Fukuoka University Hospital

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Introduction: Intravenous(IV) immunoglobulin(Ig) treatment is known to alleviate behavioral deficits in the experimentally induced model of sepsis. To delineate the mechanisms by which IVIg treatment prevents neuronal dysfunction, an array of immunological and apoptosis markers was investigated. Methods: Sepsis was induced by cecal ligation perforation(CLP) in rats. The animals were divided into five groups; sham, control, CLP + saline, CLP + immunoglobulin G IgG(250 mg/kg,iv), and CLP + immunoglobulins enriched with immunoglobulin M-IgGAM(250 mg/kg,iv). Blood and brain samples were taken in two sets of experiments after CLP to see the early(24 hrs) and late(10 days) effects of treatment. Total complement activity, complement 3(C3) and soluble complement C5b-9 levels were measured in sera of rats using ELISA-based methods. Cerebral complement content was analyzed by Western Blot. Immune cell infiltration and gliosis were examined by immunohistochemistry using cluster of differentiation 3, CD4, CD8, CD11b, CD19 and glial fibrillary acidic protein antibodies. Apoptotic neuronal death was investigated by TUNEL staining and Western Blot-based semi-quantitative evaluation of brain homogenates by bax and bcl-2 antibodies. Results: IV IgG and IgGAM administration significantly reduced systemic complement activity but increased serum C3 and soluble C5b-9 levels. Likewise, Western Blot data showed slightly increased C5b-9 expression and significantly reduced C1q expression in brain samples of IgGAM-treated but not IgG-treated septic rats especially in the first day of administration. No cerebral cellular infiltrates were observed in treated and non-treated septic rats. By contrast, IV IgG and IgGAM treatment induced considerable amelioration in glial cell proliferation which was increased in non-treated rats. IgG and IgGAM treated rats exhibited significantly reduced numbers of apoptotic neurons and cerebral expression levels of bax and bcl-2 as compared to nontreated rats. Conclusions: We suggest that IV IgG and IgGAM administration ameliorates neuronal dysfunction and behavioral deficits by reducing apoptotic cell death and glial cell proliferation. IgGAM treatment might be suppressing classical complement pathway by reducing C1q expression.

Emmprin (basigin, CD147) is a cell surface glycoprotein that belongs to the immunoglobulin superfamily. It is highly expressed on the surface of tumor cells and stimulates adjacent fibroblasts or tumor cells to produce matrix metalloproteinases. Moreover, it has recently been shown that emmprin also stimulates expression of vascular endothelial growth factor and hyaluronan, which leads to angiogenesis and anchorage-independent growth/multidrug resistance, respectively. These findings have made emmprin an important molecule in tumor progression and, thus, more attractive as a target for antitumor treatment. However, other functions of emmprin, including as an activator of T cells, a chaperone for monocarboxylate transporters, a receptor for cyclophilin A and a neural recognition molecule, are also being identified in physiological and pathological conditions. Therefore, it is essential to develop specific means to control particular functions of emmprin, for which elucidation of each mechanism is crucial. This review will discuss the role of emmprin in tumor progression and recent advances in the molecular mechanisms of diverse phenomena regulated by emmprin.

BACKGROUND AND PURPOSE: It has been speculated that the same type of hypertensive small-artery disease can cause either intracerebral hemorrhages or ischemic lesions, depending on the circumstances. METHODS: To test this hypothesis, we examined the association between spontaneous intracerebral hematomas and both small chronic hemorrhages and ischemic lesions using echo planar and T2-weighted MRI. We considered a hypointense area to represent a hemorrhage and a hyperintense area to represent an ischemic lesion. RESULTS: We identified small hypointense lesions in 56.7% of 30 patients with intracerebral hematomas (mean age, 62.2 years; total number of lesions, 108) and in 25.4% of 59 patients without hematomas (mean age, 67.6 years; total lesions, 28). The incidence of hypertension was 88.3% in patients with intracerebral hematomas and 42.3% in those without. The hypointense lesions were found in 56.0% of 50 patients with hypertension, whereas they were found only in 10.3% of 39 patients without hypertension. The hypointense lesions were most common in the subcortex, followed by the putamen, pons, thalamus, and cerebellum. The hyperintense lesions were of a higher grade in patients with intracerebral hematomas than in those without. The hypointense lesions were commonly surrounded by hyperintense areas. Additionally, in 3 of 3 autopsied brains, we found hemosiderin deposits around arteriosclerotic microvessels and a surrounding small infarction in areas that had appeared as small hypointense lesions surrounded by hyperintensity on MRI. One specimen also had an organized miliary pseudoaneurysm. CONCLUSIONS: Our findings indicate that spontaneous intracerebral hematomas are frequently associated with small chronic hemorrhages, ischemic lesions, and hypertension. We speculate that hypertensive intracerebral hemorrhage may have the same microangiopathic basis as cerebral infarction.

PAD peripheral arterial disease PCI percutaneous coronary intervention peak V O2 peak oxygen uptake PH pulmonary hypertension PVCs premature ventricular contraction QOL quality of life RCT randomized controlled trial RPE rating of perceived exertion SGA Subjective Global Assessment STEMI ST elevation myocardial infarction TG triglyceride TAVI transcatheter aortic valve implantation VAD ventricular assist device V CO2 carbon dioxide output V E minute ventilation V E/V CO2 ventilatory equivalent for carbon dioxide V E vs. V CO2 slope minute ventilation vs. carbon dioxide output slope V O2 oxygen uptake V O2/HR oxygen pulse capacity is assessed by cardiopulmonary exercise testing (CPX), an exercise prescription is prepared based on the risk in terms of severity of illness, and then a treatment and CR plan is established. If CPX cannot be performed due to complications, low physical fitness, or low left ventricular function, exercise capacity should be confirmed by the 6-minute walk test.

This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade ≥ 3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15-plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887.

BACKGROUND: Laparoscopic cholecystectomy is now accepted as a surgical procedure for acute cholecystitis when it is performed by an expert surgeon. There are several lines of strong evidence, such as randomized controlled trials (RCTs) and meta-analyses, supporting the introduction of laparoscopic cholecystectomy for patients with acute cholecystitis. The updated Tokyo Guidelines 2013 (TG13) describe the surgical treatment for acute cholecystitis according to the grade of severity, the timing, and the procedure used for cholecystitis in a question-and-answer format using the evidence concerning surgical management of acute cholecystitis. METHODS AND MATERIALS: Forty-eight publications were selected for a careful examination of their full texts, and the types of surgical management of acute cholecystitis were investigated using this evidence. The items concerning the surgical management of acute cholecystitis were the optimal surgical treatment for acute cholecystitis according to the grade of severity, optimal timing for the cholecystectomy, surgical procedure used for cholecystectomy, optimal timing of the conversion of cholecystectomy from laparoscopic to open surgery, and the complications of laparoscopic cholecystectomy. RESULTS: There were eight RCTs and four meta-analyses concerning the optimal timing of the cholecystectomy. Consequently, it was found that cholecystectomy is preferable early after admission. There were three RCTs and two meta-analyses concerning the surgical procedure, which concluded that laparoscopic cholecystectomy is preferable to open procedures. Literature concerning the surgical treatment according to the grade of severity could not be quoted, because there have been no publications on this topic. Therefore, the treatment was determined based on the general opinions of professionals. CONCLUSION: Surgical management of acute cholecystitis in the updated TG13 is fundamentally the same as in the Tokyo Guidelines 2007 (TG07), and the concept of a critical view of safety and the existence of extreme vasculobiliary injury are added in the text to call the surgeon's attention to the need to reduce the incidence of bile duct injury. Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html.

Background: The risk of cardiovascular disease and mortality in salt-sensitive patients with diabetes mellitus and uncontrolled nocturnal hypertension is high. The SACRA (Sodium-Glucose Cotransporter 2 [SGLT2] Inhibitor and Angiotensin Receptor Blocker [ARB] Combination Therapy in Patients With Diabetes and Uncontrolled Nocturnal Hypertension) study investigated changes in blood pressure (BP) with empagliflozin plus existing antihypertensive therapy. Methods: This multicenter, double-blind, parallel study was conducted in Japan. Adult patients with type 2 diabetes mellitus and uncontrolled nocturnal hypertension receiving stable antihypertensive therapy including angiotensin receptor blockers were randomized to 12 weeks’ treatment with empagliflozin 10 mg once daily or placebo. Clinic BP was measured at baseline and weeks 4, 8, and 12; 24-hour ambulatory BP monitoring was performed at baseline and week 12; and morning home BP was determined for 5 days before each visit. The primary efficacy end point was change from baseline in nighttime BP (ambulatory BP monitoring). Results: One hundred thirty-two nonobese, older patients with well-controlled blood glucose were randomized (mean age 70 years, mean body mass index 26 kg/m 2 ). Empagliflozin, but not placebo, significantly reduced nighttime systolic BP versus baseline (–6.3 mm Hg; P =0.004); between-group difference in change from baseline was –4.3 mm Hg ( P =0.159). Reductions in daytime, 24-hour, morning home, and clinic systolic BP at 12 weeks with empagliflozin were significantly greater than with placebo (–9.5, –7.7, –7.5, and –8.6 mm Hg, respectively; all P ≤0.002). Between-group differences in body weight and glycosylated hemoglobin reductions were significant, but small (–1.3 kg and –0.33%; both P <0.001). At 4 weeks, N-terminal pro-B-type natriuretic peptide levels were reduced to a greater extent in the empagliflozin versus placebo group (–12.1%; P =0.013); atrial natriuretic peptide levels decreased with empagliflozin versus placebo at weeks 4 and 12 (–8.2% [ P =0.008] and –9.7% [ P =0.019]). Changes in antihypertensive medication during the study did not differ significantly between groups. Conclusions: Nonseverely obese older diabetes patients with uncontrolled nocturnal hypertension showed significant BP reductions without marked reductions in glucose with the addition of empagliflozin to existing antihypertensive and antidiabetic therapy. Use of sodium-glucose cotransporter 2 inhibitors in specific groups (eg, those with nocturnal hypertension, diabetes, and high salt sensitivity) could help reduce the risk of heart failure and cardiovascular mortality. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03050229.

Kabuki syndrome is a congenital anomaly syndrome characterized by developmental delay, intellectual disability, specific facial features including long palpebral fissures and ectropion of the lateral third of the lower eyelids, prominent digit pads, and skeletal and visceral abnormalities. Mutations in MLL2 and KDM6A cause Kabuki syndrome. We screened 81 individuals with Kabuki syndrome for mutations in these genes by conventional methods (n = 58) and/or targeted resequencing (n = 45) or whole exome sequencing (n = 5). We identified a mutation in MLL2 or KDM6A in 50 (61.7%) and 5 (6.2%) cases, respectively. Thirty-five MLL2 mutations and two KDM6A mutations were novel. Non-protein truncating-type MLL2 mutations were mainly located around functional domains, while truncating-type mutations were scattered through the entire coding region. The facial features of patients in the MLL2 truncating-type mutation group were typical based on those of the 10 originally reported patients with Kabuki syndrome; those of the other groups were less typical. High arched eyebrows, short fifth finger, and hypotonia in infancy were more frequent in the MLL2 mutation group than in the KDM6A mutation group. Short stature and postnatal growth retardation were observed in all individuals with KDM6A mutations, but in only half of the group with MLL2 mutations.

The influence of hepatitis C virus (HCV) infection on prognosis and hepatic toxicity in patients with diffuse large B-cell lymphoma in the rituximab era is unclear. Thus, we analyzed 553 patients, 131 of whom were HCV-positive and 422 of whom were HCV-negative, with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-like chemotherapy. Survival outcomes and hepatic toxicity were compared according to HCV infection. The median follow-up was 31 and 32 months for patients who were HCV-positive and HCV-negative, respectively. HCV infection was not a significant risk factor for prognosis (3-year progression-free survival, 69% vs 77%, P = .22; overall survival, 75% vs 84%, P = .07). Of 131 patients who were HCV-positive, 36 (27%) had severe hepatic toxicity (grade 3-4), compared with 13 of 422 (3%) patients who were HCV-negative. Multivariate analysis revealed that HCV infection was a significant risk factor for severe hepatic toxicity (hazard ratio: 14.72; 95% confidence interval, 6.37-34.03; P < .001). An exploratory analysis revealed that pretreatment transaminase was predictive of severe hepatic toxicity. HCV-RNA levels significantly increased during immunochemotherapy (P = .006). These results suggest that careful monitoring of hepatic function and viral load is indicated during immunochemotherapy for HCV-positive patients.

BACKGROUND AND AIMS: Azathioprine (AZA) is associated with a high frequency of adverse reactions. We examined polymorphism of the thiopurine S-methyltransferase (TPMT) gene to determine whether the TPMT genotype would be a predictive marker for the development of adverse reactions to AZA. METHODS: The frequency of TPMT mutations was investigated in 147 Japanese inflammatory bowel disease (IBD) patients retrospectively. In these subjects, the presence of four mutant alleles (TPMT*2, *3B, *3C and *8) was determined by direct sequencing. The incidence of adverse reactions among patients carrying wild-type TPMT was investigated. The blood level of 6-thioguanine nucleotide (6-TGN) was measured and analyzed in 47 patients with wild-type TPMT. The results were analyzed in relation to the concomitant use of aminosalicylates (ASA). RESULTS: Of the 147 patients, 144 (98.0%) were wild-type for TPMT (TPMT*1/*1) and three (2.0%) carried a mutant TPMT allele (TPMT*1/*3C). The incidence of adverse reactions was 33.3% (38/114) in the wild-type group. Leukopenia (WBC < or = 3000/microL) was seen in 15.8% of the patients with wild-type TPMT. 6-TGN levels varied among 47 patients with wild-type TPMT. The blood levels of 6-TGN were significantly higher in the patients receiving concomitant ASA treatment compared with those not receiving concomitant ASA treatment (P = 0.0033). CONCLUSION: The frequency of TPMT gene mutations is low among Japanese IBD patients. The incidence of adverse reactions to AZA was high, even in patients carrying wild-type TPMT. It is concluded that determination of TPMT genotype may not be useful in Japanese IBD patients to predict adverse reactions to AZA.

Proteolytic shedding is an important step in the functional down-regulation and turnover of most membrane proteins at the cell surface. Extracellular matrix metalloproteinase inducer (EMMPRIN) is a multifunctional glycoprotein that has two Ig-like domains in its extracellular portion and functions in cell adhesion as an inducer of matrix metalloproteinase (MMP) expression in surrounding cells. Although the shedding of EMMPRIN is reportedly because of cleavage by metalloproteinases, the responsible proteases, cleavage sites, and stimulants are not yet known. In this study, we found that human tumor HT1080 and A431 cells shed a 22-kDa EMMPRIN fragment into the culture medium. The shedding was enhanced by phorbol 12-myristate 13-acetate and inhibited by TIMP-2 but not by TIMP-1, suggesting the involvement of membrane-type MMPs (MT-MMPs). Indeed, down-regulation of the MT1-MMP expression in A431 cells using small interfering RNA inhibited the shedding. The 22-kDa fragment was purified, and the C-terminal amino acid was determined. A synthetic peptide spanning the cutting site was cleaved by MT1-MMP in vitro. The cleavage site is located in the linker region connecting the two Ig-like domains. The N-terminal Ig-like domain is important for the MMP inducing activity of EMMPRIN and for cell-cell interactions, presumably through its ability to engage in homophilic interactions, and the 22-kDa fragment retained the ability to augment MMP-2 expression in human fibroblasts. Thus, the MT1-MMP-dependent cleavage eliminates the functional N-terminal domain of EMMPRIN from the cell surface, which is expected to down-regulate its function. At the same time, the released 22-kDa fragment may mediate the expression of MMPs in tumor tissues. Proteolytic shedding is an important step in the functional down-regulation and turnover of most membrane proteins at the cell surface. Extracellular matrix metalloproteinase inducer (EMMPRIN) is a multifunctional glycoprotein that has two Ig-like domains in its extracellular portion and functions in cell adhesion as an inducer of matrix metalloproteinase (MMP) expression in surrounding cells. Although the shedding of EMMPRIN is reportedly because of cleavage by metalloproteinases, the responsible proteases, cleavage sites, and stimulants are not yet known. In this study, we found that human tumor HT1080 and A431 cells shed a 22-kDa EMMPRIN fragment into the culture medium. The shedding was enhanced by phorbol 12-myristate 13-acetate and inhibited by TIMP-2 but not by TIMP-1, suggesting the involvement of membrane-type MMPs (MT-MMPs). Indeed, down-regulation of the MT1-MMP expression in A431 cells using small interfering RNA inhibited the shedding. The 22-kDa fragment was purified, and the C-terminal amino acid was determined. A synthetic peptide spanning the cutting site was cleaved by MT1-MMP in vitro. The cleavage site is located in the linker region connecting the two Ig-like domains. The N-terminal Ig-like domain is important for the MMP inducing activity of EMMPRIN and for cell-cell interactions, presumably through its ability to engage in homophilic interactions, and the 22-kDa fragment retained the ability to augment MMP-2 expression in human fibroblasts. Thus, the MT1-MMP-dependent cleavage eliminates the functional N-terminal domain of EMMPRIN from the cell surface, which is expected to down-regulate its function. At the same time, the released 22-kDa fragment may mediate the expression of MMPs in tumor tissues. The extracellular matrix metalloproteinase inducer (EMMPRIN 2The abbreviations used are: EMMPRIN, extracellular matrix metalloproteinase inducer; MMP, matrix metalloproteinase; CM, conditioned medium; ECM, extracellular matrix; HPLC, high performance liquid chromatography; MALDI-TOF, matrix-assisted laser desorption ionization time-of-flight; mAb, monoclonal antibody; MT-MMP, membrane-type MMP; pAb, polyclonal antibody; PMA, phorbol 12-myristate 13-acetate; siRNA, small interfering RNA; TCL, total cell lysate; TIMP, tissue inhibitor of metalloproteinase; Dox, doxycycline; MS/MS, tandem mass spectrometry; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; ELISA, enzyme-linked immunosorbent assay; FACS, fluorescence-activated cell sorter; PBS, phosphate-buffered saline. ; also known as CD147, tumor collagenase-stimulating factor, basigin, and M6) is a multifunctional glycoprotein that belongs to the immunoglobulin superfamily (1Biswas C. Zhang Y. DeCastro R. Guo H. Nakamura T. Kataoka H. Nabeshima K. Cancer Res. 1995; 55: 434-439PubMed Google Scholar, 4Gabison E.E. Hoang-Xuan T. Mauviel A. Menashi S. Biochimie (Paris). 2005; 87: 361-368Crossref PubMed Scopus (244) Google Scholar). EMMPRIN-null mice are sterile and have defects in spermato-genesis, fertilization, sensory and memory functions, and mixed lymphocyte responses (5Igakura T. Kadomatsu K. Kaname T. Muramatsu H. Fan Q.W. Miyauchi T. Toyama Y. Kuno N. Yuasa S. Takahashi M. Senda T. Taguchi O. Yamamura K. Arimura K. Muramatsu T. Dev. Biol. 1998; 194: 152-165Crossref PubMed Scopus (252) Google Scholar, 7Naruhashi K. Kadomatsu K. Igakura T. Fan Q.W. Kuno N. Muramatsu H. Miyauchi T. Hasegawa T. Itoh A. Muramatsu T. Nabeshima T. Biochem. Biophys. Res. Commun. 1997; 236: 733-737Crossref PubMed Scopus (86) Google Scholar). However, the exact mechanisms underlying the observed defects are still largely unknown. The protein backbone of EMMPRIN is 28 kDa, but the molecular mass of the glycosylated form varies between 44 and 66 kDa (4Gabison E.E. Hoang-Xuan T. Mauviel A. Menashi S. Biochimie (Paris). 2005; 87: 361-368Crossref PubMed Scopus (244) Google Scholar). The extracellular portion of EMMPRIN contains two Ig-like motifs and three potential N-glycosylation sites (8Muramatsu T. Miyauchi T. Histol. Histopathol. 2003; 18: 981-987PubMed Google Scholar). EMMPRIN is expressed at high levels in many types of tumors and stromal cells (9Kanekura T. Chen X. Kanzaki T. Int. J. Cancer. 2002; 99: 520-528Crossref PubMed Scopus (285) Google Scholar, 14Dalberg K. Eriksson E. Enberg U. Kjellman M. Backdahl M. World J. Surg. 2000; 24: 334-340Crossref PubMed Google Scholar), and the N-terminal Ig-like domain, which can form homodimers (15Yoshida S. Shibata M. Yamamoto S. Hagihara M. Asai N. Takahashi M. Mizutani S. Muramatsu T. Kadomatsu K. Eur. J. Biochem. 2000; 267: 4372-4380Crossref PubMed Scopus (87) Google Scholar, 16Fadool J.M. Linser P.J. Biochem. Biophys. Res. Commun. 1996; 229: 280-286Crossref PubMed Scopus (41) Google Scholar), may modulate cell-cell interactions within tumor tissues or during metastasis. EMMPRIN is released from tumor cells and acts as an inducer of collagenase (MMP-1) expression in the surrounding stroma and tumor cells (17Biswas C. Cancer Lett. 1984; 24: 201-207Crossref PubMed Scopus (70) Google Scholar, 19Nabeshima K. Lane W.S. Biswas C. Arch. Biochem. Biophys. 1991; 285: 90-96Crossref PubMed Scopus (53) Google Scholar). Matrix metalloproteinases (MMPs) are zinc-binding endopeptidases responsible for the turnover of many proteins in the extracellular space, including those that compose the extracellular matrix (ECM), cell adhesion molecules, cytokines, growth factors, and receptors (20Egeblad M. Werb Z. Nat. Rev. Cancer. 2002; 2: 161-174Crossref PubMed Scopus (5134) Google Scholar). Most tumor types and the surrounding stromal cells overexpress multiple MMPs, which are important players in promoting tumor growth, invasion, and metastasis (20Egeblad M. Werb Z. Nat. Rev. Cancer. 2002; 2: 161-174Crossref PubMed Scopus (5134) Google Scholar). EMMPRIN also induces MMP-2, -3, and -9, MT1-MMP, and MT2-MMP in addition to MMP-1 (9Kanekura T. Chen X. Kanzaki T. Int. J. Cancer. 2002; 99: 520-528Crossref PubMed Scopus (285) Google Scholar, 21Kataoka H. DeCastro R. Zucker S. Biswas C. Cancer Res. 1993; 53: 3154-3158PubMed Google Scholar, 25Tang Y. Kesavan P. Nakada M.T. Yan L. Mol. Cancer Res. 2004; 2: 73-80PubMed Google Scholar); only glycosylated EMMPRIN is able to induce these MMPs (26Sun J. Hemler M.E. Cancer Res. 2001; 61: 2276-2281PubMed Google Scholar), and the N-terminal Ig-like domain is also indispensable for the MMP inducing activity (26Sun J. Hemler M.E. Cancer Res. 2001; 61: 2276-2281PubMed Google Scholar), as well as for the homophilic interactions of the protein (26Sun J. Hemler M.E. Cancer Res. 2001; 61: 2276-2281PubMed Google Scholar). Therefore, EMMPRIN potentially mediates the excessive production of MMPs in tumor tissue and is expected to act as a modulator of ECM in tumor tissues through the activity of the MMPs that it induces. According to the literature, EMMPRIN is released from tumor cells in at least two different ways. A significant amount of intact EMMPRIN is released from tumor cells (27Taylor P.M. Woodfield R.J. Hodgkin M.N. Pettitt T.R. Martin A. Kerr D.J. Wakelam M.J. Oncogene. 2002; 21: 5765-5772Crossref PubMed Scopus (131) Google Scholar, 28Sidhu S.S. Mengistab A.T. Tauscher A.N. LaVail J. Basbaum C. Oncogene. 2004; 23: 956-963Crossref PubMed Scopus (227) Google Scholar), possibly contained within membrane vesicles (microvesicles) that some tumor cells release upon stimulation (28Sidhu S.S. Mengistab A.T. Tauscher A.N. LaVail J. Basbaum C. Oncogene. 2004; 23: 956-963Crossref PubMed Scopus (227) Google Scholar). The other pathway is proteolytic shedding. In addition to inducing MMPs, EMMPRIN is likely to be cleaved and shed by MMPs or other metalloproteinases, because the shedding of EMMPRIN is inhibited by zinc chelators (25Tang Y. Kesavan P. Nakada M.T. Yan L. Mol. Cancer Res. 2004; 2: 73-80PubMed Google Scholar, 29Haug C. Lenz C. Diaz F. Bachem M.G. Arterioscler. Thromb. Vasc. Biol. 2004; 24: 1823-1829Crossref PubMed Scopus (62) Google Scholar). Supporting this, MMP-1 and MMP-2 can cleave EMMPRIN at the membrane-proximal region, at least in vitro (29Haug C. Lenz C. Diaz F. Bachem M.G. Arterioscler. Thromb. Vasc. Biol. 2004; 24: 1823-1829Crossref PubMed Scopus (62) Google Scholar). The proteolytic shedding of EMMPRIN from the cell surface is not only important for regulating EMMPRIN function at the cell surface but is also a mechanism to release a soluble MMP inducer. However, the details of the proteolytic processing of EMMPRIN, such as the responsible proteinases, cleavage sites, and stimulants, is very limited. In this context, MT1-MMP (MMP-14) is an interesting candidate for the EMMPRIN shedding as an integral membrane protease responsible for pericellular proteolysis (30Seiki M. Koshikawa N. Yana I. Cancer Metastasis Rev. 2003; 22: 129-143Crossref PubMed Scopus (73) Google Scholar, 31Itoh Y. Seiki M. J. Cell Physiol. 2006; 206: 1-8Crossref PubMed Scopus (419) Google Scholar). MT1-MMP is expressed in human tumors, and its potential substrates are ECM proteins, such as collagens, fibronectin, laminins, vitronectin, and aggrecan (30Seiki M. Koshikawa N. Yana I. Cancer Metastasis Rev. 2003; 22: 129-143Crossref PubMed Scopus (73) Google Scholar, 31Itoh Y. Seiki M. J. Cell Physiol. 2006; 206: 1-8Crossref PubMed Scopus (419) Google Scholar). Other functional proteins that can be cleaved by MT1-MMP include pro-MMPs, CD44, the integrin αv chain, low density lipoprotein receptor-related protein, interleukin 8, and pro-tumor necrosis factor (32Sato H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Crossref PubMed Scopus (2373) Google Scholar, 37Tam E.M. Morrison C.J. Wu Y.I. Stack M.S. Overall C.M. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 6917-6922Crossref PubMed Scopus (249) Google Scholar). Thus, the proteolytic activity of MT1-MMP is a potent modulator of the pericellular environment and promotes tumor growth and invasion, particularly in 2003; PubMed Scopus Google Scholar). the substrates of MT1-MMP is still but proteins that can be cleaved by MT1-MMP are it from cell and EMMPRIN is the proteins we as N. T. K. T. and M. Thus, we in the that MT1-MMP and EMMPRIN from tumor cells. In this study, we the proteolytic shedding of EMMPRIN by MT1-MMP for the of the three human tumor cell released a small 22-kDa fragment of The shedding was enhanced by of the cells phorbol 12-myristate 13-acetate and inhibited by tissue inhibitor of metalloproteinase but not by TIMP-1, the involvement of Indeed, and in vitro cleavage the involvement of MT1-MMP in EMMPRIN the interesting that MT1-MMP may the expression of MMPs in tumor tissues. and human cell human cell and human cell from the and the cell was from The cell was a from E. cells from to the for in and human cells in and and cells in and expression cell using the expression as H. N. K. H. K. M. Okada Y. Seiki M. Cancer Res. 2004; PubMed Scopus Google Scholar). The cells in and for using to the and TIMP-2 from of and as M. Itoh Y. T. H. Okada A. H. Seiki M. J. Cell Biol. 2001; PubMed Scopus Google Scholar, S. Itoh Y. S. Y. Seiki M. Lett. 2000; PubMed Scopus Google Scholar). The other into using the a to the of human EMMPRIN using the and expression for a form or a form in which was of its by a also an expression for a EMMPRIN fragment to the N-terminal Ig-like domain by a of EMMPRIN or MT1-MMP using the expression the The for MT1-MMP, or and the into cells within the The in the conditioned and using A431 cells. at a of of and the cells and in the of proteins in the conditioned proteins in the and and in cell and proteins in the by and and proteins in the to a membrane the membrane in phosphate-buffered the membrane was a to protein, including an polyclonal an polyclonal an monoclonal an monoclonal and an monoclonal The a and the in of of in of was used to was using of Cell EMMPRIN by A431 cells that MT1-MMP in a The cells in for in the or of The cells and an was used as a The amount of EMMPRIN was a of MT1-MMP and MT2-MMP by RNA interfering the MT1-MMP and MT2-MMP and by and was using the cells in the or of for RNA was using the and at of the was and for MT1-MMP and MT2-MMP by using and the The used and for MT1-MMP, and for and and for the the and of EMMPRIN from the cells that and MT1-MMP in a used to the EMMPRIN shed by MT1-MMP, and cells that used to the EMMPRIN fragment N-terminal Ig-like The cells in for to The the EMMPRIN fragment was an to an monoclonal a the EMMPRIN fragment retained in the was the peptide the was to a and was using an at a of the EMMPRIN fragment and The of the EMMPRIN fragment was and The of the fragment was by using an and a protein was using in a at for of the C-terminal of the EMMPRIN by fragment was of in of for at The was to a and by a from to was and to a of matrix and by matrix-assisted laser desorption ionization mass used to human protein in the using the of the EMMPRIN by MT1-MMP in EMMPRIN peptide was the fragment of human MT1-MMP M. Itoh Y. T. H. Okada A. H. Seiki M. J. Cell Biol. 2001; PubMed Scopus Google in a in the or of synthetic MMP a from at for the to mass of MMP-2 by the EMMPRIN in human cells in a for the culture was to the EMMPRIN fragment or it was for or The amount of MMP-2 in the was using an MMP-2 to the in the cells MT1-MMP in protease inhibitor at for Cell by at for at and the was and at for The and the to the The to and cells MT1-MMP for in the of and in for a step using in PBS, the cells a polyclonal or a and an used as The a laser tissue of human by Y. Okada at and was in for The was by it for in was using a for an a of or at three PBS, used as and a activity was by a of in a which a EMMPRIN in an EMMPRIN is expressed in most human tumor cell used three such cell for study, the human the human and the human the expression of EMMPRIN in cell and its shedding into the using The cells also PMA, because the expression and activity of cell expressed EMMPRIN a molecular mass between 44 and 66 kDa, as and the of the to be at kDa A that presumably an glycosylated form Nabeshima K. Biswas C. Cancer Res. Google was also of the cells not the expression levels or the in the cells. EMMPRIN of the same as the form was in the is that the intact form of EMMPRIN is released into the CM, not this shedding In addition to the intact a small 22-kDa fragment that not was also shed into the of HT1080 and A431 but not cells. enhanced the shedding of the 22-kDa fragment from cell and it was inhibited by a synthetic MMP However, the shedding is not an to because the 22-kDa fragment to stimulation not The shedding of cells was not by or by of the for EMMPRIN the responsible for the EMMPRIN we the of the MMP and soluble MMPs and some and metalloproteinases but not membrane-type TIMP-2 MMPs, including but not most A431 cells in the or of the and the shedding of the 22-kDa fragment the 22-kDa EMMPRIN fragment was in the CM, and its amount was enhanced by TIMP-2 inhibited the shedding but inhibited the as it in the in Thus, the 22-kDa EMMPRIN fragment to be by the of which are to TIMP-2 but not to the of EMMPRIN of was expressed as a form in and EMMPRIN was expressed as a form levels of by Although the expression levels of the MT2-MMP and expressed at levels the the 22-kDa EMMPRIN fragment was in the culture of cells that expressed MT1-MMP or MT2-MMP Thus, at least MT1-MMP and MT2-MMP can induce the shedding of the 22-kDa EMMPRIN the cell used for was by using or HT1080 and A431 cells but not cells expressed MT1-MMP MT2-MMP was in three cell not of the 22-kDa fragment from the cell surface in the of MT1-MMP the amount of EMMPRIN, as by A that for MT1-MMP and MT2-MMP in A431 cells and that expression was three upon of the cells the of the EMMPRIN we using The for MT1-MMP MT1-MMP by and that for MT2-MMP the for MT2-MMP by for the used as a not the the of the shedding from A431 cells of MT1-MMP inhibited shedding of the 22-kDa fragment and down-regulation of MT2-MMP inhibited the shedding. the for MT1-MMP and MT2-MMP the Thus, MT1-MMP to be a protease to EMMPRIN shedding from A431 MT2-MMP also has some of the for the 22-kDa EMMPRIN the 22-kDa EMMPRIN we cells that MT1-MMP the of a of from the culture expression of MT1-MMP The was by the of an which can be inhibited by K. J. H. J. Biochem. J. 1998; PubMed Scopus Google Scholar). The expression levels of EMMPRIN not by of MT1-MMP the shedding of the 22-kDa which was inhibited by it to the 22-kDa the cells to EMMPRIN a at its The 22-kDa fragment was shed upon expression of MT1-MMP The 22-kDa fragment to the intact of the EMMPRIN, because it was by the The of the cells was and the EMMPRIN fragment was a of an using an and a the EMMPRIN fragment was to the the molecular to a the C-terminal amino acid of the the 22-kDa fragment was and the peptide was using mass the EMMPRIN spanning amino and The amino acid of the two the tandem from the the of for and for and not and for and and for and the at the the peptide is not the cleaved by at the Thus, we expected to be the of the 22-kDa fragment The fragment from the expected cleavage site was to be MT1-MMP EMMPRIN at the MT1-MMP EMMPRIN at the expected a synthetic spanning the expected cutting site was and the fragment of MT1-MMP The using mass two that inhibited by not The molecular of the to and and amino acid by tandem not Thus, MT1-MMP is able to cleave EMMPRIN at and we to a fragment cleaved at in the MMP of the 22-kDa EMMPRIN The N-terminal Ig-like domain is in the 22-kDa is to be important for the MMP inducing activity of EMMPRIN, we the shed fragment retained this this we expressed two of EMMPRIN and in cells The fragment to the EMMPRIN fragment the N-terminal Ig-like domain, and is EMMPRIN at the that in the The fragment shed in a multiple presumably in its The of the by a and a protein and by The activity of the in inducing expression of MMP-2 was using human cells. The in the of or for and MMP-2 into the was by MMP-2 was expressed in and its expression was enhanced in a The fragment shed from production of MMP-2 to a Thus, the 22-kDa fragment the MMP inducing of MT1-MMP and EMMPRIN in Cancer and for the cleavage to MT1-MMP and EMMPRIN be expected to in the same of the cells. Indeed, have that these proteins at (30Seiki M. Koshikawa N. Yana I. Cancer Metastasis Rev. 2003; 22: 129-143Crossref PubMed Scopus (73) Google Scholar, S. M. J.M. H. Zucker S. P. J. PubMed Scopus Google Scholar), but has not yet used of A431 cells the form of MT1-MMP to the of the proteins, as in the in A was also observed HT1080 cells not of the proteins was by the that of MT1-MMP also EMMPRIN from the cell the same used as a was not EMMPRIN and MT1-MMP have to be in a of human the proteins are in the same tumors, we of human and to A of is in expression of MT1-MMP was in some and cells EMMPRIN was in most of the cells at the tumor cell Although EMMPRIN from the MT1-MMP in in cells and in the MT1-MMP and EMMPRIN are at least expressed in cells from the same EMMPRIN is shed through the release of or by proteolytic In this study, we the release of the intact form (27Taylor P.M. Woodfield R.J. Hodgkin M.N. Pettitt T.R. Martin A. Kerr D.J. Wakelam M.J. Oncogene. 2002; 21: 5765-5772Crossref PubMed Scopus (131) Google Scholar, 28Sidhu S.S. Mengistab A.T. Tauscher A.N. LaVail J. Basbaum C. Oncogene. 2004; 23: 956-963Crossref PubMed Scopus (227) Google and a EMMPRIN fragment in the of two tumor cell and of the 22-kDa fragment was enhanced by that of the intact form was In tumor cell not shed the 22-kDa fragment at these cells released the intact form of that MT1-MMP is the responsible for the shedding of the 22-kDa fragment for the we from that HT1080 and A431 cells MT1-MMP, but cells not H. T. Koshikawa N. M. Itoh Y. H. H. Yana I. Seiki M. J. 2002; 21: PubMed Scopus Google Scholar, T. K. Itoh Y. Yana I. Seiki M. Mol. Cancer 2005; PubMed Scopus Google Scholar). the and of the shedding well the of (30Seiki M. Koshikawa N. Yana I. Cancer Metastasis Rev. 2003; 22: 129-143Crossref PubMed Scopus (73) Google Scholar). the expression and activity of MT1-MMP are to be enhanced by K. J. H. J. Biochem. J. 1998; PubMed Scopus Google Scholar). we EMMPRIN as a protein possibly MT1-MMP in a not MT1-MMP was to be expressed in A431 and of the expression using inhibited the shedding MT2-MMP may also to the shedding because of MT1-MMP and MT2-MMP expression HT1080 cells not Thus, MT1-MMP to be a to the shedding of the 22-kDa EMMPRIN In in vitro proteolytic cleavage to the shedding of EMMPRIN was to at the region of the to the membrane (25Tang Y. Kesavan P. Nakada M.T. Yan L. Mol. Cancer Res. 2004; 2: 73-80PubMed Google Scholar, 29Haug C. Lenz C. Diaz F. Bachem M.G. Arterioscler. Thromb. Vasc. Biol. 2004; 24: 1823-1829Crossref PubMed Scopus (62) Google Scholar), the released into the not The 22-kDa fragment we not in because the 22-kDa fragment be by that the membrane-proximal region of the C-terminal amino acid of the 22-kDa fragment as and MT1-MMP cleaved at this in an in vitro Although an cleavage site was observed in the MT1-MMP in the fragment was not by mass of the fragment from the of EMMPRIN by MT1-MMP the total amount of EMMPRIN as by Thus, the shedding of EMMPRIN by MT1-MMP to be a mechanism for protein turnover at the cell surface. The is located in the linker connecting the two Ig-like that the 22-kDa EMMPRIN fragment contains the Ig-like domain has to be indispensable for the MMP inducing activity and for homophilic interactions (26Sun J. Hemler M.E. Cancer Res. 2001; 61: 2276-2281PubMed Google Scholar). Thus, the shedding may down-regulate the functions by EMMPRIN, because MT1-MMP the important N-terminal Ig-like may be particularly important at the because of the proteins The 22-kDa fragment retained the MMP inducing activity suggesting the that MT1-MMP acts as a to MMP expression in tumor by the 22-kDa EMMPRIN In addition to shedding the 22-kDa EMMPRIN three tumor cell released the intact form of EMMPRIN, presumably released from the cells intact form is also expected to the MMP inducing not at this these two of the MMP inducer have some in or The intact form of EMMPRIN is glycosylated the 22-kDa and the EMMPRIN are the Thus, it may be for the intact form of EMMPRIN to cells that can be by the 22-kDa is a that the responsible for shedding the cell and the stimulants tumor cells have to release a soluble EMMPRIN (25Tang Y. Kesavan P. Nakada M.T. Yan L. Mol. Cancer Res. 2004; 2: 73-80PubMed Google Scholar), we have not able to this fragment in the cells in the and not EMMPRIN induces expression of MMP In high of EMMPRIN fragment for of MMP-2 may that the MMP inducing activity of the 22-kDa fragment not have or that the inducer only in the of The shedding of EMMPRIN in to MT1-MMP stimulation may be important as a mechanism to down-regulate EMMPRIN function the cell surface as an MMP inducer. In we MT1-MMP as the responsible for the shedding of MT1-MMP cleaved the N-terminal Ig-like domain that is important for MMP and cell-cell the released 22-kDa fragment acts as an MMP MT1-MMP may an in the of MMP expression in tumor and for and and for

KCNT1 mutations have been found in epilepsy of infancy with migrating focal seizures (EIMFS; also known as migrating partial seizures in infancy), autosomal dominant nocturnal frontal lobe epilepsy, and other types of early onset epileptic encephalopathies (EOEEs). We performed KCNT1-targeted next-generation sequencing (207 samples) and/or whole-exome sequencing (229 samples) in a total of 362 patients with Ohtahara syndrome, West syndrome, EIMFS, or unclassified EOEEs. We identified nine heterozygous KCNT1 mutations in 11 patients: nine of 18 EIMFS cases (50%) in whom migrating foci were observed, one of 180 West syndrome cases (0.56%), and one of 66 unclassified EOEE cases (1.52%). KCNT1 mutations occurred de novo in 10 patients, and one was transmitted from the patient's mother who carried a somatic mosaic mutation. The mutations accumulated in transmembrane segment 5 (2/9, 22.2%) and regulators of K(+) conductance domains (7/9, 77.8%). Five of nine mutations were recurrent. Onset ages ranged from the neonatal period (<1 month) in five patients (5/11, 45.5%) to 1-4 months in six patients (6/11, 54.5%). A generalized attenuation of background activity on electroencephalography was seen in six patients (6/11, 54.5%). Our study demonstrates that the phenotypic spectrum of de novo KCNT1 mutations is largely restricted to EIMFS.

OBJECTIVE: We tried to identify indications for cerebrospinal fluid shunting in patients with normal pressure hydrocephalus. METHODS: We studied the cerebral blood flow (CBF) and vascular response to acetazolamide in the white matter, cortex, and thalamus of 21 patients with normal pressure hydrocephalus, comparing patients who improved clinically after shunting with those who did not. We used xenon-enhanced computed tomography for the CBF measurements. RESULTS: Preoperatively, both groups had globally reduced CBF, but the reduction was more pronounced in the unimproved patients. The vascular response was impaired only in the white matter of the patients who improved later. After shunting, restoration of CBF, more marked in the white matter, and recovery of vascular response in the white matter paralleled clinical improvement and a reduction in ventricular dilation and periventricular lucency on computed tomographic scans in nine patients. The CBF reduction, however, deteriorated in the 12 patients who did not improve clinically. CONCLUSION: We conclude that the underlying disease in the improved patients was ischemia, with a loss of autoregulatory capacity in the periventricular white matter caused by cerebrospinal fluid diffusion. Those who did not improve had irreversible brain damage in which the CBF reduction was secondary to metabolic depression and autoregulation was preserved. We also conclude that patients suspected of having normal pressure hydrocephalus will improve clinically after shunting if preoperative hemispheric CBF is greater than 20 ml/100 g per minute and the vascular response to acetazolamide is impaired only in the periventricular white matter. They will not improve, however, if the preoperative CBF is less than 20 ml/100 g per minute and the vascular response to acetazolamide is intact.

BACKGROUND: Homozygous deletion of 9p21 detected by fluorescence in situ hybridization (FISH) and loss of BRCA1-associated protein 1 (BAP1) expression detected by immunohistochemistry (IHC) are useful for the differentiation between malignant pleural mesothelioma (MPM) and reactive mesothelial hyperplasia. The authors previously described that IHC expression of the protein product of the methylthioadenosine phosphorylase (MTAP) gene, which is localized in the 9p21 chromosomal region, was correlated with the deletion status of 9p21 FISH in MPM tissues. In the current study, the authors investigated whether a combination of MTAP and BAP1 IHC could distinguish MPM from reactive mesothelial cells (RMC) in cell blocks obtained from pleural effusions. METHODS: The authors examined IHC expression of MTAP and BAP1 in cell blocks obtained from pleural effusions of 45 cases of MPM and 21 cases of reactive mesothelial hyperplasia. Furthermore, IHC expression of MTAP was compared with the deletion status of 9p21 FISH. RESULTS: MTAP and BAP1 IHC differentiated MPM from RMC with 100% specificity for both and sensitivities of 42.2% and 60.0%, respectively. The combination of MTAP and BAP1 IHC yielded a sensitivity of 77.8%, which was higher than that of BAP1 IHC alone or 9p21 FISH alone (62.2%). Moreover, a high degree of concordance was observed between the results of MTAP IHC and 9p21 FISH in cell blocks. CONCLUSIONS: A combination of MTAP and BAP1 IHC in cell blocks from pleural effusions appears to be a reliable and useful method for differentiating MPM cells from RMC and can be used in the routine diagnosis of MPM. Cancer Cytopathol 2018;126:54-63. © 2017 American Cancer Society.

After stroke, peripheral immune cells are activated and these systemic responses may amplify brain damage, but how the injured brain sends out signals to trigger systemic inflammation remains unclear. Here we show that a brain-to-cervical lymph node (CLN) pathway is involved. In rats subjected to focal cerebral ischemia, lymphatic endothelial cells proliferate and macrophages are rapidly activated in CLNs within 24 h, in part via VEGF-C/VEGFR3 signalling. Microarray analyses of isolated lymphatic endothelium from CLNs of ischemic mice confirm the activation of transmembrane tyrosine kinase pathways. Blockade of VEGFR3 reduces lymphatic endothelial activation, decreases pro-inflammatory macrophages, and reduces brain infarction. In vitro, VEGF-C/VEGFR3 signalling in lymphatic endothelial cells enhances inflammatory responses in co-cultured macrophages. Lastly, surgical removal of CLNs in mice significantly reduces infarction after focal cerebral ischemia. These findings suggest that modulating the brain-to-CLN pathway may offer therapeutic opportunities to ameliorate systemic inflammation and brain injury after stroke.

BACKGROUND: Laparoscopic surgery for rectal cancer is widely performed all over the world and several randomized controlled trials have been reported. However, the usefulness of laparoscopic surgery compared with open surgery has not been demonstrated sufficiently, especially for the low rectal area. OBJECTIVE: The aim of this study was to investigate the hypothesis that laparoscopic primary tumor resection is safe and effective when compared with the open approach for locally advanced low rectal cancer. PATIENTS AND METHODS: Data from patients with clinical stage II to III low rectal cancer below the peritoneal reflection were collected and analyzed. The operations were performed from 2010 to 2011. Short-term outcomes and long-term prognosis were analyzed with propensity score matching. RESULTS: Of 1608 cases collated from 69 institutes, 1500 cases were eligible for analysis. The cases were matched into 482 laparoscopic and 482 open cases. The mean height of the tumor from the anal verge was 4.6 cm. Preoperative treatment was performed in 35% of the patients. The conversion rate from laparoscopic to open surgery was 5.2%. Estimated blood loss during laparoscopic surgery was significantly less than that during open surgery (90 vs 625 mL, P < 0.001). Overall, the occurrence of complications after laparoscopic surgeries was less than that after open surgeries (30.3% vs 39.2%, P = 0.005). Three-year overall survival rates were 89.9% [95% confidence interval (95% CI) 86.7-92.4] and 90.4% (95% CI 87.4-92.8) in the laparoscopic and open groups, respectively, and no significant difference was seen between the 2 groups. No significant difference was observed in recurrence-free survival (RFS) between the 2 groups (3-year RFS: 70.9%, 68.4 to 74.2 vs 71.8%, 67.5 to 75.7). CONCLUSION: Laparoscopic surgery could be considered as a treatment option for advanced, low rectal cancer below the peritoneal reflection, based on the short-term and long-term results of this large cohort study (UMIN-ID: UMIN000013919).

Investigating the role of host genetic factors in COVID-19 severity and susceptibility can inform our understanding of the underlying biological mechanisms that influence adverse outcomes and drug development 1 , 2 . Here we present a second updated genome-wide association study (GWAS) on COVID-19 severity and infection susceptibility to SARS-CoV-2 from the COVID-19 Host Genetic Initiative (data release 7). We performed a meta-analysis of up to 219,692 cases and over 3 million controls, identifying 51 distinct genome-wide significant loci—adding 28 loci from the previous data release 2 . The increased number of candidate genes at the identified loci helped to map three major biological pathways that are involved in susceptibility and severity: viral entry, airway defence in mucus and type I interferon.

Patients with cancer should appropriately receive antiemetic therapies against chemotherapy-induced nausea and vomiting (CINV). Antiemetic guidelines play an important role in managing CINV. Accordingly, the first Japanese antiemetic guideline published in 2010 by the Japan Society of Clinical Oncology (JSCO) has considerably aided Japanese medical staff in providing antiemetic therapies across chemotherapy clinics. With the yearly advancements in antiemetic therapies, the Japanese antiemetic guidelines require revisions according to published evidence regarding antiemetic management worldwide. A revised version of the first antiemetic guideline that considered several upcoming evidences had been published online in 2014 (version 1.2), in which several updated descriptions were included. The 2015 JSCO clinical practice guideline for antiemesis (version 2.0) (in Japanese) has addressed clinical antiemetic concerns and includes four major revisions regarding (1) changes in emetogenic risk categorization for anti-cancer agents, (2) olanzapine usage as an antiemetic drug, (3) the steroid-sparing method, and (4) adverse drug reactions of antiemetic agents. We herein present an English update summary for the 2015 JSCO clinical practice guideline for antiemesis (version 2.0).

This study evaluated the clinical features of 276 patients with aggressive adult T-cell leukaemia-lymphoma (ATL) in 3 Japan Clinical Oncology Group (JCOG) trials. We assessed the long-term survivors who survived >5 years and constructed a prognostic index (PI), named the JCOG-PI, based on covariates obtained by Cox regression analysis. The median survival time (MST) of the entire cohort was 11 months. In 37 patients who survived >5 years, no disease-related deaths in 10 patients with lymphoma-type were observed in contrast to the 10 ATL-related deaths in other types. In multivariate analysis of 193 patients, the JCOG-PI based on corrected calcium levels and performance status identified moderate and high risk groups with an MST of 14 and 8 months respectively (hazard ratio, 1·926). The JCOG-PI was reproducible in an external validation. Patients with lymphoma-type who survived >5 years might have been cured. The JCOG-PI is valuable for identifying patients with extremely poor prognosis and will be useful for the design of future trials combining new drugs or investigational treatment strategies.