Search

Although the overall survival rate of B cell acute lymphoblastic leukemia (B-ALL) in childhood is more than 80%, it is merely 30% in refractory/relapsed and adult patients with B-ALL. This demonstrates a need for improved therapy targeting this subgroup of B-ALL. Here, we show that the ten-eleven translocation 1 (TET1) protein, a dioxygenase involved in DNA demethylation, is overexpressed and plays a crucial oncogenic role independent of its catalytic activity in B-ALL. Consistent with its oncogenic role in B-ALL, overexpression of TET1 alone in normal precursor B cells is sufficient to transform the cells and cause B-ALL in mice within 3 to 4 months. We found that TET1 protein is stabilized and overexpressed because of its phosphorylation mediated by protein kinase C epsilon (PRKCE) and ATM serine/threonine kinase (ATM), which are also overexpressed in B-ALL. Mechanistically, TET1 recruits STAT5B to the promoters of CD72 and JCHAIN and promotes their transcription, which in turn promotes B-ALL development. Destabilization of TET1 protein by treatment with PKC or ATM inhibitors (staurosporine or AZD0156; both tested in clinical trials), or by pharmacological targeting of STAT5B, greatly decreases B-ALL cell viability and inhibits B-ALL progression in vitro and in vivo. The combination of AZD0156 with staurosporine or vincristine exhibits a synergistic effect on inhibition of refractory/relapsed B-ALL cell survival and leukemia progression in PDX models. Collectively, our study reveals an oncogenic role of the phosphorylated TET1 protein in B-ALL independent of its catalytic activity and highlights the therapeutic potential of targeting TET1 signaling for the treatment of refractory/relapsed B-ALL.

The relationship of lexical tone production and perception has not been well studied. Using Mandarin tone, this research tests the hypothesis that a production-perception link is revealed by critical perceptual cues. The critical status of perceptual tonal cues was determined by perceptual cue weights, showing fundamental frequency (F0) contour as being more critical than height. Then, tone production features were examined for critical F0 contour (slope, curvature, turning-point location) and non-critical F0 height (mean, onset) cues. A production-perception correlation was found for F0 contour but not height cues, suggesting that critical perceptual cues dictate the relationship between production and perception.

RNABy analyzing The Cancer Genome Atlas (TCGA) dataset, we found that elevated expression ofWe show that YTHDC1 plays a critical oncogenic role in TNBC metastasis through promoting the nuclear export and expression of

N

Introduction: Albeit that over 170 types of chemical modifications have been identified in RNAs, the biological functions of most of those decorations are still elusive. N7-methylguanosine (m7G), routinely occurring at the 5’ cap of mRNA or within tRNA and rRNA, also exists in internal mRNA. However, the “reader” proteins that recognize internal mRNA m7G and regulate the metabolism and fate of target mRNAs have yet to be identified. Here, we aim to identify the reader(s) of internal mRNA m7G and elucidate the biological function. Methods: To identify internal m7G reader(s), we utilized RNA-pull down, mass spectrometry (MS), RNA immunoprecipitation (RIP)-seq, and m7G-seq. To evaluate the interaction between QKI and G3BP1, we used Co-IP, immunofluorescence (IF) and proximity ligation assay (PLA). To investigate the function of QKI in stress granule (SG), we performed polyA & m7G RNA fluorescence in situ hybridization (FISH), triple quadrupole MS (QQQ-MS), and Ribo-seq. To assess the role of QKI in drug resistance, we carried out both in vitro cell survival assays and in vivo xenograft mouse model. Results: Our QQQ-MS results suggest cytoplasmic mRNA, in contrast to nuclei mRNA, are highly enriched with internal m7G modification. Quaking proteins (QKI), especially QKI7, can selectively recognize the internal mRNA m7G decoration in the cytosol of various cell types. Our high-throughput sequence data revealed over 1000 confident m7G-modified and QKI-binding RNA targets with a conserved motif, “GANGAN (N=A/U/G)”. Those transcripts are functionally enriched in the “pathways in cancer” and “Hippo signaling pathway”. More strikingly, internal m7G reader QKI7 directly interacts with the SG core protein G3BP1 and can shuttle a subset of m7G-modified transcripts into SG mRNA pool under oxidative stress condition. Additionally, we identified 314 confident m7G-modified & QKI7-binding & SG-enriched target genes in U2OS cells. Ribo-seq indicated that QKI7 modulates the translation efficiency of a set of m7G-modified transcripts via sequestering and silencing them in SGs. Moreover, in line with the observation that many chemotherapy drugs could trigger the assembly of SGs, QKI7 increases the sensitivity of cancer cells to drug treatment (e.g., doxorubicin) in vitro and in vivo in a m7G-dependent manner. Consistently, by analyzing the hepatocellular carcinoma (HCC) pharmacogenomic landscape study dataset, we found that HCC cell lines with higher QKI expression levels are more sensitive to a variety of chemotherapy or targeted therapeutic drugs. Conclusion: Our study identifies QKI as the first internal mRNA m7G reader, provides insights into the biological function of internal mRNA m7G modification in remodeling stress granules transcriptome, and highlights the therapeutic potential of targeting the QKI7/m7G axis in overcoming drug resistance. Citation Format: Zhicong Zhao, Lei Dong, Li Han, Yangchan Li, Jianhuang Xue, Keren Zhou, Wei Li, Xiaolan Deng, Ying Qing, Brandon Tan, Zhenhua Chen, Chao Shen, Andrew Small, Kitty Wang, Keith Leung, Zheng Zhang, Xi Qin, Qiang Xia, Rui Su, Jianjun Chen. Recognition of internal mRNA N7-methylguanosine by QKI shuttles transcripts into stress granules and modulates drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5685.

Background: As the most prevalent internal decorations in mammalian mRNA, N6-methyladenosine (m6A) has been reported to be involved in many physiological and pathological processes, including acute myeloid leukemia (AML). METTL3 and METTL14, the well-recognized m6A methyltransferase complex, contribute to AML. METTL16 is a recently identified m6A methyltransferase that has been reported to deposit m6A in a few targets. While, unlike METTL3/14, the biological functions of METTL16 are largely unknown. Here, we explored the function and mechanism of METTL16 in AML pathogenesis and evaluated its therapeutic potential for AML treatment. Methods: We performed CRISPR-Cas9 screen to evaluate the dependency of METTL16 in AML cells. We created METTL16 knockout (KO) cells and conditional KO mice to evaluate its role in leukemogenesis and normal hematopoiesis. We employed bone marrow transplantation (BMT), xenograft, and AML patient-derived xenograft (PDX) models to determine its role in AML development and progression. To identify the targets of METTL16, we performed m6A-seq and RNA-seq, followed m6A-qPCR, CLIP-qPCR, in vitro methyltransferase assays and RNA stability assays. To examine the effect of METTL16 on branched chain amino acid (BCAA) metabolism, we performed metabolic profiling with 13C, 15N-leucine. Results: CRISPR-Cas9 screen showed METTL16 is one of the most essential genes for the survival of AMLs. The AML cells display more robust dependency on METTL16 than METTL3/14. We found METTL16 is highly expressed in AML patients compared to healthy controls. METTL16 KO significantly inhibited AML cell proliferation, promoted cell apoptosis and myeloid differentiation in vitro, which could be totally reversed by forced expression of wild-type METTL16, but not catalytic-dead mutant. METTL16 depletion dramatically inhibited AML progression and prolonged survival of recipient mice in the BMT, xenograft and PDX models. In addition, METTL16 is highly expressed in LSCs contrast to leukemic bulk cells and METTL16 KO significantly attenuates LSC self-renewal in vitro and in vivo. By contrast, the role of METLL16 is largely spared in normal hematopoietic cells. Via integrated analysis of m6A-seq data and RNA-seq data, we identified two bona fide targets of METTL16, BCAT1 and BCAT2, which encode two critical BCAA transaminases in BCAA biosynthesis pathway. METTL16 promotes the expression of BCAT1 and BCAT2 via an m6A dependent manner. Metabolomics with 13C, 15N-leucine tracing showed that METTL16 KO results in suppressed pools of TCA cycle intermediates, some non-essential amino acids and nucleotides. Conclusion: We uncover a tumor-promoting role of METTL16 in AML and LSC self-renewal via reprogramming BCAA metabolism, in which METTL16 functions as an m6A methyltransferase to regulate expression of BCAT1 and BCAT2. Our data suggest that METTL16 is an attractive target for AML therapy. Citation Format: Li Han, Lei Dong, Keith Leung, Zhicong Zhao, Yangchan Li, Ying Qing, Jianhuang Xue, Chao Shen, Zhenhua Chen, Lei Gao, Kitty Wang, Keren Zhou, Wei Li, Brandon Tan, Zheng Zhang, Xi Qin, Rui Su, Xiaolan Deng, Jianjun Chen. METTL16 drives leukemogenesis and maintains leukemia stem cell self-renewal via reprogramming BCAA metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3617.

BackgroundSGLT2I and DPP4I are medications prescribed for type 2 diabetes mellitus patients. However, there are few population-based studies comparing their effects on incident atrial fibrillation or ischemic stroke.MethodsThis was a territory-wide cohort study of type 2 diabetes mellitus patients prescribed SGLT2I or DPP4I between January 1st, 2015 to December 31st, 2019 in Hong Kong. Patients with both DPP4I and SGLT2I use and patients with drug discontinuation were excluded. Patients with prior AF or stroke were excluded for the respective analysis. 1:2 propensity-score matching was conducted for demographics, past comorbidities and medications using nearest-neighbor matching method. Cox models were used to identify significant predictors for new onset heart failure (HF) or myocardial infarction (MI), cardiovascular and all-cause mortality.ResultsThe AF-free cohort included 49108 patients (mean age: 66.48 years old [SD: 12.89], 55.32% males) and the stroke-free cohort included 49563 patients (27244 males [54.96%], mean baseline age: 66.7 years old [SD: 12.97, max: 104.6 years old]). After propensity score matching, SGLT2i use was associated with a lower risk of new onset AF (HR: 0.43[0.28, 0.66]), cardiovascular mortality (HR: 0.79[0.58, 1.09]) and all-cause mortality (HR: 0.69[0.60, 0.79]) in the AF-free cohort. It was also associated with a lower risk of new onset stroke (0.46[0.33, 0.64]), cardiovascular mortality (HR: 0.74[0.55, 1.00]) and all-cause mortality (HR: 0.64[0.56, 0.74]) in the stroke-free cohort.ConclusionsThe novelty of our work si that SGLT2 inhibitors are protective against atrial fibrillation and stroke development for the first time. These findings should be validated in other cohorts.

BackgroundThe triglyceride glucose (TyG) index has been proposed to be a surrogate of insulin resistance. In the study, we aimed to examine the relationship between TyG index and the risk of new onset DM and secondary outcomes included atrial fibrillation (AF), heart failure (HF), acute myocardial infarction (AMI), ventricular tachycardia/fibrillation (VTF), cardiovascular mortality (CAD) and all-cause mortality.MethodsThe retrospective observational study analyzed patients recruited from 1st January 2000 to 31st December 2003 and followed up until 31st December 2019. Demographics, past comorbidities, medications and laboratory tests were extracted. At baseline and follow-up, DM was defined as 1) any occasion Hb1Ac ≥14 g/dL, 2) fasting glucose≥7 mmol/L on two occasions, or 3) with DM diagnosis. We excluded 1) patients with prior DM or with the use of antidiabetic medications; 2) patients with prior AMI/HF/AF or with the use of diuretic/beta blockers for HF were excluded. Univariate analysis and multivariate Cox analysis with adjustments on demographics, past comorbidities and medications were conducted to identify the significant risk predictors of primary and secondary outcomes. Optimal cutoffs of TyG index for the primary and secondary outcomes were found with maximally selected rank statistics approach.ResultLager TyG index is significantly associated with new onset DM (HR: 1.51, 95% CI: [1.47, 1.55], P vlaue1, P valueConclusionHigher TyG index remained significantly associated with the elevated risk of new onset DM, AF, HF, AMI, VTF, CAD and all-cause mortality after adjustments on demographics, past comorbidities, and medications.

This study aims to characterize distinctive acoustic features of Mandarin tones based on a corpus of 1025 monosyllabic words produced by 21 native Mandarin speakers. For each tone, 22 acoustic cues were extracted. Besides standard F0, duration, and intensity measures, further cues were determined by fitting two mathematical functions to the pitch contours. The first function is a parabola, which gives three parameters: a mean F0, an F0 slope, and an F0 second derivative. The second is a broken-line function, which models the contour as a continuous curve consisting of two lines with a single breakpoint. Cohen's d, sparse Principal Component Analysis, and other statistical measures are used to identify which of the cues, and which combinations of the cues, are important for distinguishing each tone from each other among all the speakers. Although the specific cues that best characterize the tone contours depend on the particular tone and the statistical measure used, this paper shows that the three cues obtained by fitting a parabola to the tone contour are broadly effective. This research suggests using these three cues as a canonical choice for defining tone characteristics.

Traditional challenges in online condition monitoring systems for power transformer are usually due to discrepant results between online condition monitoring system and lab-based measurements (e.g....

Speaking involves both retrieving the sounds of a word (phonological planning) and realizing these selected sounds in fluid speech (articulation). Recent phonetic research on speech errors has argued that multiple candidate sounds in phonological planning can influence articulation because the pronunciation of mis-selected error sounds is slightly skewed towards unselected target sounds. Yet research to date has only examined these phonetic distortions in experimentally-elicited errors, leaving doubt as to whether they reflect tendencies in spontaneous speech. Here, we analyzed the pronunciation of speech errors of English-speaking adults in natural conversations relative to matched correct words by the same speakers, and found the conjectured phonetic distortions. Comparison of these data with a larger set of experimentally-elicited errors failed to reveal significant differences between the two types of errors. These findings provide ecologically-valid data supporting models that allow for information about multiple planning representations to simultaneously influence speech articulation.

The effect of clear speech on the integration of auditory and visual cues to the tense-lax vowel distinction in English was investigated in native and non-native (Mandarin) perceivers. Clear speech benefits for tense vowels /i, ɑ, u/ were found for both groups across modalities, while lax vowels /ɪ, ʌ, ʊ/ showed a clear speech disadvantage for both groups when presented in the visual-only modality, with Mandarin perceivers showing a further disadvantage for lax vowels presented audio-visually, and no difference in speech styles auditorily. English perceiver responses were then simulated in an ideal perceiver model which both identified auditory (F1, F2, spectral change, duration) and visual (horizontal lip stretch, duration) cues predictive of the clear speech advantage for tense vowels, and indicated which dimensions presented the greatest conflict between cues to tensity and modifications from clear speech (F2 and duration acoustically, duration visually). Altogether, by combining clear speech acoustics, articulation, and perception into a single integrated framework we are able to identify some of the signal properties responsible for both beneficial and detrimental speech style modifications.

Background: Obesity, a risk factor for colorectal cancer, raises systemic levels of proinflammatory mediators. Whether increased levels also reside in the colons of obese individuals and are accompanied by procancerous alterations in the mucosal transcriptome is unknown. Methods: Concentrations of TNFα, IL1β, and IL6 in blood and colonic mucosa of 16 lean and 26 obese individuals were examined. Differences in the mucosal transcriptome between the two groups were defined. Results: Plasma IL6 and TNFα were 1.4- to 3-fold elevated in obese subjects [body mass index (BMI) ≥ 34 kg/m2] compared with the lean controls (P < 0.01). Among individuals with BMI ≥ 34 kg/m2 colonic concentrations of IL6 and TNFα were 2- to 3-fold greater than in lean subjects (P < 0.03). In a general linear model, adjusted for NSAID use, colonic IL6 (partial r = 0.41; P < 0.01) and TNFα (partial r = 0.41; P = 0.01) increased incrementally over the entire range of BMIs (18.1–45.7). Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with a reduction in colonic IL6 (β = −0.65, P < 0.02). RNA sequencing (NSAID users excluded) identified 182 genes expressed differentially between lean and obese subjects. The two gene networks most strongly linked to changes in expression included several differentially expressed genes known to regulate the procarcinogenic signaling pathways, NFκB and ERK 1/2, in a pattern consistent with upregulation of each in the obese subjects. Conclusions: Incremental increases in two major proinflammatory colonic cytokines are associated with increasing BMI, and in the obese state are accompanied by procancerous changes in the transcriptome. Impact: These observations delineate means by which an inflammatory milieu may contribute to obesity-promoted colon cancer.

Patients with BRCA-1 and BRCA-2 germ line mutations are at an increased risk of developing pancreatic adenocarcinoma (PAC). In particular, the BRCA-2 mutation has been associated with a relative risk of developing PAC of 3.51. The BRCA-2 protein is involved in repair of double-stranded DNA breaks. Recent reports have suggested that in the setting of impaired DNA repair, chemotherapeutic agents that induce DNA damage, such as platinum-based antineoplastic drugs (platins) and poly(ADP-ribose) polymerase inhibitors (PARP inhibitors), have improved efficacy. However, because of the relative rarity of BRCA-related PAC, studies evaluating such agents in this setting are scarce. Patients with a known BRCA-2 mutation and PAC were retrospectively reviewed. Ten patients with PAC and BRCA-2 mutation were identified. Four patients (40%) were of Ashkenazi Jewish descent. Seven patients (70%) received platinum agents, two (20%) received mitomycin-C, one (10%) received a PARP inhibitor, and seven (70%) received a topoisomerase-I inhibitor. Overall, chemotherapy was well tolerated with expected side effects. Patients with a BRCA-2 mutation and PAC represent a group with a unique biology underlying their cancer. Chemotherapies such as platinum derivatives, mitomycin-C, topoisomerase-I inhibitors, and PARP inhibitors targeting DNA require further investigation in this population. Genetic testing may guide therapy in the future.

Clearly produced vowels exhibit longer duration and more extreme spectral properties than plain, conversational vowels. These features also characterize tense relative to lax vowels. This study explored the interaction of clear-speech and tensity effects by comparing clear and plain productions of three English tense–lax vowel pairs (/i-ɪ/, /ɑ-ʌ/, /u-ʊ/ in /kVd/ words). Both temporal and spectral acoustic features were examined, including vowel duration, vowel-to-word duration ratio, formant frequency, and dynamic spectral characteristics. Results revealed that the tense−lax vowel difference was generally enhanced in clear relative to plain speech, but clear-speech modifications for tense and lax vowels showed a trade-off in the use of temporal and spectral cues. While plain-to-clear vowel lengthening was greater for tense than lax vowels, clear-speech modifications in spectral change were larger for lax than tense vowels. Moreover, peripheral tense vowels showed more consistent clear-speech modifications in the temporal than spectral domain. Presumably, articulatory constraints limit the spectral variation of these extreme vowels, so clear-speech modifications resort to temporal features and reserve the primary spectral features for tensity contrasts. These findings suggest that clear-speech and tensity interactions involve compensatory modifications in different acoustic domains.

Speech communication can adopt different styles as a function of speaking environments and communicative needs. In auditorily or visually challenging contexts, speakers often alter their speech production using a clarified, hyper-articulated speech style with the intention of enhancing speech intelligibility. Such modifications may result in perceptible articulatory and acoustic changes. Questions thus arise as to whether and what clear-speech modifications facilitate perception. This presentation surveys recent research conducted in our labs, investigating clear-speech production and its associated effects on perception. In a series of three-stream studies, this research relates analyses of visible articulatory features using computer image-processing techniques, measurements of acoustic properties, and perceptual patterns of clear-speech segments and suprasegmentals by native and non-native perceivers. Results reveal that clear (relative to plain) speech modulates different and compensatory articulatory-acoustic cues within each sound category to enhance intelligibility. However, our results also show that clear-speech modifications that reduce phonemic category distinctiveness inhibit intelligibility. These findings indicate that clear-speech effects are governed by the collateral principles of within-category cue enhancement and maintenance of category distinctiveness.

This pilot study explores the potential production-perception relation of Mandarin tones by examining the association between the acoustic features of native Mandarin tone production and perception of such features, using Tone 2 (rising tone) as a testing case. The perception stimuli were resynthesized by varying F0 onset (spectral feature) and F0 turning-point location (temporal feature) orthogonally forming a grid of tone contours. The endpoints of these dimensions were determined by natural Tone 1 and 3 productions, presumably corresponding to perceptual boundaries for Tone 2. A parabola was fitted to the resynthesized tones to determine the overall shape of the tone contour. Native Mandarin participants were asked to identify the best exemplar of Tone 2. The acoustic analysis of Tone 2 productions by the same participants included measurements of the same features. Preliminary correlation analysis showed a positive production-perception correlation for the temporal feature of F0 turning-point location, but no significant correlation for the spectral features of F0 onset and F0 contour shape, indicating F0 turning-point location as a critical perceptual cue for Tone 2. Further research will include additional tones and additional acoustic features found to characterize these tones to identify the nature of production-perception relation of Mandarin tones.

Using mathematical modeling, this study aims to characterize distinctive acoustic features of Mandarin tones based on a corpus of 1013 monosyllabic words produced by 21 native Mandarin speakers. For each tone, 22 acoustic cues were extracted. Besides standard F0, duration, and intensity measures, further cues were determined by fitting two mathematical models to the pitch contours. The first is a broken-line model, which models the contour as a continuous curve consisting of two lines with a single breakpoint. The second model is a parabola, which gives three parameters: a mean F0, an F0 slope, and an F0 curvature. Using Cohen’s d, we identify which of the 22 cues are important for distinguishing each tone from the others for all speakers, as well as identifying cues that are used idiosyncratically by particular speakers. Although the specific cues that best characterize each tone differ, we show that the three cues obtained by fitting a parabola to the tone contour are an effective small set of cues such that any pair of tones is well distinguished by at least one of them. We propose using these three cues as a canonical choice for defining tone characteristics.Using mathematical modeling, this study aims to characterize distinctive acoustic features of Mandarin tones based on a corpus of 1013 monosyllabic words produced by 21 native Mandarin speakers. For each tone, 22 acoustic cues were extracted. Besides standard F0, duration, and intensity measures, further cues were determined by fitting two mathematical models to the pitch contours. The first is a broken-line model, which models the contour as a continuous curve consisting of two lines with a single breakpoint. The second model is a parabola, which gives three parameters: a mean F0, an F0 slope, and an F0 curvature. Using Cohen’s d, we identify which of the 22 cues are important for distinguishing each tone from the others for all speakers, as well as identifying cues that are used idiosyncratically by particular speakers. Although the specific cues that best characterize each tone differ, we show that the three cues obtained by fitting a parabola to the tone contour are an effective small set of cues such...

Clearly enunciated speech (relative to conversational, plain speech) involves articulatory and acoustic modifications that have been shown to enhance segmental intelligibility. However, little research has explored clear-speech effects on the perception of suprasegmental properties such as lexical tone, particularly involving visual (facial) perception. Moreover, research has not determined if visual tonal cues are linguistically significant, presumably because tone production does not rely on vocal tract configurations. Investigating clear-speech effects may help validate the contribution of visual information, since improved visual tone intelligibility in clear speech would indicate the linguistic relevance of visual cues. The present study tested this hypothesis by examining the intelligibility of clear and plain Mandarin tones by native (Mandarin) and non-native (English) perceivers with auditory/visual input modalities (AO: audio-only; VO: visual-only; and AV: audio-visual). Results showed small but significant clear-speech benefits in each modality for both natives and non-natives. However, while the natives revealed an overall visual gain and auditory dominance (AV>AO>VO), visual gain appeared to be less prominent in non-native perception (AV VO in plain, AV = AO>VO in clear). These results demonstrate clear-speech facilitation in visual as well as auditory perception, particularly with native perceivers, suggesting the existence of linguistically relevant visual tonal cues.

Studies on acoustic and visual characteristics of English tense and lax vowels show consistent enhancement of tensity contrasts in clear speech. However, the degree to which listeners utilize these enhancements in speech perception remains unclear. The present study addresses this issue by testing speech style effects on tense and lax vowel perception by 23 native English and 30 non-native Mandarin-Chinese listeners in audio-only (AO), audio-visual (AV), and visual-only (VO) stimulus modes. English and Chinese listeners showed similar relative differences in performance by mode (VO < AO < AV) and style (plain < clear). However, the two groups differed in the nature of the interaction between tensity, style, and stimulus mode. English listeners showed advantages for clear speech for both tense and lax vowels in all but VO stimuli, whereas Chinese listeners showed a clear speech advantage only for tense vowels, while clear lax vowels showed no improvement in AO and reduced accuracy in AV and VO. While tempo...

Background Despite regular colonoscopy, interval colorectal cancer (CRC) may occur. Long-term studies examining CRC rates in patients with previous colonoscopy are lacking. Objective We examined the rate of interval CRC in the Polyp Prevention Trial Continued Follow-up Study (PPT-CFS), an observational study of PPT participants that began after the PPT ended. Design Prospective. Setting A national U.S. community-based polyp prevention trial. Main Outcome Measurements Medical records of patients with CRC were collected, reviewed, and abstracted in a standardized fashion. Results Among 2079 PPT participants, 1297 (62.4%) agreed to participate in the PPT-CFS. They were followed for a median of 6.2 years after 4.3 years of median follow-up in the main PPT. Nine cases of CRC were diagnosed over 7626 person-years of observation (PYO), for an incidence rate of 1.2/1000 PYO. The ratio of CRCs observed compared with that expected by Surveillance, Epidemiology, and End Results was 0.64 (95% CI, 0.28-1.06). Including all CRCs (N = 22) since the beginning of the PPT, the observed compared with expected rate by Surveillance, Epidemiology, and End Results was 0.74 (95% CI, 0.47-1.05). Of patients in whom CRC developed in the PPT-CFS, 78% had a history of an advanced adenoma compared with only 43% of patients who remained cancer free ( P = .04). Limitation A relatively small number of interval cancers were detected. Conclusions Despite frequent colonoscopy during the PPT, in the years after the trial, there was a persistent ongoing risk of cancer. Subjects with a history of advanced adenoma are at increased risk of subsequent cancer and should be followed closely with continued surveillance.

Anti-microbial cecropins are humoral immune peptides originally found in insects. They possess a particular function of membrane permeabilization on both gram-positive and gram-negative bacteria. Yet, they are not capable of lysing eucaryotic cells. In this experiment, we confirmed that cecropin A (CA) is a special agent able to lyse leukemia cells while exerting little toxic effect on normal lymphocytes, based on the IC50 measurements. The therapeutic index of CA ranged from 6 to 17. In contrast, chemical anti-cancer agents (ACAs) are non-specific drugs capable of damaging both cancer and normal cells. Due to the functional differences between CA and ACAs, the experiments on the combined effects of CA and ACAs were conducted in vitro. Under certain conditions, synergistic effects were found with CA/S-FU and CA/Ara-C combinations. The results suggest the need for further study into the possible application of combining anti-cancer agents with antibacterial peptides for cancer treatment.