by ATM, plays an important role in maintaining the fidelity of DNA repair to prevent the etoposide-induced 11q23 abnormalities.
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- Functional promoter rs189037 variant of ATM is associated with decrease in lung diffusing capacity after irradiation for non-small-cell lung cancer. [Journal Article]
- CDChronic Dis Transl Med 2018; 4(1):59-66
- CONCLUSIONS: The AA genotype of ATM rs189037 was associated with higher risk of lung injury than were the GG/AG genotypes in patients with NSCLC treated with radiotherapy. This finding should be validated prospectively with other patient populations.