Chosen Ciphertext Secure Keyed Two-Level Homomorphic Encryption

Homomorphic encryption (HE) is a useful variant of public key encryption (PKE), but it has a drawback that HE cannot fully achieve IND-CCA2 security, which is a standard security notion for PKE. Beyond existing HE schemes achieving weaker IND-CCA1 security, Emura et al.\ (PKC 2013) proposed the notion of \lq\lq keyed\rq\rq{} version of HE, called KH-PKE, which introduces an evaluation key controlling the functionality of homomorphic operations and achieves security stronger than IND-CCA1 and as close to IND-CCA2 as possible. After Emura et al.\u27s scheme which can evaluate linear polynomials only, Lai et al.\ (PKC 2016) proposed a fully homomorphic KH-PKE, but it requires indistinguishability obfuscation and hence has a drawback in practical feasibility. In this paper, we propose a \lq\lq two-level\rq\rq{} KH-PKE scheme for evaluating degree-two polynomials, by cleverly combining Emura et al.\u27s generic framework with a recent efficient two-level HE by Attrapadung et al.\ (ASIACCS 2018). Our scheme is the first KH-PKE that can handle non-linear polynomials while keeping practical efficiency

Spondylolysis with pedicle fracture

We describe successful surgical treatment in a case of L5 unilateral spondylolysis with contralateral pedicle stress fracture that was not resolved by conservative treatment in a high-performing college baseball player. The 20-year-old man presented with left low back pain that stopped his sports activities. Over the previous year, he had experienced a couple of episodes of pain that subsided with cessation of sports but reappeared after a return to sports. Computed tomography and magnetic resonance imaging revealed a right terminal stage pars fracture and a left pedicle stress fracture at L5. The pain originated from the left pedicle fracture, with no pain from the right unilateral spondylolysis. Given that conservative treatment for 1 year had not been effective, we decided on surgical treatment. Bilateral pedicle screws and the smiley face rod method were applied, and both fractures subsequently healed. In the 2 years since the surgery, the patient has returned to sports and has the potential to become a professional player

レゾルシル酸ラクトンLL-Z1640-2の成人T細胞白血病/リンパ腫に対する治療効果

Adult T-cell leukaemia/lymphoma (ATL) remains incurable. The NF-κB and interferon regulatory factor 4 (IRF4) signalling pathways are among the critical survival pathways for the progression of ATL. TGF-β-activated kinase 1 (TAK1), an IκB kinase-activating kinase, triggers the activation of NF-κB. The resorcylic acid lactone LL-Z1640-2 is a potent irreversible inhibitor of TAK1/extracellular signal-regulated kinase 2 (ERK2). We herein examined the therapeutic efficacy of LL-Z1640-2 against ATL. LL-Z1640-2 effectively suppressed the in vivo growth of ATL cells. It induced in vitro apoptosis and inhibited the nuclear translocation of p65/RelA in ATL cells. The knockdown of IRF4 strongly induced ATL cell death while downregulating MYC. LL-Z1640-2 as well as the NF-κB inhibitor BAY11-7082 decreased the expression of IRF4 and MYC at the protein and mRNA levels, indicating the suppression of the NF-κB-IRF4-MYC axis. The treatment with LL-Z1640-2 also mitigated the phosphorylation of p38 MAPK along with the expression of CC chemokine receptor 4. Furthermore, the inhibition of STAT3/5 potentiated the cytotoxic activity of LL-Z1640-2 against IL-2-responsive ATL cells in the presence of IL-2. Therefore, LL-Z1640-2 appears to be an effective treatment for ATL. Further studies are needed to develop more potent compounds that retain the active motifs of LL-Z1640-2

HTVL‐1キャリアへの免疫抑制療法中に発症したATLL

A ６４-year-old woman presented with lower leg edema, fever, and bilateral joint pain, involving the wrists, fingers, and knees, in April ２０１X. Serological test results were negative for rheumatoid factor, antinuclear antibody, and anti-cyclic citrullinated peptide antibody. A diagnosis of remitting seronegative symmetrical synovitis with pitting edema syndrome, a type of seronegative rheumatoid arthritis, was made and prednisolone was administered. The joint pain was refractory to prednisolone therapy. In February, ２０１X＋２, the patient presented with right cervical lymphadenopathy. The CT scan revealed swelling of the cervical, axillary, and inguinal lymph nodes bilaterally and rapidly enlarged. In April, １８F-fluorodeoxyglucose PET/CT scan showed an abnormal collection in the enlarged lymph nodes. The patient subsequently developed hoarseness with dyspnea and attended our department. Blood test results showed high levels of lactate dehydrogenase （５４７U/L） and soluble interleukin‐２ receptor （３４２００ IU/L） and were positive for anti-human T-cell leukemia virus type１ （HTLV‐１） antibody. Biopsy of the right cervical lymph node showed proliferation of abnormal lymphoid cells positive for CD３, CD４, and CD２５ and negative for CD７. Monoclonal integration of HTLV‐１ proviral DNA was detected in the lymph node. A diagnosis of adult T-cell leukemia/lymphoma （ATLL）, lymphoma type was made. The pain involving multiple joints was attributed to HTLV‐１associated arthropathy. Immunosuppressive therapy for HTLV‐１ carrier status may have played a role in the development of ATLL

NUDT16 is a (deoxy)inosine diphosphatase, and its deficiency induces accumulation of single-strand breaks in nuclear DNA and growth arrest

Nucleotides function in a variety of biological reactions; however, they can undergo various chemical modifications. Such modified nucleotides may be toxic to cells if not eliminated from the nucleotide pools. We performed a screen for modified-nucleotide binding proteins and identified human nucleoside diphosphate linked moiety X-type motif 16 (NUDT16) protein as an inosine triphosphate (ITP)/xanthosine triphosphate (XTP)/GTP-binding protein. Recombinant NUDT16 hydrolyzes purine nucleoside diphosphates to the corresponding nucleoside monophosphates. Among 29 nucleotides examined, the highest kcat/Km values were for inosine diphosphate (IDP) and deoxyinosine diphosphate (dIDP). Moreover, NUDT16 moderately hydrolyzes (deoxy)inosine triphosphate ([d]ITP). NUDT16 is mostly localized in the nucleus, and especially in the nucleolus. Knockdown of NUDT16 in HeLa MR cells caused cell cycle arrest in S-phase, reduced cell proliferation, increased accumulation of single-strand breaks in nuclear DNA as well as increased levels of inosine in RNA. We thus concluded that NUDT16 is a (deoxy)inosine diphosphatase that may function mainly in the nucleus to protect cells from deleterious effects of (d)ITP

Anti-myeloma Activity by Thiazolidine-2,4-dione compounds

Proviral Integrations of Moloney virus 2 (PIM2) kinase is overexpressed in multiple myeloma (MM) cells, and regarded as an important therapeutic target. Here, we aimed to validate the therapeutic efficacy of different types of PIM inhibitors against MM cells for their possible clinical application. Intriguingly, the thiazolidine 2,4 dione family compounds SMI 16a and SMI 4a reduced PIM2 protein levels and impaired MM cell survival preferentially in acidic conditions, in contrast to other types of PIM inhibitors, including AZD1208, CX 6258 and PIM447. SMI 16a also suppressed the drug efflux function of breast cancer resistance protein, minimized the sizes of side populations, and reduced in vitro colony forming capacity and in vivo tumorigenic activity in MM cells, suggesting impairment of their clonogenic capacity. PIM2 is known to be subject to ubiquitination-independent proteasomal degradation. Consistently, the proteasome inhibitors bortezomib and carfilzomib increased PIM2 protein levels in MM cells without affecting its mRNA levels. However, SMI 16a mitigated the PIM2 protein increase and cooperatively enhanced anti MM effects in combination with carfilzomib. Collectively, the thiazolidine 2,4 dione family compounds SMI 16a and SMI 4a uniquely reduce PIM2 protein in MM cells, which may contribute to their profound efficacy in addition to their immediate kinase inhibition. Their combination with proteasome inhibitors is envisioned

Effective impairment of myeloma cells and their progenitors by hyperthermia

Multiple myeloma (MM) remains incurable, and MM-initiating cells or MM progenitors are considered to contribute to disease relapse through their drug-resistant nature. In order to improve the therapeutic efficacy for MM, we recently developed novel superparamagnetic nanoparticles which selectively accumulate in MM tumors and extirpate them by heat generated with magnetic resonance. We here aimed to clarify the therapeutic effects on MM cells and their progenitors by hyperthermia. Heat treatment at 43°C time-dependently induced MM cell death. The treatment upregulated endoplasmic reticulum (ER) stress mediators, ATF4 and CHOP, while reducing the protein levels of Pim-2, IRF4, c-Myc and Mcl-1. Combination with the proteasome inhibitor bortezomib further enhanced ER stress to potentiate MM cell death. The Pim inhibitor SMI-16a also enhanced the reduction of the Pim-2-driven survival factors, IRF4 and c-Myc, in combination with the heat treatment. The heat treatment almost completely eradicated “side population” fractions in RPMI8226 and KMS-11 cells and suppressed their clonogenic capacity as determined by in vitro colony formation and tumorigenic capacity in SCID mice. These results collectively demonstrated that hyperthermia is able to impair clonogenic drug-resistant fractions of MM cells and enhance their susceptibility to chemotherapeutic drugs

Mycobacterium shinjukuense infection successfully treated with clarithromycin, rifampicin, and ethambutol

We present the case of a 59-year-old woman diagnosed with Mycobacterium shinjukuense infection using mass spectrometry of bronchioalveolar lavage fluid. We initiated treatment with clarithromycin, rifampicin, and ethambutol based on the results of drug susceptibility testing, which improved lung opacities. Most previous cases were treated with the standard regimen for Mycobacterium tuberculosis. However, our regimen may provide a therapeutic option for this rare nontuberculous Mycobacterium infection