Endocervical glandular neoplasia associated with lobular endocervical glandular hyperplasia is HPV-independent and correlates with carbonic anhydrase-IX expression: a Gynaecological Oncology Group Study.

BackgroundLobular endocervical glandular hyperplasia (LEGH) is a rare lesion of the uterine cervix. It has been proposed that LEGH may represent a precursor lesion to a group of mucinous adenocarcinoma with gastric phenotype (GA) that is independent of high-risk human papillomavirus (H-HPV) infection. Carbonic anhydrase-IX (CA-IX) is highly expressed in conventional glandular lesions (CGLs). However, expression of CA-IX in LEGH or GA has not been studied.MethodsIn all, 12 CGLs, 7 LEGHs, 6 LEGHs with coexisting adenocarcinoma in situ (AIS, 3) and GA (3) were identified from Japanese women with a cytological diagnosis of atypical glandular cells of undetermined significance. Immunostaining was used to detect CA-IX and p16(INK)4(a) (hereafter termed p16) protein expression in the tissues and CA-IX protein expression in the Papanicolaou smears (PSs). Polymerase chain reaction was used to detect H-HPV DNA in liquid-based cytology.ResultsOut of 12 (83%) CGLs, 10 were positive with H-HPV and high levels of CA-IX expression were seen in all (100%) cases. P16 protein expression was observed in 11 out of 12 (92%) cases. None of the LEGHs, LEGHs with AIS or GA were positive for H-HPV and only 8 out of 13 (62%) showed focal weak (1+) p16 expression. In contrast, all cases (100%) exhibited strong CA-IX protein expression.ConclusionOur study suggests that there are different molecular mechanisms of carcinogenesis resulting in CGLs vs LEGHs associated with AIS or GA. There is also a possible link between LEGHs and GAs. Furthermore, CA-IX expression may serve as a useful biomarker for the detection of GAs in the absence of H-HPV infection

Long-range heteronuclear J-coupling constants in esters: Implications for 13C metabolic MRI by side-arm parahydrogen-induced polarization

Side-arm parahydrogen induced polarization (PHIP-SAH) presents a cost-effective method for hyperpolarization of 13C metabolites (e.g. acetate, pyruvate) for metabolic MRI. The timing and efficiency of typical spin order transfer methods including magnetic field cycling and tailored RF pulse sequences crucially depends on the heteronuclear J coupling network between nascent parahydrogen protons and 13C, post-parahydrogenation of the target compound. In this work, heteronuclear nJHC (1 < n ≤ 5) couplings of acetate and pyruvate esters pertinent for PHIP-SAH were investigated experimentally using selective HSQMBC-based pulse sequences and numerically using DFT simulations. The CLIP-HSQMBC technique was used to quantify 2/3-bond JHC couplings, and 4/5-bond JHC ≲ 0.5 Hz were estimated by the sel-HSQMBC-TOCSY approach. Experimental and numerical (DFT-simulated) nJHC couplings were strongly correlated (P < 0.001). Implications for 13C hyperpolarization by magnetic field cycling, and PH-INEPT and ESOTHERIC type spin order transfer methods for PHIP-SAH were assessed, and the influence of direct nascent parahydrogen proton to 13C coupling when compared with indirect homonuclear TOCSY-type transfer through intermediate (non-nascent parahydrogen) protons was studied by the density matrix approach

Quasi-Drugs Developed in Japan for the Prevention or Treatment of Hyperpigmentary Disorders

Excess production of melanin or its abnormal distribution, or both, can cause irregular hyperpigmentation of the skin, leading to melasma and age spots. To date, various quasi-drugs that prevent or improve hyperpigmentary disorders have been developed and officially approved by the Ministry of Health, Labor and Welfare of Japan. Many of these inhibit the activity of tyrosinase, an enzyme required for melanin synthesis, for example, by competitive or non-competitive inhibition of its catalytic activity, by inhibiting its maturation, or by accelerating its degradation. In this review, we categorize the quasi-drugs developed in Japan to prevent or treat hyperpigmentary disorders, or both, and discuss perspectives for future development

Carbonic anhydrase IX (CA-IX) and high-risk human papillomavirus (H-HPV) as diagnostic biomarkers of cervical dysplasia/neoplasia in Japanese women with a cytologic diagnosis of atypical glandular cells (AGC): a Gynecologic Oncology Group (GOG) Study

BackgroundHigh-risk human papillomavirus (H-HPV) infection is linked to cervical neoplasia but its role in detecting cervical glandular lesions (GLs) is unclear. Carbonic anhydrase IX (CA-IX) is a hypoxic biomarker that is highly expressed in neoplastic cervical GLs. The diagnostic utility of these biomarkers was evaluated by the Gynecologic Oncology Group in Japanese women with a cytological diagnosis of atypical glandular cells.MethodsImmunostaining was used to detect CA-IX in a conventional Pap smear. Immunoreactivity of CA-IX was interpreted by a panel of pathologists blinded to the histological diagnosis. Polymerase chain reaction was used to detect H-HPV in a liquid-based cytology specimen.ResultsSignificant cervical lesions (SCLs), defined as cervical intraepithelial neoplasia (CIN2, CIN3), adenocarcinoma in situ or invasive carcinoma, were observed in 37/88 (42%) of women. CA-IX testing alone (n=88) had a sensitivity of 89, 100 or 73% for SCLs, GLs or significant squamous lesions (SLs), respectively, with a false negative rate (FNR) of 14%. Testing for H-HPV (n=84) had a sensitivity of 65, 53 or 80% for SCLs, GLs or SLs, respectively, with a FNR of 22%. The combination of CA-IX and H-HPV testing had a sensitivity of 97, 100 or 93% for SCLs, GLs or SLs, respectively, with a FNR of 5%. Among eight H-HPV-negative GLs, six (75%) had a diagnosis of lobular endocervical glandular hyperplasia (LEGH).ConclusionThe combination of CA-IX and HPV testing improved the diagnostic accuracy. The low rate of H-HPV positivity in the GLs was associated with coexisting LEGH independent of H-HPV