Dietary inflammatory index, mediating biomarkers and incident frailty in Chinese community-dwelling older adults.

OBJECTIVES: Diet can modulate systemic inflammation, while inflammation is a critical contributory factor of frailty. However, longitudinal data on the association between dietary inflammatory index (DII) and frailty are limited, and the intermediate mechanisms remain unclear. This study aimed to examine the association between DII and incident frailty and the potential mediating roles of frailty-related biomarkers. DESIGN: Prospective cohort study. SETTING: The Mr. OS and Ms. OS (Hong Kong) study. PARTICIPANTS: A total of 3,035 community-dwelling men and women aged above 65 years without frailty at baseline were included. MEASUREMENTS: DII scores were calculated using the locally validated food frequency questionnaire. Incident frailty at year four was defined using the Fried frailty phenotype. Logistic regression was used to examine the association between DII and frailty onset. Mediation analysis was used to explore the mediating roles of frailty-related biomarkers in the DII-frailty association. RESULTS: During four years of follow-up, 208 individuals developed frailty. Compared with the lowest tertile of DII, the highest tertile was associated with an increased risk of incident frailty (OR: 1.82; 95% CI: 1.17-2.82; p = 0.008) after adjustment for relevant confounders. The DII-frailty association was significant in men but not in women. Furthermore, increasing serum homocysteine, decreasing serum folate, and reducing estimated glomerular filtration rate (eGFR) mediated 11.6%, 7.1%, and 9.6 % of the total relation between DII and frailty onset, respectively. CONCLUSION: In this cohort study, a pro-inflammatory diet was associated with a higher risk of frailty onset, mediated by homocysteine, folate, and renal function.

Association of dietary protein intake, inflammation with muscle mass, physical performance and incident sarcopenia in Chinese community-dwelling older adults.

OBJECTIVES: Inflammation and impaired muscle synthesis are important factors of sarcopenia. Plant protein may reduce inflammation but may not be as efficient as animal protein in providing essential amino acids. We therefore examined the associations between dietary protein intake and changes in muscle mass and physical performance, incident sarcopenia, and the interaction effect of inflammation. DESIGN: Prospective cohort study. SETTING: The Mr. OS and Ms. OS (Hong Kong) cohort. PARTICIPANTS: A total of 2,811 sarcopenia-free participants and 569 sarcopenia participants aged ≥65 years were recruited from communities. MEASUREMENTS: Dietary protein intake was assessed using a validated food frequency questionnaire. Serum high-sensitivity C-reactive protein (hs-CRP) was measured. Linear regression examined the associations between dietary protein intake and 4-year changes in muscle mass and physical performance. Cox regression examined the association between dietary protein intake and incident sarcopenia. RESULTS: Higher plant protein intake, but not total and animal protein, was associated with less decline in muscle mass and gait speed among sarcopenia-free participants. Conversely, higher ratio of animal-to-plant protein was associated with reduced muscle mass loss among participants with sarcopenia. The highest tertile of plant protein intake was associated with lower incident sarcopenia risk (HR: 0.75, 95% CI: 0.57-0.98; P-trend = 0.034) compared to the lowest tertile. Notably, this association was observed among participants with higher serum hs-CRP levels (HR: 0.57, 95% CI: 0.34-0.95), but not in those with lower hs-CRP levels. CONCLUSION: Dietary animal and plant protein intake have differential associations with muscle mass and physical performance in older adults with and without sarcopenia. The role of plant protein in preventing sarcopenia involves modulation of inflammation.

Quantity and Variety of Fruit and Vegetable Intake with Changes in Measures of Adiposity among Community-Dwelling Chinese Older Adults.

BACKGROUND: The association between fruit and vegetable intake, considering both quantity and variety, and weight change among older adults remains controversial. We aimed to investigate the association between fruit and vegetable intake, variety, and changes in adiposity measures among community-dwelling Chinese older adults. METHODS: A total of 2944 participants aged ≥65 years from Hong Kong communities were included. Fruit and vegetable intake was estimated by a locally validated food frequency questionnaire. Adiposity measures (weight, body mass index (BMI), waist circumference, fat and lean mass) were assessed at baseline and the year four follow-up. Restricted cubic spline and logistic models were performed to estimate the associations between fruit and vegetable intake, variety, and changes in adiposity measures. RESULTS: A nonlinear association between vegetable intake and weight change was found, following a J-shape curve. Increased vegetable intake was associated with less increases in weight, BMI, and fat mass among those below median intakes. However, these associations became insignificant at higher intakes (all P-nonlinearity < 0.05). The ORs (95% CIs) for weight gain across the quartiles of vegetable intake were as follows: 1.00 (reference), 0.81 (0.56, 1.17), 0.55 (0.36, 0.83), and 0.88 (0.58, 1.33). Similar patterns were observed in overweight and normal weight participants, but not in those with low body weight. No associations with weight change were found for fruit intake or fruit and vegetable variety. CONCLUSIONS: Moderate vegetable intake was associated with less weight gain among community-dwelling Chinese older adults, but not in those with low body weight. No association was observed between fruit intake or variety with weight change.

Multidomain Object Detection Framework Using Feature Domain Knowledge Distillation.

Object detection techniques have been widely studied, utilized in various works, and have exhibited robust performance on images with sufficient luminance. However, these approaches typically struggle to extract valuable features from low-luminance images, which often exhibit blurriness and dim appearence, leading to detection failures. To overcome this issue, we introduce an innovative unsupervised feature domain knowledge distillation (KD) framework. The proposed framework enhances the generalization capability of neural networks across both low-and high-luminance domains without incurring additional computational costs during testing. This improvement is made possible through the integration of generative adversarial networks and our proposed unsupervised KD process. Furthermore, we introduce a region-based multiscale discriminator designed to discern feature domain discrepancies at the object level rather than from the global context. This bolsters the joint learning process of object detection and feature domain distillation tasks. Both qualitative and quantitative assessments shown that the proposed method, empowered by the region-based multiscale discriminator and the unsupervised feature domain distillation process, can effectively extract beneficial features from low-luminance images, outperforming other state-of-the-art approaches in both low-and sufficient-luminance domains.

IRF5 promotes glycolysis in the progression of hepatocellular carcinoma and is regulated by TRIM35.

OBJECTIVES: The interferon regulatory factor (IRF) family of proteins are involved in tumor progression. However, the role of IRF5 in tumorigenesis remains unknown. In this study we aimed to elucidate the functions of IRF5 in the progression of hepatocellular carcinoma (HCC). METHODS: IRF5 expression in HCC was analyzed through quantitative polymerase chain reaction (qPCR), western blot, and immunohistochemistry (IHC), etc. The Cell Counting Kit 8 (CCK8) assay, anchorage-independent assay, and EdU assay were used to evaluate the role of IRF5. The molecular mechanisms were studied by analyzing the metabolites with mass spectrum and immunoprecipitation. RESULTS: IRF5 was upregulated in HCC. Interfering with IRF5 inhibited the proliferation and tumorigenic potential of HCC cells. When studying the molecular mechanism, IRF5 was found to upregulate the expression of lactate dehydrogenase A (LDHA) and promoted glycolysis. Additionally, tripartite motif containing 35 (TRIM35) interacted with IRF5, promoting its ubiquitination and degradation. In the clinically obtained HCC samples, TRIM35 was negatively correlated with the expression of IRF5. CONCLUSION: These findings reveal the oncogenic function of IRF5 in the progression of HCC by enhancing glycolysis, further supporting the potential of IRF5 as a viable target for HCC therapy.

Osteoporotic-like vertebral fracture with less than 20% height loss is associated with increased further vertebral fracture risk in older women: the MrOS and MsOS (Hong Kong) year-18 follow-up radiograph results.

Background: For osteoporotic fractures in men (MrOS) and in women (MsOS) (Hong Kong) baseline (BL) study, Chinese men and women ≥65 years were recruited during 2001 to 2003. This study presents the year-18 follow-up (FU) results. We were particularly interested in whether women with 'minimal' grade osteoporotic-like vertebral fracture (OLVF) of <20% height loss have an increased vertebral fracture (VF) risk than those without BL OLVF. Methods: At year-18 FU, spine radiography was performed on 144 males (mean: 87.4±3.1 years) and 156 females (mean: 87.0±3.2 years). OLVF classification included no OLVF (grade 0), and OLVFs with <20%, ≥20-25%, ≥25%-1/3, ≥1/3-40%, ≥40%-2/3, ≥2/3 height loss (grades 1-6). With an existing OLVF, a further height loss of ≥15% was an OLVF progression. A new incident OLVF was a change from grade 0 to ≥ grade 2 or to grade 1 with the appearance of endplate and/or cortex fracture (ECF) during FU. Both OLVF progression and incident OLVF were considered incident VF. Acquired short vertebra (aSV) was defined as with decreased vertebral anterior and middle heights, while without anterior wedging and bi-concave changes, and only those with at least two adjacent aSVs were recorded as aSV cases. Results: For subjects without BL OLVF, 12.5% of the males and 27.1% of the females had incident VF. For subjects with BL OLVF of ≥20% height loss, males' and females' incident VF rate were 20% and 66.7% respectively. Females subjects with BL minimal OLVF, while all without radiographic ECF, had an incident VF rate of 59.3% during the FU. For males with and without aSV, 11.8% and 15% have incident fracture of other vertebrae. For females with and without aSV, 35.3% and 34.5% have incident fracture of other vertebrae. Recovery from minimal or mild grades OLVF to normal shape was observed in a number of cases. Conclusions: OLVF with less than 20% height loss is associated with increased VF risk in older females, but not in older males. Acquired short vertebra (SV) is not associated with increased incident fracture risk for other vertebrae, both for females and males. OLVF among older subjects can repair and heal.

BMI1 induces ubiquitination and protein degradation of Nod-like receptor family CARD domain containing 5 and suppresses human leukocyte antigen class I expression to induce immune escape in non-small cell lung cancer.

The Nod-like receptor (NLR) family CARD domain containing 5 (NLRC5) has been reported as an activator of human leukocyte antigen (HLA) class I that is responsible for immune activity in cancer treatment. This work focuses on the role of BMI1 proto-oncogene (BMI1) in the NLRC5-HLA class I axis and in immune escape in non-small cell lung cancer (NSCLC). First, immunoblot analysis and/or reverse transcription-quantitative polymerase chain reaction were performed, which identified decreased NLRC5 and HLA class I levels in NSCLC tissues and cell lines. NSCLCs were co-cultured with activated CD8+ T cells. Overexpression of NLRC5 in NSCLC cells elevated the expression of HLA class I and increased the activity of T cells and IL-2 production, and it reduced the PD-1/PD-L1 levels. The ubiquitination and immunoprecipitation assays confirmed that BMI1 bound to NLRC5 to induce is ubiquitination and protein degradation. Downregulation of BMI1 in NSCLC cells elevated NLRC5 and HLA class I levels, and consequently promoted T cell activation and decreased PD-1/PD-L1 levels in the co-culture system. However, overexpression of BMI1 in cells led to inverse trends. In summary, this study demonstrates that BMI1 induces ubiquitination and protein degradation of NLRC5 and suppresses HLA class I expression, which potentially helps immune escape in NSCLC.

The Resilience and the Subsequent Hospitalization of Older People with Different Frailty Status: A Prospective Cohort Study.

OBJECTIVE: To evaluate the difference in resilience across frailty status by measuring the impact of unplanned hospitalization across people with different frailty condition on (1) 2-year changes in lean mass, physical performance, and quality of life, and (2) subsequent hospitalization. DESIGN: A prospective cohort study. SETTING AND PARTICIPANTS: Three thousand seventeen older people (73.7 ± 4.9 years) were recruited from the community in Hong Kong. METHODS: Frailty status was defined using the Cardiovascular Health Study scale at baseline. Unplanned hospitalization between the 2 visits was obtained from the Hong Kong Hospital Authority. The interaction of frailty and hospitalization status on the 2-year changes in lean mass, physical performance, and quality of life were examined using 2-way analysis of covariance. Risk of subsequent hospitalization was estimated using Poisson regression. The effect of prolonged hospitalization, which was defined as 6 or more total hospitalized days, was also examined. RESULTS: Upon unplanned hospitalization, frail older people had significantly augmented decline than prefrail and robust people in appendicular skeletal mass (-0.44 ± 0.08 kg), height-adjusted appendicular skeletal mas (-0.13 ± 0.03 kg/m2), 5-time chair-stand (4.79 ± 0.60 s), and mental health (-3.72 ± 0.88). The reduction increased with the length of hospitalization. Unplanned hospitalization conferred an augmented risk of subsequent hospitalization for those who were prefrail and frail (IRR = 1.44, 95% confidence interval = 1.30-1.59 and IRR = 1.69, 95% confidence interval = 1.45-1.97, respectively). CONCLUSIONS AND IMPLICATIONS: The resilience of older people varies according to their frailty status, and the poor resilience may translate to a higher chance of having subsequent hospitalization for prefrail and frail people. These findings emphasized the importance of having the frailty screening in making posthospitalization plans for older people depending on their frailty status and encouraging prefrail and frail older people to build up their resilience.

Effects of Host Plants on Bacterial Community Structure in Larvae Midgut of Spodoptera frugiperda.

The fall armyworm (FAW), Spodoptera frugiperda, is one of the most important invasive species and causes great damage to various host crops in China. In this study, the diversity and function of gut bacteria in the 5th instar larvae of FAW fed on maize, wheat, potato and tobacco leaves were analyzed through 16S rRNA sequencing. A total of 1324.25 ± 199.73, 1313.5 ± 74.87, 1873.00 ± 190.66 and 1435.25 ± 139.87 operational taxonomic units (OTUs) from the gut of FAW fed on these four different host plants were detected, respectively. Firmicutes, Proteobacteria and Bacteroidetes were the most abundant bacterial phyla. Beta diversity analysis showed that the gut bacterial community structure of larvae fed on different host plants was significantly differentiated. At the genus level, the abundance of Enterococcus in larvae fed on wheat was significantly lower than those fed on the other three host plants. Enterobacter and ZOR0006 were dominant in FAW fed on tobacco leaves, and in low abundance in larvae fed on wheat. Interestingly, when fed on Solanaceae (tobacco and potato) leaves which contained relative higher levels of toxic secondary metabolites than Gramineae (wheat and maize), the genera Enterococcus, Enterobacter and Acinetobacter were significantly enriched. The results indicated that gut bacteria were related to the detoxification and adaptation of toxic secondary metabolites of host plants in FAW. Further analysis showed that replication, repair and nucleotide metabolism functions were enriched in the gut bacteria of larvae fed on tobacco and potato. In conclusion, the gut bacterial diversity and community composition in FAW larvae fed on different host plants showed significant differences, and the insect is likely to regulate their gut bacteria for adaptation to different host plants.

Reference Interval for Pulse Oxygen Saturation in Neonates at Different Altitudes: A Systematic Review.

Introduction: The reference interval for pulse oxygen saturation (SpO2) in neonates born at high altitudes has not been defined to date. The purpose of this study was to systematically review published studies and determine the reference interval of SpO2 in neonates at different altitudes. Methods: Databases of PubMed, Embase, Cochrane Library, Clinicaltrials.Gov, Chinese National Knowledge Infrastructure Database, Wanfang Database, Chinese Science Technology Journals Database, and Chinese Clinical Trial Registry were searched for studies reporting SpO2 in healthy neonates at different altitudes. Retrieval time was from inception of the database to August 16, 2021. The Agency for Healthcare Research and Quality checklist was used to evaluate the quality of studies. Python v3.8 was used to analyze the data. This systematic review was drafted in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results: Seven cross-sectional studies, published between 1991 and 2020, were identified. They were from US, Mexico, Israel, Ecuador, and China. Three studies were rated as high quality and four as moderate quality. The mean SpO2 (with standard deviation or standard error) of neonates born in 40 different altitudes (ranging from 25 meters to 3,100 meters) were obtained. The prediction equation for calculation of the lower limit of the reference interval was established, and the reference intervals for SpO2 at different altitudes were determined. Conclusions: In healthy neonates, the lower limit of the reference interval of SpO2 decreases with increase in altitude. High-quality prospective studies are need to confirm our findings.

Cumulative and Incremental Value of Sarcopenia Components on Predicting Adverse Outcomes.

OBJECTIVES: To examine the incremental value of sarcopenia components, following the diagnosis algorithm of the Asian consensus, on predicting adverse outcomes. DESIGN: A prospective cohort study. SETTING AND PARTICIPANTS: Four thousand community-dwelling Chinese adults (2000 men) aged 65 years or older in Hong Kong (mean age = 72.5 ± 5.2). METHODS: SARC-F was used as the initial predictor of 9 adverse outcomes. In step 2, muscle strength (ie, grip strength) and/or functions (ie, chair-stand, walking speed) were added on top of SARC-F. In step 3, height-, weight-, and body mass index-adjusted appendicular skeletal mass (ASM) measured by dual-energy x-ray absorptiometry (DXA) were added separately to all models formulated in step 2. The areas under the receiver operating characteristic curve (AUCs) were calculated for the models formulated in all steps. Each cumulative AUC would be compared with the AUC yielded in the previous step to evaluate the incremental prediction value. RESULTS: On top of SARC-F, assessing grip strength, walking speed, or 5-time chair-stand significantly increased the AUC for most adverse outcomes. In particular, assessing both grip strength and gait speed yielded the highest AUC in most prediction models (AUC = 0.539-0.770) and significantly increased the AUC for all outcomes except for recurrent falls. With both muscle strength and function assessed, adding ASM failed to significantly increase the AUC except for 2 conditions. In the 2 conditions, however, a higher height-adjusted ASM was associated with a higher risk of having worsened physical limitations [OR 1.25, 95% confidence interval (CI) 1.12-1.40] and decline in the physical quality of life (OR 1.18, 95% CI 1.06-1.33) in women. CONCLUSIONS AND IMPLICATIONS: Assessing muscle strength and function provides additional power to predict adverse outcomes on top of SARC-F. Further assessment of muscle mass with DXA provides no extra constructive value ito bettering the prediction regardless of the adjustment parameters. Alternative technologies to measure muscle mass might be required.

Longitudinal Association of Built Environment Pattern with Physical Activity in a Community-Based Cohort of Elderly Hong Kong Chinese: A Latent Profile Analysis.

A large number of studies have focused on the associations between single built environment (BE) characteristics and physical activity (PA). Combinations of BE characteristics offer a more comprehensive approach to identify the BE-PA associations. We aimed to examine the BE-PA associations in a cohort of elderly Hong Kong Chinese. Between 2001 and 2003, 3944 participants (65-98 years of age) were recruited and followed for a mean of 7.8 years. BE characteristics were assessed via geographic information system. PA levels were obtained using the Physical Activity Scale for the Elderly questionnaire at baseline and three follow-ups. Latent profile analysis was first conducted to classify the BE characteristics, and linear mixed-effects models were then used to explore the longitudinal associations between the BE classes and changes in the PA levels. Three classes of BE were identified. Class 3 (characterized by greater green space and sky view factor) demonstrated a significant decline in household PA (ß = -1.26, 95% confidence interval: -2.20, -0.33) during the study period, and a slower decline in walking PA (1.19 (0.42, 1.95)) compared with Class 2 (characterized by a greater proportion of residential land use). Our results indicate that BE patterns characterized by high green space and a sky view factor may help promote the walking PA level.

A persistent outbreak of varicella in a primary school in Dongguan City, Guangdong Province, China.

OBJECTIVES: To describe the epidemiological features of a school varicella outbreak in Dongguan City, China, to identify the reasons underlying persistent spread, and to assess the effectiveness of the varicella vaccine. METHODS: We identified all cases during the outbreak. We described the outbreak epidemic course and examined the influence of the following variables on the outbreak: sleeping in the dormitory, eating in school, taking school transportation, hand-washing habits, morning examinations, and effectiveness of case isolation. Logistic regression was used to estimate the odds ratio and 95% confidence interval (CI) of contracting varicella. RESULTS: A total of 92 varicella cases were reported, accounting for 5.53% (92/1663) of all students. Among cases, 64.13% (59/92) were vaccinated. The outbreak lasted for 93 days and occurred in six generations. Vaccination coverage was between 78.05% and 85.67%. The varicella vaccine was effective in 56.63% of recipients (95% CI: 35.49-70.84%). Vaccine effectiveness significantly decreased after 4-6 years. CONCLUSIONS: The varicella vaccine was unable to prevent virus spread even with high vaccination coverage. Delayed and inefficient isolation of cases was the primary cause of the persistent outbreak.

Association between genetic polymorphisms of inflammatory response genes and the risk of ovarian cancer.

BACKGROUND/PURPOSE: Inflammation plays an important role in promoting ovarian tumorigenesis and cancer progression. However, the relationship between polymorphisms in inflammatory response genes and risk of ovarian cancer remains poorly understood. In this study, we investigated the association of PPARG Pro12Ala, IL6-174G/C, E-selectin S128R, NFKB1-94 ins/del, NFKBIA-826C/T, and ICAM-1 K469E polymorphisms with ovarian cancer risk in a Chinese population. METHODS: Genotyping of the polymorphisms was performed on 687 cases and 687 controls employing the PCR-RFLP technique, and the logistic regression model was used to measure the risk association. RESULTS: A significantly increased risk association was observed for the heterozygous genotypes of PPARG [odds ratio (OR) = 1.52, 95% confidence interval (CI) = 1.01-2.29] and E-selectin (OR = 1.77, 95% CI = 1.07-2.93) polymorphisms, as well as the homozygous ins/ins genotype of NFKB1 polymorphism (OR = 1.39, 95% CI = 1.00-1.92). By contrast, ICAM-1 KE genotype was associated with a decreased ovarian cancer risk (OR = 0.77, 95% CI = 0.60-0.98). In addition, the NFKB1 del/del + NFKBIA TT combination was also found to be associated with a decreased ovarian cancer risk, with OR = 0.12 (95% CI = 0.01-0.95). The associations of the NFKB1 and ICAM-1 polymorphisms replicated the findings of previous reports, assuring the reliability of the results obtained. CONCLUSION: NFKB1 and ICAM-1 polymorphisms could serve as useful ovarian cancer risk prediction biomarkers for the Chinese population, while the utility of PPARG and E-selectin polymorphisms as biomarkers requires further confirmation in independent ovarian cancer cohorts.

E2F2 induction in related to cell proliferation and poor prognosis in non-small cell lung carcinoma.

E2F transcription factors regulate a wide range of biological processes, including cell cycle, apoptosis and DNA damage response. In the present study, we examined whether E2F2 is related to the poor prognosis of NSCLC and its role in progress of NSCLC. Firstly, we analyzed 86 NSCLC samples by immunohistochemistry and found that E2F2 expression was markedly increased in 62.8% (54/86) of all samples compared with the normal tissues. Further study showed that E2F2 expression was closely associated with clinical stage (P = 0.039) and tumor size (P = 0.045). Furthermore, Kaplan-Meier analysis indicated that high Bad expression was significantly correlated to overall survival (P = 0.045) but not disease-free survival (P = 0.288). In addition, our results showed that knockdown E2F2 expression could reduce cell viability and colony formation in NSCLC cells. The results in our study for the first time revealed that E2F2 act as an activator in tumor progress of NSCLC and could become a promising marker for the prognosis of patients with NSCLC.

[Comparison of the therapeutic effects of paclitaxel liposome-5-Fu versus paclitaxel-5-Fu on 67 patients with advanced gastric cancer].

OBJECTIVE: To explore the efficacy, time to disease progression (TTP), overall survival (OS) and toxicity of paclitaxel liposome versus paclitaxel combined with 5-fluorouracil (5-Fu) for patients with advanced gastric cancer. METHODS: The therapeutic efficacy of chemotherapy with either of the two regimens for 67 cases of naïve advanced gastric cancer was analyzed. Among them, 31 patients in the paclitaxel liposome-5-Fu group received paclitaxel liposome 175 mg/m(2) d1, CF 200 mg/m(2) d1, 5-Fu 2.6 g/m(2) civ. 46 hours, 21 days as one cycle, and 34 patients in the paclitaxel-5-Fu group received paclitaxel 175 mg/m(2) d1, CF 200 mg/m(2) d1, 5-Fu 2.6 g/m(2) civ. 46 hours, 21 days as one cycle. RESULTS: The objective response rate was 54.8% in the paclitaxel liposome group and 44.1% in the paclitaxel group (P = 0.388). The median time to progression was 5.10 months vs. 5.20 months (P = 0.266) and the median survival time was 10.07 months vs. 8.97 months (P = 0.186). The most frequent side-effects were nausea, vomit and hematological toxicities. The rates of grade III-IV nausea and vomit were 16.1% and 50.0% (P = 0.038), muscle and joint pain were 9.7% and 29.4% (P = 0.047). CONCLUSION: Both regimens are effective in the treatment of advanced gastric cancer. However, less adverse effects occur in the paclitaxel liposome group.

Synthesis of Discodermolide Subunits by S(E)2' Addition of Nonracemic Allenylstannanes to Aldehydes.

Three subunits, 15, 29, and 34, of the immunosuppressant discodermolide were prepared starting from (S)-3-[(tert-butyldimethylsilyl)oxy]-2-methylpropanal ((S)-1) and the enantioenriched allenylstannanes (P)-2a, (P)-2b, and (P)-31. The route to 15 involved BF(3)-promoted addition of stannane (P)-2a to aldehyde (S)-1 which afforded the syn,syn-homopropargylic alcohol adduct 3 in 97% yield. The derived p-methoxybenzylidene acetal 5 was treated with Red-Al to effect cleavage of the pivalate and reduction of the double bond leading to the (E)-allylic alcohol 6. Sharpless epoxidation and subsequent addition of Me(2)CuCNLi(2) yielded the syn,syn,syn,anti stereopentad, diol 8. Protection of the secondary alcohol and oxidation of the primary gave aldehyde 12, which was treated with the alpha-bromo allylsilane 13 and CrCl(2), followed by NaH to effect elimination to the diene 15. A similar sequence was employed to prepare aldehyde 29. In this case aldehyde (S)-1 was converted to the anti,syn-homopropargylic alcohol 20 by treatment with the allenyl indium reagent formed in situ from allenylstannane (P)-2b and InBr(3). Epoxy alcohol 24, prepared from alcohol 20 by the above-described sequence, was reduced with Red-Al to afford diol 25. Protection of the secondary alcohol and oxidation of the primary completed the synthesis of 29. The anti,syn-homopropargylic alcohol 32 was obtained through addition of the allenic indium reagent, from allenylstannane (P)-31, to aldehyde (S)-1. Protection of the derived diol 33 as the p-methoxybenzylidene acetal afforded the third subunit, acetylene 34. Addition of the lithio derivative of 34 to aldehyde 29 gave alcohol 35 with the carbinyl stereochemistry needed for C7 of discodermolide as the major product.