Helicobacter pylori infection combined with DENA revealed altered expression of p53 and 14-3-3 isoforms in Gulo−/− mice

AbstractUnlike most other mammals, human bodies do not have the ability to synthesize vitamin C inside of their own bodies. Therefore, humans must obtain vitamin C through daily diet. Gulo−/− mice strain is known with deficiency, in which vitamin C intake can be controlled by diet like human, and would be valuable for investigating the molecular mechanism of various diseases. In the present study, we established Gulo−/− mice model and investigated the differentially expressed proteins in stomach tissue of Gulo−/− mice after Helicobacter pylori-infected, and followed by DENA, using immunohistochemistry and proteomic approach. The results of immunohistochemistry analysis of stomach tissue showed that the tumor suppressor, p53 protein, expression was significantly decreased (p<0.05) but not messenger RNA (mRNA) transcriptional level, and 14-3-3ε, 14-3-3δ, Ki-67 and cleaved caspase 3 expressions were significantly increased (p<0.05) by H. Pylori infection, and followed by DENA treatment in Gulo−/− mice. Moreover, knockdown of 14-3-3 isoforms (14-3-3ε, 14-3-3σ, 14-3-3ζ and 14-3-3η) were significantly increased sub-G1 phase (characteristics of apoptosis) in AGS cells and, phenotypic changes like cell shrinkage, density and cleaved nuclei were also observed. Proteome analyses showed that 14-3-3σ, 14-3-3η, and tropomyosin alpha-1 chain were down-regulated, and Hspd1 protein and HSC70 were up-regulated after H. Pylori-infection, and followed by DENA. The combined results of immunohistochemistry and proteomic analysis suggest that H. pylori altered the p53 and 14-3-3 isoforms expression and DENA further enhanced the H. pylori effect, which might be involved in carcinogenesis and metastasis of gastric cancer on Gulo−/− mice

Synergistic surface modification for high-efficiency perovskite nanocrystal light-emitting diodes: divalent metal ion doping and halide-based ligand passivation

Surface defects of metal halide perovskite nanocrystals (PNCs) substantially compromise the optoelectronic performances of the materials and devices via undesired charge recombination. However, those defects, mainly the vacancies, are structurally entangled with each other in the PNC lattice, necessitating a delicately designed strategy for effective passivation. Here, a synergistic metal ion doping and surface ligand exchange strategy is proposed to passivate the surface defects of CsPbBr3 PNCs with various divalent metal (e.g., Cd2+, Zn2+, and Hg2+) acetate salts and didodecyldimethylammonium (DDA+) via one-step post-treatment. The addition of metal acetate salts to PNCs is demonstrated to suppress the defect formation energy effectively via the ab initio calculations. The developed PNCs not only have near-unity photoluminescence quantum yield and excellent stability but also show luminance of 1175 cd m−2, current efficiency of 65.48 cd A−1, external quantum efficiency of 20.79%, wavelength of 514 nm in optimized PNC light-emitting diodes with Cd2+ passivator and DDA ligand. The “organic–inorganic” hybrid engineering approach is completely general and can be straightforwardly applied to any combination of quaternary ammonium ligands and source of metal, which will be useful in PNC-based optoelectronic devices such as solar cells, photodetectors, and transistors

Prospective study of oncologic outcomes after laparoscopic modified complete mesocolic excision for non-metastatic right colon cancer (PIONEER study): study protocol of a multicentre single-arm trial

Abstract Background The introduction of complete mesocolic excision (CME) with central vascular ligation (CVL) for right-sided colon cancer has improved the oncologic outcomes. Recently, we have introduced a modified CME (mCME) procedure that keeps the same principles as the originally described CME but with a more tailored approach. Some retrospective studies have reported the favourable oncologic outcomes of laparoscopic mCME for right-sided colon cancer; however, no prospective multicentre study has yet been conducted. Methods This study is a multi-institutional, prospective, single-arm study evaluating the oncologic outcomes of laparoscopic mCME for adenocarcinoma arising from the right side of the colon. A total of 250 patients will be recruited from five tertiary referral centres in South Korea. The primary outcome of this study is 3-year disease-free survival. Secondary outcome measures include 3-year overall survival, incidence of surgical complications, completeness of mCME, and distribution of metastatic lymph nodes. The quality of laparoscopic mCME will be assessed on the basis of photographs of the surgical specimen and the operation field after the completion of lymph node dissection. Discussion This is a prospective multicentre study to evaluate the oncologic outcomes of laparoscopic mCME for right-sided colon cancer. To the best of our knowledge, this will be the first study to prospectively and objectively assess the quality of laparoscopic mCME. The results will provide more evidence about oncologic outcomes with respect to the quality of laparoscopic mCME in right-sided colon cancer. Trial registration ClinicalTrials.gov ID: NCT03992599 (June 20, 2019). The posted information will be updated as needed to reflect protocol amendments and study progress

TRIP13 Participates in Immediate-Early Sensing of DNA Strand Breaks and ATM Signaling Amplification through MRE11

Thyroid hormone receptor-interacting protein 13 (TRIP13) participates in various regulatory steps related to the cell cycle, such as the mitotic spindle assembly checkpoint and meiotic recombination, possibly by interacting with members of the HORMA domain protein family. Recently, it was reported that TRIP13 could regulate the choice of the DNA repair pathway, i.e., homologous recombination (HR) or nonhomologous end-joining (NHEJ). However, TRIP13 is recruited to DNA damage sites within a few seconds after damage and may therefore have another function in DNA repair other than regulation of the pathway choice. Furthermore, the depletion of TRIP13 inhibited both HR and NHEJ, suggesting that TRIP13 plays other roles besides regulation of choice between HR and NHEJ. To explore the unidentified functions of TRIP13 in the DNA damage response, we investigated its genome-wide interaction partners in the context of DNA damage using quantitative proteomics with proximity labeling. We identified MRE11 as a novel interacting partner of TRIP13. TRIP13 controlled the recruitment of MDC1 to DNA damage sites by regulating the interaction between MDC1 and the MRN complex. Consistently, TRIP13 was involved in ATM signaling amplification. Our study provides new insight into the function of TRIP13 in immediate-early DNA damage sensing and ATM signaling activation

Combined inhibition of Bcl-2 family members and YAP induces synthetic lethality in metastatic gastric cancer with RASA1 and NF2 deficiency

Background Targetable molecular drivers of gastric cancer (GC) metastasis remain largely unidentified, leading to limited targeted therapy options for advanced GC. We aimed to identify molecular drivers for metastasis and devise corresponding therapeutic strategies. Methods We performed an unbiased in vivo genome-wide CRISPR/Cas9 knockout (KO) screening in peritoneal dissemination using genetically engineered GC mouse models. Candidate genes were validated through in vivo transplantation assays using KO cells. We analyzed target expression patterns in GC clinical samples using immunohistochemistry. The functional contributions of target genes were studied through knockdown, KO, and overexpression approaches in tumorsphere and organoid assays. Small chemical inhibitors against Bcl-2 members and YAP were tested in vitro and in vivo. Results We identified Nf2 and Rasa1 as metastasis-suppressing genes through the screening. Clinically, RASA1 mutations along with low NF2 expression define a distinct molecular subtype of metastatic GC exhibiting aggressive traits. NF2 and RASA1 deficiency increased in vivo metastasis and in vitro tumorsphere formation by synergistically amplifying Wnt and YAP signaling in cancer stem cells (CSCs). NF2 deficiency enhanced Bcl-2-mediated Wnt signaling, conferring resistance to YAP inhibition in CSCs. This resistance was counteracted via synthetic lethality achieved by simultaneous inhibition of YAP and Bcl-2. RASA1 deficiency amplified the Wnt pathway via Bcl-xL, contributing to cancer stemness. RASA1 mutation created vulnerability to Bcl-xL inhibition, but the additional NF2 deletion conferred resistance to Bcl-xL inhibition due to YAP activation. The combined inhibition of Bcl-xL and YAP synergistically suppressed cancer stemness and in vivo metastasis in RASA1 and NF2 co-deficiency. Conclusion Our research unveils the intricate interplay between YAP and Bcl-2 family members, which can lead to synthetic lethality, offering a potential strategy to overcome drug resistance. Importantly, our findings support a personalized medicine approach where combined therapy targeting YAP and Bcl-2, tailored to NF2 and RASA1 status, could effectively manage metastatic GC.This research was supported by grants of the National Research Foundation (NRF) funded by the Korean government (NRF-RS-2023–00208984, NRF-2021M3H9A1030260, NRF-2021R1F1A1051220, NRF-2016M3A9D5A01952416)

Comparison of first-line treatment with CHOP versus ICED in patients with peripheral T-cell lymphoma eligible for upfront autologous stem cell transplantation

IntroductionUpfront autologous stem cell transplantation (ASCT) has been recommended for patients who are newly diagnosed with peripheral T-cell lymphoma (PTCL), and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), an anthracycline-based chemotherapy has been the frontline chemotherapy for PTCL. However, it is not clear whether anthracycline-based chemotherapies such as CHOP could be standard induction therapy for PTCL.MethodsWe conducted a randomized phase II study to compare CHOP with fractionated ifosfamide, carboplatin, etoposide, and dexamethasone (ICED) for patients eligible for ASCT. The primary endpoint was progression-free survival (PFS) and secondary endpoints included objective response rate, overall survival (OS), and safety profiles.ResultsPatients were randomized into either CHOP (n = 69) or ICED (n = 66), and the characteristics of both arms were not different. PTCL-not otherwise specified (NOS, n = 60) and angioimmunoblastic T-cell lymphoma (AITL, n = 53) were dominant. The objective response rate was not different between CHOP (59.4%) and ICED (56.1%), and the 3-year PFS was not different between CHOP (36.7%) and ICED (33.1%). In AITL patients, CHOP was favored over ICED whereas ICED was associated with more cytopenia and reduced dose intensity. Patients who received upfront ASCT after achieving complete response to CHOP or ICED showed 80% of 3-year OS.DiscussionIn summary, our study showed no therapeutic difference between CHOP and ICED in terms of response and PFS. Thus, CHOP might remain the reference regimen especially for AITL based on its better outcome in AITL, and upfront ASCT could be recommended as a consolidation of complete response in patients with PTCL

Morphological and genetic differentiation of heteromorphy in Labidocera rotunda (Copepoda, Calanoida, Pontellidae)

Jeong, Hyeon Gyeong, Soh, Ho Young, Suh, Hae-Lip (2014): Morphological and genetic differentiation of heteromorphy in Labidocera rotunda (Copepoda, Calanoida, Pontellidae). Zootaxa 3764 (2): 181-191, DOI: http://dx.doi.org/10.11646/zootaxa.3764.2.

Two New Species of Leptochelia (Crustacea, Tanaidacea) from the West Coast of Korea

Two new species of Leptochelia Dana, 1849 are described from the western coast of Korea. Leptochelia grandidentata n. sp. is similar to L. itoi and L. lusei characterized by pleonites 4 and 5 of subequal lengths and a uropod endopod with 4 articles but differentiated by a cheliped fixed finger longer than the dactylus and with 4 teeth along the incisive margin, a maxilliped basis with 4 distal setae, and pereopod 1 propodus that is much longer than the combined length of unguis and dactylus. Leptochelia suhi n. sp. shares some features of L. myora with the first article of the uropod endopod longer than the second article and a maxilliped endite with 3 spiniform distal setae but can be differentiated by the cephalothorax being longer than the pleon, the relatively longer antennule article 3 compared to article 2, and the cheliped fixed finger with 3 robust teeth along the incisive margin. In this study, full descriptions of L. grandidentata and L. suhi are given, and a comparison with closely related species belonging to the ‘dubia/savignyi group’ is tabulated and discussed

Labidocera rotunda Mori 1929

Labidocera rotunda Mori, 1929 (Figs. 1–4) Labidocera rotunda Mori, 1929: 177, pl. 10, figs. 1–8 (type locality: Pusan, Korea); Mori, 1964: 35; Fleminger et al., 1982: 264, figs. 4m –n, 5 f, 6 k–l, 7 f–g, 8 f. Labidocera bipinnata Tanaka, 1936: 31, pl. 2, figs. 1–10, pl. 3, figs. 1–7; Tanaka, 1964: 25; Mori, 1964: 94, pl. 43, figs. 1–8; Brodsky, 1950, p. 410, fig. 291; Shen and Bai, 1956: 191, pl. 5, figs. 36–41; Shen and Lee, 1963: 581; Chen and Zhang, 1965: 97, pl. 39, figs. 10–13, pl. 40, figs. 1–5; Silas and Pillai, 1973: 814; Kim, 1985: 118, pl. 38, figs. e–g, pl. 39, figs. a, b; Yoo, 1995: 200, pl. 145. Labidocera rotundata Mori, 1964: 52 (misspelling of specific name). Material examined. Twenty females and twenty males were collected from the northeastern area of the East China Sea on 30 May (34 ° 10 ’ N 127 ° 49 ’ E), 24 July (34 ° 39 ’ N 127 ° 52 ’ E) and 23 October 2002 (34 ° 23 ’ N 128 ° 7 ’ E), of which ten females and five males were dissected and closely examined. Female. Body length 1.78–2.57 mm (n= 20). Prosome cylindrical: fourth and fifth pedigerous somites incompletely fused; posterior corners of prosome with pointed spiniform process extending to two-thirds of the genital double-somite (Fig. 1 A, B). Cephalosome with lateral hooks and pair of dorsal lenses; rostrum bifid, gap between rostral rami narrow. Urosome with 3 free somites: genital double-somite with wide spur on right mediolaterally and two spiniform processes ventro-laterally (Figs. 1 C, 2 C, 4 A–D); genital operculum concaved on central part of tip (Fig. 4 B, D); second urosomite with well developed spur on right anterior-laterally; anal somite and caudal rami partly fused; caudal rami asymmetrical, left ramus with blunt process along inner margin (Fig. 1 C). Antennule (Fig. 1 D) 24 -segmented, posterior margin of second to 12 th segments fringed with fine hairs; ancestral segment II to IV, XXVII to XXVIII completely fused, and VIII and IX incompletely separated. Fusion pattern and setal formula as follows: I– 3 +ae (aesthetasc), II– IV– 4 +ae, V– 2 +ae, VI– 2, VII– 2 +ae, VIII– IX– 4 +ae, X– 2, XI– 2 +ae, XII– 2, XIII– 2 +ae, XIV– 2 +ae, XV– 2 +ae, XVI– 2 +ae, XVII– 2 +ae, XVII– 2 +ae, XVIII– 2 +ae, XIX– 2 +ae, XX– 2 +ae, XXI– 2 +ae, XXII– 1, XXIII– 1, XXIV– 1 + 1, XXV– 1 + 1 +ae, XXVI– 1 + 1, XXVII–XXVIII– 4 +ae. Fifth leg (Fig. 1 E) asymmetrical; coxa and intercoxal sclerite completely fused; basis with outer seta; right exopodal segment with small intercalary denticle between unequal apical processes, two to five unequal denticles along inner margin and 2 outer setae; left exopodal segment with 2 unequal processes distally and 2 outer setae; both endopods with nine denticles or, sometimes, reductions. Male: Body length 1.62–2.31 mm (n= 20). Prosome more compact than in female with well-developed dorsal lenses: posterior corners of prosome asymmetrical, right corner bifurcate with minute denticles between processes (Fig. 2 A, B). Urosome of 5 free somites: genital somite wider than long, with spine ventrally; anal somite and caudal rami partly fused. Antennule (Fig. 2 C) geniculate on right side only, left one resembling that of females: right one indistinctly 13 - segmented; segments XII–XIV with arthrodial membranes incompletely formed, segments II–IV, XV and XVI, XXI–XXIII completely fused. Fusion pattern and setal formula as follows: I– 3 +ae, II– IV– 4 +ae, V– XI– 14 + 4 aes (aesthetascs), XII–XIV– 6 + 2 aes, XV–XVI– 4 + 2 aes, XVII– 2 +ae, XVIII– 2 +ae, XIX– 1 +p (hooked process)+ae, XX– 1 +p+ae, XXI–XXIII– 2 +p+ae, XXIV– 1 + 1 +p, XXV– 1 + 1 +ae, XXVI–XXVIII– 6 +ae. Segment XIX with anterior setiform process, segment XX and compound segment XXI–XXIII with toothed ridge provided with serrated denticles, respectively, and segment XXIV with spur-like process distally, expanding to middle of next segment (Fig. 2 D). Fifth leg (Fig. 2 E) uniramous and asymmetrical: coxa of left exopod coalescent with intercoxal sclerite; right exopod 2 -segmented, first segment with conical process, 2 spines and thumb-like process; second segment elongated, curved inwards with 4 spines on the concave surface; left exopod 2 -segmented, first segment with bluntly triangular process postero-laterally, second segment with spine-like process proximally, 2 unequal spiniform processes, 2 unequal setiform processes distally, and base of processes proximal to spine-like process apex. Remarks. In Korean waters, some female specimens of L. rotunda exhibited morphological differences such as: 1) posterior corners of prosome with triangular processes are extending to one-third of the genital doublesomite (Fig. 3 A, B), 2) the genital double-somite is having four spiniform processes ventro-laterally (Fig. 3 C), 3) the second urosomite is having a small knob on right antero-lateral surface (Fig. 3 C), 4) the caudal rami is symmetrical (Fig. 3 A, C), and 5) the length is similar between the apical processes on the exopod of the fifth leg (Fig. 3 D, E). Chen and Zhang (1965) described females having the aforementioned features as a variety, together with the typical form of L. rotunda from the East China Sea. Fleminger et al. (1982) and Othman and Toda (2006) also found some discrepancies in the individuals of female L. rotunda. Molecular results. The genetic analysis was obtained for 5 pontellid species (Table 1). The sequences of mt 16 S rRNA and mtCOI differed by 1.4 %– 2.9 % among a 286 base-pair region and by 3.7 %– 4.7 % among a 616 base-pair region between the typical form of L. rotunda and its variant, respectively (Tables 2, 3). The cladograms obtained indicate a monophyletic clade, suggesting a lack of divergence at the species level despite considerable morphological differences (Fig. 5). On the other hand, intraspecific differences were observed for the mt 16 S rRNA and mtCOI of L. japonica, which is morphologically very similar to L. rotunda. The differences were between 6.1 %– 7.2 % for a 286 base-pair region of 16 S rRNA and 15.1 %– 16.7 % for a 616 base-pair region of mtCOI. The cladograms also demonstrated separation at the species level (Fig. 5). Pontellid species show a considerable intraspecific variation in complex, sexually modified structures and, as a result, display different phenotypes (Chen & Zhang 1965; Fleminger et al. 1967; Zheng et al. 1982). Of these species, L. rotunda showed some extreme morphological variability in its female genital double-somite, second urosomite, caudal rami, and fifth legs. Such morphological differences, in particular, in the structures that function in mating might be enough to establish a new candidate species, as in similar cases of other centropagoid species (Fleminger 1975; Blade & Youngbluth 1979; Barthlélémy et al. 1998, 1999; Soh et al. 2001, 2012; Walter et al. 2002; Jeong et al. 2009 a, 2009 b; Sakaguch & Ueda 2010). Recently, however, molecular analysis has provided a useful tool in identifying cryptic species as well as extensive intraspecific morphological variants, and in elucidating evolutionary relationships (Bucklin et al. 1999, 2003; Goetze 2003; Ueda & Bucklin 2006; Sakaguchi & Ueda 2010). In the present study, sequence data from two highly variable regions of DNA showed that differences between the typical form of L. rotunda and its variants were only 1.4 %– 2.9 % for 16 S rRNA and 3.9 %– 4.7 % for mtCOI sequences, despite their pronounced morphological differences. Considering that in calanoid copepods, 16 S rRNA and mtCOI genes usually vary by over 7 % at the species level (Bucklin et al. 1995, 2003), these data suggested that the variants belong to the same species. Similarly, the sequence differences between the two male morphs of Pseudodiaptomus koreanus Soh, Kwon, Lee & Yoon, 2012 is low (1.2 % for ITS 1 region and 3.8 % for mtCOI), and they represent variants within a single species (Soh et al. 2012). Nevertheless, it is very interesting to note that the morphological and genetic differences are pronounced between the typical form and its variant; the local populations also comprise an independent clade within mtCOI analysis, except for the northeastern population of the East China Sea (Fig. 5). On the other hand, the genetic differences between L. rotunda and L. japonica were 6.1 %– 7.2 % for mt 16 S rRNA and 15.1 %– 16.7 % for mtCOI sequences. Although the differences for 16 S rRNA are relatively low for species level separation in calanoid copepods, it is sufficient to separate L. japonica from L. rotunda, as the mtCOI and morphological characteristics are clearly distinguished. Labidocera rotunda and L. japonica are placed in the pectinata group, and display the following diagnostic characteristics: in female, the fifth leg is asymmetrical, the left exopod is long and strongly curved and the endopod is denticulated at apex; in male, the second exopodal segment of left leg is bearing hirsute and short lobiform process medially, and two or three spiniform processes and two setiform aesthete-like processes are located distally (Fleminger et al. 1982; Mulyadi 1997). The distribution of these species overlaps in the East Sea (Sea of Japan) and off northeastern Japan, but the distribution of L. rotunda extends to the continental coast south to the Malay Archipelago, off northeastern Sumatra and the Andaman Sea off the southern Myanmar coast (Razouls et al. 2013). The presence of L. rotunda in the Andaman Sea places it in proximity of the easternmost populations of L. pectinata (see Fleminger et al. 1982). The latter authors also suggested that L. rotunda might have extended northward in recent postglacial times via the Strait of Malacca, while L. japonica may have undergone a more recent regional speciation.Published as part of Jeong, Hyeon Gyeong, Soh, Ho Young & Suh, Hae-Lip, 2014, Morphological and genetic differentiation of heteromorphy in Labidocera rotunda (Copepoda, Calanoida, Pontellidae), pp. 181-191 in Zootaxa 3764 (2) on pages 183-188, DOI: 10.11646/zootaxa.3764.2.5, http://zenodo.org/record/22633