Search

Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors rarely elicit complete responses in patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC), as a small population of tumor cells survives due to adaptive resistance. Therefore, we focused on the mechanisms underlying adaptive resistance to lorlatinib and therapeutic strategies required to overcome them. We found that epidermal growth factor receptor (EGFR) signaling was involved in the adaptive resistance to lorlatinib in ALK-rearranged NSCLC, activation of which was induced by heparin-binding EGF-like growth factor production via c-Jun activation. EGFR inhibition halted ALK-rearranged lung cancer cell proliferation by enhancing ALK inhibition-induced apoptosis via suppression of Bcl-xL. Xenograft models showed that the combination of EGFR inhibitor and lorlatinib considerably suppressed tumor regrowth following cessation of these treatments. This study provides new insights regarding tumor evolution due to EGFR signaling after lorlatinib treatment and the development of combined therapeutic strategies for ALK-rearranged lung cancer.

Many anticancer drugs have been reported to damage the kidneys. Olaparib (ORB) is known not to largely affect renal function due to its specific pharmacological mechanism, and there are no reports on renal dysfunction associated with the drug. The patient was found to have diagnosed with recurrent ovarian cancer. She started therapy with Bevacizumab (BEV). Unfortunately, BEV was discontinued due to development of progressive renal dysfunction with proteinuria. Therefore, she started administration of ORB. However, after switching to ORB, her renal dysfunction progressed. Renal histopathology revealed membranoproliferative glomerulonephritis (MPGN) and thrombotic microangiopathy (TMA). During the clinical course, her renal function deteriorated after administration of ORB and improved after the drug was discontinued because of bone marrow suppression. Moreover, sustained improvement of renal function was observed after complete discontinuation of the drug. This case is considered to be the first report of renal dysfunction due to ORB. Although ORB is not considered to cause renal damage when administered alone, it can be considered to further exacerbate the preceding BEV-induced renal dysfunction. Since switching of anticancer drugs is common, clinicians should be aware of the risk of developing renal dysfunction.

Bleeding is the most important clinical outcome in patients with immune thrombocytopenia (ITP), and the goal of therapy in such cases is to treat or prevent bleeding. The frequency of and risk factors for bleeding events in ITP have only recently been identified in several large-scale studies. However, there is little published information about severe life-threatening bleeding in ITP. To clarify the clinical features of life-threatening bleeding in patients with primary ITP, we systematically reviewed the medical records of all ITP patients that were admitted to our hospital between January 1, 1992, and December 31, 2015. Of 169 consecutive inpatients with primary ITP, 8 suffered life-threatening bleeding (10 episodes: gastrointestinal, 4 cases; pulmonary, 1 case; and intracranial, 5 cases). All of these patients were ≥ 60 years of age and had platelet counts of

Lymphoma-associated hemophagocytic syndrome (LAHS), which is the major subtype of adult-onset secondary hemophagocytic lymphohistiocytosis (HLH), has a poor outcome. Although the early diagnosis and treatment of LAHS contributes to a better outcome, the lack of mass formation and the absence of distinct lymph node enlargement often delay the diagnosis of underlying lymphoma. A recent study, which statistically analyzed HLH cases in the literature, showed that the serum soluble interleukin-2 receptor (sIL-2R)/ferritin ratio could be used as a marker to diagnosis of LAHS. To verify this finding, we retrospectively analyzed the laboratory findings of 21 patients with HLH (10 benign disease-associated HLH and 11 LAHS). No significant differences were observed in the levels of LDH or CRP levels. The mean sIL-2R levels (units per milliliter) were significantly higher in the LAHS group (4,176 vs. 13,451, p = 0.0031), and ferritin levels (nanogram per milliliter) were higher in the benign disease-associated HLH group (20,462 vs. 2,561, p = 0.0031). Consequently, the mean serum sIL-2R/ferritin ratio of patients with LAHS was markedly higher than that of patients with benign disease-associated HLH (0.66 vs. 8.56, p = 0.0004). Thus, the results of this study demonstrated that the serum sIL-2R/ferritin ratio is a very useful marker for diagnosing of LAHS, which was further supported by clinical case analysis. Further studies to clarify the pathophysiology of secondary HLH caused by various triggers are needed.

A novel production process of biodiesel fuel was developed using an expanded-bed reactor packed with an anion-exchange resin having catalytic and adsorption abilities. Waste cooking oil was used as a cheaper feedstock, and methanol was added at the stoichiometric molar ratio of 3:1. The main constituent of the feedstock, triglyceride was completely converted to the biodiesel by the resin’s catalytic ability. The impurities of the feedstock, free fatty acid, water, and dark brown pigment were removed from the product by the adsorption on the resin. In addition, the by-product glycerin was also removed from the product by the adsorption on the resin. The product eluted from the reactor was directly used for the standard tests of the biodiesel properties. The eluted product almost met the biodiesel quality standards (EN14214 in Europe and ASTM D6751 in North America). Thus, the proposed system permitted the simple production of biodiesel from the waste cooking oil without the upstream processing to remove the impurities (free fatty acid and water) and the downstream processing to remove the catalyst and by-products (glycerin and soap).

The Tax protein encoded by human T-cell leukaemia virus type 1 (HTLV-1) has a pivotal role in T-cell transformation by deregulating cellular signalling pathways. Using the yeast two-hybrid system to screen a human leukocyte cDNA library, we identified BCL6 (B-cell lymphoma 6) as a cellular protein, which interacts with Tax 1. The BCL6 gene encodes a sequence-specific transcriptional repressor that contains a conserved N-terminal poxvirus and zinc finger (POZ) repressor domain and a C-terminal Kruppel-like zinc finger DNA binding domain. Using both in vivo and in vitro methods, we demonstrate that the POZ domain of BCL6 is sufficient for its interaction with Tax 1. Using functional assays, we demonstrate that Tax 1 enhanced the repressive activity of BCL6 and increased the levels of apoptosis induced by BCL6 in osteosarcoma cells indicating that both proteins cooperate in vivo to cause a physiological affect. Furthermore, BCL6 recruited Tax 1 into punctate nuclear structures, which suggests that Tax 1 colocalizes with BCL6 in repressor complexes in vivo. BCL6 expression significantly downregulated both basal and Tax-induced nuclear factor-kappaB and long terminal repeat activation. This suggests that the expression of BCL6 in HTLV infected cells may contribute to the silencing of viral gene expression and to the long clinical latency associated with HTLV infection.

Background Appropriate parental care by fathers greatly facilitates health in human family life. Much less is known from animal studies regarding the factors and neural circuitry that affect paternal behavior compared with those affecting maternal behavior. We recently reported that ICR mouse sires displayed maternal-like retrieval behavior when they were separated from pups and caged with their mates (co-housing) because the sires receive communicative interactions via ultrasonic and pheromone signals from the dams. We investigated the brain structures involved in regulating this activity by quantifying c-Fos-immunoreactive cells as neuronal activation markers in the neural pathway of male parental behavior. Results c-Fos expression in the medial preoptic area (mPOA) was significantly higher in sires that exhibited retrieval behavior (retrievers) than those with no such behavior (non-retrievers). Identical increased expression was found in the mPOA region in the retrievers stimulated by ultrasonic vocalizations or pheromones from their mates. Such increases in expression were not observed in the ventral tegmental area (VTA), nucleus accumbens (NAcc) or ventral palladium (VP). On the following day that we identified the families of the retrievers or non-retrievers, c-Fos expression in neuronal subsets in the mPOA, VTA, NAcc and VP was much higher in the retriever sires when they isolated together with their mates in new cages. This difference was not observed in the singly isolated retriever sires in new cages. The non-retriever sires did not display expression changes in the four brain regions that were assessed. Conclusion The mPOA neurons appeared to be activated by direct communicative interactions with mate dams, including ultrasonic vocalizations and pheromones. The mPOA-VTA-NAcc-VP neural circuit appears to be involved in paternal retrieval behavior.

Hemophagocytic lymphohistiocytosis/hemophagocytic syndrome (HLH/HPS) is a reactive disorder of the mononuclear phagocytic system, characterized by generalized histiocytic proliferation with marked hemophagocytosis in the bone marrow [1]. It comprises two different categories: a primary (genetic) and a secondary (acquired) form. Malignant neoplasm-associated HPS (MAHS) is categorized as a secondary HLH. MAHS is mainly associated with lymphoma and rarely with other carcinomas [2]. To our knowledge, HLH associated with myelodysplastic syndromes (MDS) has not been described, although MDS with hemophagocytosis has been observed. Here, we describe a case of HLH associated with MDS, which presented with abundant CD8 T cells in the bone marrow and elevated plasma-soluble interleukin 2 receptor (sIL-2R). A 60-year-old Japanese man was admitted with pancytopenia, epitaxis, fever and general fatigue. A hematological examination showed a hemoglobin concentration of 6.5 g/dL, a platelet count of 14,000/lL and a leukocyte count of 3,200/lL with 42.8% atypical lymphocytes (Fig. 1a). Blood biochemistry showed increased levels of lactate dehydrogenase (LDH) (331 IU/L), ferritin (649 ng/mL) and sIL-2R (4,054 U/mL). NK cytolytic activity was measured by the standard 51-chromium (Cr) release assay. NK cytolytic activity was not reduced at both the E/T ratios of 10:1 (13.1%, normal range 8.9–29.5%) and 20:1 (22.5%, normal range 17.1–48.7%). Serological studies for hepatitis B, hepatitis C and HTLV-1 were negative. IgM antibodies to parvovirus were negative. Serological test for EBV revealed that anti-viral capsid antigen IgM was negative in the presence of anti-viral capsid antigen IgG (1609) and anti-EBV nuclear antigen antibody (409). The number of EBV DNA copies in serum was under 2.0 9 10 copies/mL (normal \200 copies/mL). Computed tomography (CT) revealed hepato-splenomegaly, ascites and bilateral pleural effusion. Bone marrow aspirate showed dyserythropoietic changes (abnormally lobulated nuclei) (Fig. 1c) and dysplastic megakaryocytes (micromegakaryocytes) (Fig. 1d). Erythrocytic precursors were 10.4% and bone marrow myeloblasts were 2.0% (Fig. 1e). Chromosome analysis showed severe complex karyotype: 54–57XY, ?1[2],?3[2],?4[4],?6[4],?8[4],add(9)(p22)[2],?11[3],add (15)(p11.2)[4],add(16)(q24)[4],add(19)(p13.1)[4],add(20) (p13)[4],?21[2],2–5mar[cp4]/46,XY[8]. A diagnosis of refractory anemia with excess blasts-1 (WHO classification) was made. In addition, bone marrow examination revealed increased numbers of atypical lymphocytes (Fig. 1b) and multiple sites of active hemophagocytosis (Fig. 2a–c). Atypical lymphocytes in bone marrow were positive for CD2, CD3 (surface, cytoplasmic), CD5, CD7, CD8, HLA-DR, TCR-ab, and negative for CD4. No monoclonal rearrangement of TCR beta, gamma and delta chain genes was detected by Southern blotting. These findings suggested that the atypical lymphocytes were reactive CD8 T cells. Combining fever, hemophagocytosis, splenomegaly, increased levels of ferritin and sIL-2R, a diagnosis of HLH was established. Although steroid therapy was administered for HLH, pancytopenia was not improved. Two months after the initial diagnosis, the levels of LDH and ferritin were further elevated (LDH 1,474 U/mL, ferritin 4,347 ng/mL). Bone marrow examination T. Tsuji (&) H. Yamasaki H. Tsuda Division of Hematology and Oncology, Kumamoto City Hospital, Kotoh 1-1-60, Kumamoto 862-8505, Japan e-mail: tsuji.takahiro@city.kumamoto.lg.jp