Generation and characterization of mature hepatocyte organoids for liver metabolic studies.

Hepatocyte organoids (HOs) generated in vitro are powerful tools for liver regeneration. However, previously reported HOs have mostly been fetal in nature with low expression levels of metabolic genes characteristic of adult liver functions, hampering their application in studies of metabolic regulation and therapeutic testing for liver disorders. Here, we report development of novel culture conditions that combine optimized levels of triiodothyronine (T3) with the removal of growth factors to enable successful generation of mature hepatocyte organoids (MHOs) of both mouse and human origin with metabolic functions characteristic of adult livers. We show that the MHOs can be used to study various metabolic functions including bile and urea production, zonal metabolic gene expression, and metabolic alterations in both alcoholic liver disease and non-alcoholic fatty liver disease, as well as hepatocyte proliferation, injury and cell fate changes. Notably, MHOs derived from human fetal hepatocytes also show improved hepatitis B virus infection. Therefore, these MHOs provide a powerful in vitro model for studies of human liver physiology and diseases. The human MHOs are potentially also a robust research tool for therapeutic development.

Temporal trends in disease burden and attributable risk factors for tracheal, bronchus, and lung cancer in Nepal, 1990-2019.

BACKGROUND: Tracheal, bronchus, and lung (TBL) cancer is one of the most common cancers in Nepal. The aim of this study was to analyze the changing disease burden and risk factors for TBL cancer in Nepal from 1990 to 2019. METHODS: TBL cancer burden data were obtained from the Global Burden of Disease Study 2019. A decomposition analysis was used to explore the impact of changes in population size, population age structure, age-specific prevalence, and disease severity on long-term trends of the TBL cancer burden in Nepal. RESULTS: In 2019, TBL cancer resulted in the loss of 45.2 thousand (95% uncertainty interval [UI]: 32.3-59.2 thousand) disability-adjusted life years (DALYs) in Nepal, with the age-standardized incidence and prevalence rates increasing by 12.7% (95% UI: -21.0 to 63.9%) and 12.8% (95% UI: -21.1 to 62.0%), respectively, compared with 1990. The proportion of DALYs due to TBL cancer increased significantly among people aged 70 years and older from 1990 to 2019. However, the proportion of DALYs due to TBL cancer still dominated among males and females aged 50-69 years. Population growth, population aging, and increased age-specific prevalence led to an increased disease burden of TBL cancer, while disease severity led to a decreased burden. In 2019, smoking remained the major risk factor for TBL cancer in Nepal, while ambient particulate matter pollution exhibited the most significant rise. CONCLUSIONS: The disease burden of TBL cancer in Nepal has continued to increase over the past three decades, and given the continuing population growth and aging process, TBL cancer is likely to have a considerable impact on health in Nepal in the future. There is a need to further establish effective TBL cancer prevention and control policies.

Abrogation of the G2/M checkpoint as a chemosensitization approach for alkylating agents.

BACKGROUND: The cell cycle is tightly regulated by checkpoints, which play a vital role in controlling its progression and timing. Cancer cells exploit the G2/M checkpoint, which serves as a resistance mechanism against genotoxic anticancer treatments, allowing for DNA repair prior to cell division. Manipulating cell cycle timing has emerged as a potential strategy to augment the effectiveness of DNA damage-based therapies. METHODS: In this study, we conducted a forward genome-wide CRISPR/Cas9 screening with repeated exposure to the alkylating agent temozolomide (TMZ) to investigate the mechanisms underlying tumor cell survival under genotoxic stress. RESULTS: Our findings revealed that canonical DNA repair pathways, including the Ataxia-telangiectasia mutated (ATM)/Fanconi and mismatch repair, determine cell fate under genotoxic stress. Notably, we identified the critical role of PKMYT1, in ensuring cell survival. Depletion of PKMYT1 led to overwhelming TMZ-induced cytotoxicity in cancer cells. Isobologram analysis demonstrated potent drug synergy between alkylating agents and a Myt1 kinase inhibitor, RP-6306. Mechanistically, inhibiting Myt1 forced G2/M-arrested cells into an unscheduled transition to the mitotic phase without complete resolution of DNA damage. This forced entry into mitosis, along with persistent DNA damage, resulted in severe mitotic abnormalities. Ultimately, these aberrations led to mitotic exit with substantial apoptosis. Preclinical animal studies demonstrated that the combination regimen involving TMZ and RP-6306 prolonged the overall survival of glioma-bearing mice. CONCLUSIONS: Collectively, our findings highlight the potential of targeting cell cycle timing through Myt1 inhibition as an effective strategy to enhance the efficacy of current standard cancer therapies, potentially leading to improved disease outcomes.

Insect transient receptor potential vanilloid channels as potential targets of insecticides.

Chordotonal organs are miniature sensory organs present in insects. Chordotonal organs depend on transient receptor potential (TRP) channels. Transient receptor potential vanilloid (TRPV) channels are the only TRPs identified that can act as targets of insecticides. By binding with TRPV channels, insecticides targeting the chordotonal organs trigger the inflow of calcium ions, resulting in abnormal function of the chordotonal organ to achieve the goal of eliminating pests. TRPV channels are highly expressed in various developmental stages and tissue parts of insects and play an important role in the whole life history of insects. In this review, we will discuss the structure and types of TRPV channels as well as their genetic relationships in different species. We also systematically reviewed the recent progress of TRPV channels as insecticide targets, demonstrating that TRPV channels can be used as the target of new high-efficiency insecticides.

The epidemic of acute lymphoid leukemia in China: current trends and future prediction.

Background: China has experienced one of the fastest increases in the incidence of acute lymphoid leukemia (ALL). The aim of this study was to assess the long-term trends of the incidence and mortality of ALL in mainland China between 1990 and 2019 and to project these trends through 2028. Methods: Data on ALL were extracted from the Global Burden of Disease Study 2019; population data were extracted from World Population Prospects 2019. An age-period-cohort framework was used in the analysis. Results: The net drift for the incidence of ALL was 7.5% (95% confidence interval [CI]: 7.1%, 7.8%) per year in women and 7.1% (95% CI: 6.7%, 7.6%) in men, and local drift was found to be higher than 0 in every studied age group (p<0.05). The net drift for mortality was 1.2% (95% CI: 1.0%, 1.5%) in women and 2.0% (95% CI: 1.7%, 2.3%) in men. Local drift was lower than 0 in boys aged 0-4 years and girls aged 0-9 years and higher than 0 in men aged 10-84 years and women aged 15-84 years. The estimated period relative risks (RRs) for both incidence and mortality showed increasing trends in the recent period. The cohort RRs for incidence showed increasing trends in both sexes; however, the cohort RR for mortality was decreased in the recent birth cohort (women born after 1988-1992 and men born after 2003-2007). Compared with that in 2019, the incidence of ALL in 2028 is projected to increase by 64.1% in men and 75.0% in women, and the mortality is predicted to decrease by 11.1% in men and 14.3% in women. The proportion of older adult/adults individuals with incident ALL and ALL-related death was projected to increase. Conclusions: Over the last three decades, the incidence and mortality rates of ALL have generally increased. It is projected that the incidence rate of ALL in mainland China will continue to increase in the future, but the associated mortality rate will decline. The proportion of older adult/adults individuals with incident ALL and ALL-related death was projected to increase gradually among both sexes. More efforts are needed, especially for older adult/adults individuals.

Shikonin triggers GSDME-mediated pyroptosis in tumours by regulating autophagy via the ROS-MAPK14/p38α axis.

BACKGROUND: Shikonin (SK), a botanical drug extracted from Lithospermum erythrorhizon, has been shown to inhibit tumour growth through apoptosis and necrosis. However, whether SK induces pyroptosis in cancer cells is still unknown. PURPOSE: This study aims to investigated the mechanisms of SK-induced pyroptosis in tumour cells and mice. METHODS: In vivo and in vitro methods were used in this study. Cell deaths were analysed by LDH and CCK-8 assay and western blotting. To investigated the signalling pathway of SK-induced pyroptosis, various genes expressions were supressed by shRNA or inhibitors. High-sensitivity mass spectrometry assay was used to identified potential factors that regulate GSDME-mediated pyroptosis. Finally, a mouse model was used to investigate the effect of SK administration on tumour growth in vivo. RESULTS: The activation of BAX/caspase-3 signalling was essential for GSDME-mediated pyroptosis by SK. Mechanistically, the intracellular reactive oxygen species (ROS) generation induced by SK treatment initiated GSDME-dependant pyroptosis. SK stimulation induced protective autophagy in a ROS-dependant manner, and repressed autophagy significantly enhanced SK-induced pyroptosis. Moreover, MAPK14/p38α, a ROS sensor, modulated SK-induced autophagy and ultimately affected GSDME-dependant pyroptosis. CONCLUSION: Here, for the first time we demonstrated that SK treatment induced GSDME-dependant pyroptosis in tumour cells. Our results demonstrated that SK initiates ROS signalling to drive pyroptosis in cancer cells.

Effects of tolfenpyrad exposure on development and response mechanism in the silkworm, Bombyx mori.

Tolfenpyrad is a broad spectrum of insecticide that can effectively kill different types of pests, including Lepidoptera. However, due to improper use, the adverse effects of tolfenpyrad on beneficial or economic insects have not been well studied. In this study, we systematically investigated the toxic effect of sublethal tolfenpyrad on silkworms. Sublethal tolfenpyrad exposure can affect the body weight, developments days, cocooning rate, eclosion rate and pupation rate. To further study the response mechanism of silkworms to tolfenpyrad stimulation, we compared the different expression genes by transcriptome sequencing and verified them by qRT-PCR. We found that significant changes in the genes expression was involved in xenobiotics biodegradation and metabolism, immune system and digestive system after tolfenpyrad treatment. To further investigate the possible mechanisms by which intestinal microbia in the response to tolfenpyrad, we analysed the microbia changes in the midgut of silkworms by 16S rRNA gene sequencing. The results showed that the relative abundances of Enterobacter and Staphylococcus were increased whereas the Tyzzerella and Methylobacterium-Methylorubrum were decreased after tolfenpyrad stimulation. Taken together, these results indicated that low concentration of tolfenpyrad affect the growth and development of silkworms. Silkworms respond to the toxicity of tolfenpyrad by inducing immune and detoxification-related gene expression or altering microbial composition in the midgut.

The epidemic of stroke mortality attributed to high body mass index in mainland China: Current trends and future prediction.

Background: High body mass index (BMI) is an important risk factor for stroke. The aim of this study was to assess the long-term trend of high BMI-attributed stroke mortality and make projections through 2030. Methods: Data were extracted from the Global Burden of Disease Study 2019 and World Population Prospects 2019. An age-period-cohort framework was used in the analysis. Results: From 1990 to 2019, the age-standardized mortality rate (ASMR) of high BMI-attributed stroke among females decreased by 15.2%, while among males, it increased by 31.1%. All of the age groups studied showed an increasing pattern over the last 30 years in males, and in female, the age groups encompassing participants who were 25-69 years old showed a decreasing pattern. In the same birth cohort, high BMI-attributable stroke mortality rates increased exponentially with age in both sexes. For females, the period rate ratios (RR) showed a downward trend after 2000-2004, and the cohort RR also showed a downward trend after the birth cohort 1930-1934. For males, the period RR showed an upward trend, but this increase was halted in the most recent period, and the cohort RRs showed a monotonic increasing pattern. It was projected that the ASMR of high BMI-attributed stroke would decrease among females and increase among males in the near future and that the proportion of elderly individuals with death due to high BMI-attributed stroke was projected to increase. Conclusions: Over the last three decades, the high BMI-attributed stroke mortality rate decreased among females and increased among males, and these trends are projected to continue in the future. In addition, the proportion of elderly individuals with high BMI-attributed stroke mortality was projected to increase gradually in both men and women. More health-promoting efforts are needed, especially for elderly individuals and males.

Incidence and mortality trends of nasopharynx cancer from 1990 to 2019 in China: an age-period-cohort analysis.

BACKGROUND: Nasopharynx cancer (NPC) is a great health burden in China. This study explored the long-term trends of NPC incidence and mortality in China. METHODS: We retrospectively analyzed data from the Global Burden of Disease Study 2019 using an age-period-cohort framework. RESULTS: The age-standardized incidence rate (ASIR) of NPC increased by 72.7% and age-standardized mortality rate (ASMR) of NPC decreased by 51.7% for both sexes between 1990 and 2019. For males, the local drift for incidence was higher than 0 (P < 0.05) in those aged 20 to 79 years. For females, the local drift was higher than 0 (P < 0.05) in those aged 30 to 59 years, and lower than 0 (P < 0.05) in those aged 65 to 84 years. The local drift for mortality rates were less than 0 (P < 0.05) in every age group for both sexes. The estimated period relative risks (RRs) for incidence of NPC were increased monotonically for males, and increased for females after 2000. The increasing trend of cohort RRs of incidence was ceased in recent birth cohorts. Both period and cohort effects of NPC mortality in China decreased monotonically. CONCLUSIONS: Over the last three decades, the ASMR and crude mortality rate (CMR) of NPC has decreased, but the ASIR and crude incidence rate (CIR) increased in China. Although the potential mortality risk of NPC decreased, the risk of NPC incidence was found to increase as the period move forward, and suggested that control and prevention efforts should be enhanced.

Lentivector cryptic splicing mediates increase in CD34+ clones expressing truncated HMGA2 in human X-linked severe combined immunodeficiency.

X-linked Severe Combined Immunodeficiency (SCID-X1) due to IL2RG mutations is potentially fatal in infancy where 'emergency' life-saving stem cell transplant may only achieve incomplete immune reconstitution following transplant. Salvage therapy SCID-X1 patients over 2 years old (NCT01306019) is a non-randomized, open-label, phase I/II clinical trial for administration of lentiviral-transduced autologous hematopoietic stem cells following busulfan (6 mg/kg total) conditioning. The primary and secondary objectives assess efficacy in restoring immunity and safety by vector insertion site analysis (VISA). In this ongoing study (19 patients treated), we report VISA in blood lineages from first eight treated patients with longer follow up found a > 60-fold increase in frequency of forward-orientated VIS within intron 3 of the High Mobility Group AT-hook 2 gene. All eight patients demonstrated emergence of dominant HMGA2 VIS clones in progenitor and myeloid lineages, but without disturbance of hematopoiesis. Our molecular analysis demonstrated a cryptic splice site within the chicken ß-globin hypersensitivity 4 insulator element in the vector generating truncated mRNA transcripts from many transcriptionally active gene containing forward-oriented intronic vector insert. A two base-pair change at the splice site within the lentiviral vector eliminated splicing activity while retaining vector functional capability. This highlights the importance of functional analysis of lentivectors for cryptic splicing for preclinical safety assessment and a redesign of clinical vectors to improve safety.

Prevalence of and Factors Associated With Nutritional Supplement Use Among Older Chinese Adults: A Nationwide Cross-Sectional Study in China.

Objective: This study identified the prevalence of nutritional supplement (NS) use among older Chinese adults and explored the factors associated with NS use in this population. Methods: We used data from 11,089 Chinese men and women aged ≥ 65 years from the 2018 Chinese Longitudinal Healthy Longevity Survey. The chi-square test was used to examine the differences in demographics, health status and lifestyles at different levels. Multivariate logistic regression was used to assess the association between NS use and demographic and lifestyle characteristics. Results: Twelve percent of Chinese adults aged 65 years and above used NS. In terms of the type of supplement used, the most commonly used was calcium (8.49%), followed by protein (2.73%) and multivitamins (2.40%). In terms of demographic characteristics, women, older people, urban residents with other marital status, higher educational level, better living conditions and better lifestyle habits showed a greater use of some kinds of NS to varying degrees. Factors associated with the use of any NS included female gender [OR = 1.71, 95% confidence intervals (95% CI): 1.09-1.44], age 85-94 (OR = 1.30, 95% CI: 1.08-1.58), urban household registration (hukou) (OR = 1.25, 95% CI:1.46-2.00), higher education (primary school and middle school: OR = 1.32, 95% CI:1.14-1.52; high school and above: OR = 1.56, 95% CI:1.25-1.94), average and poor living standard (average: OR = 0.64, 95% CI:0.56-0.73; poor: OR = 0.42, 95% CI:0.32-0.55), poor health status (OR = 1.36, 95% CI:1.13-1.63), former smoking (OR = 1.33, 95% CI:1.11-1.60), and having exercise habits (former exercise: OR = 2.24, 95% CI:1.83-2.74; current exercise: OR = 2.28, 95% CI:2.00-2.61). Women reported taking 2-3 kinds of NSs, and more than 50% of NS users reported taking supplements often. Conclusion: This study provides information on the current prevalence of NS use among older Chinese adults, and it clarifies the association of NS use with demographic, lifestyle and other factors. Providing scientifically based health guidance on NS use for older people is crucial to promoting their health.

Molecular mechanism and potential application of bacterial infection in the silkworm, Bombyx mori.

As a representative species of Lepidoptera, Bombyx mori has been widely studied and applied. However, bacterial infection has always been an important pathogen threatening the growth of silkworms. Bombyx mori can resist various pathogenic bacteria through their own physical barrier and innate immune system. However, compared with other insects, such as Drosophila melanogaster, research on the antibacterial mechanism of silkworms is still in its infancy. This review systematically summarized the routes of bacterial infection in silkworms, the antibacterial mechanism of silkworms after ingestion or wounding infection, and the intestinal bacteria and infection of silkworms. Finally, we will discuss silkworms as a model animal for studying bacterial infectious diseases and screening antibacterial drugs.

Temporal Trends in the Incidence and Disability Adjusted Life Years of Schizophrenia in China Over 30 Years.

Background: Schizophrenia is an important public health problem in China. This study aims to assess the long-term trends in the incidence and disability-adjusted life years (DALYs) rate of schizophrenia in China between 1990 and 2019. Methods: The incidence and DALYs data were drawn from the Global Burden of Disease Study 2019, and an age-period-cohort model was used in the analysis. Results: The age-standardized incidence rate (ASIR) and age-standardized DALYs rate (ASDR) of schizophrenia increased by 0.3 and 3.7% for both sexes between 1990 and 2019. For males, the local drift for incidence was higher than 0 (P < 0.05) in those aged 10 to 29 years (local drifts, 0.01 to 0.26%) and lower than 0 (P < 0.05) in those aged 35 to 74 years (local drifts, -1.01 to -0.06%). For females, the local drift was higher than 0 (P < 0.05) in those aged 10 to 34 years (local drifts, 0.05 to 0.26%) and lower than 0 (P < 0.05) in those aged 40 to 74 years (local drifts, -0.86 to -0.11%). The local drift for DALYs rate was higher than 0 (P < 0.05) in the age group from 10 to 69 years (local drifts, 0.06 to 0.26% for males and 0.06 to 0.28% for females). The estimated period and cohort relative risks (RR) for DALYs rate of schizophrenia were found in monotonic upward patterns, and the cohort RR for the incidence increased as the birth cohort moved forward starting with those born in 1972. Conclusion: Although the crude incidence of schizophrenia has decreased in China, the ASIR, ASDR, and crude DALYs rate all showed a general increasing trend over the last three decades. The DALYs rate continue to increase as the birth cohort moved forward, and the increasing trend of incidence was also found in individuals born after 1972. More efforts are needed to promote mental health in China.

Yap-Sox9 signaling determines hepatocyte plasticity and lineage-specific hepatocarcinogenesis.

BACKGROUND & AIMS: Primary liver tumors comprise distinct subtypes. A subset of intrahepatic cholangiocarcinoma (iCCA) can arise from cell fate reprogramming of mature hepatocytes in mouse models. However, the underpinning of cell fate plasticity during hepatocarcinogenesis is still poorly understood, hampering therapeutic development for primary liver cancer. As YAP activation induces liver tumor formation and cell fate plasticity, we investigated the role of Sox9, a transcription factor downstream of Yap activation that is expressed in biliary epithelial cells (BECs), in Yap-induced cell fate plasticity during hepatocarcinogenesis. METHODS: To evaluate the function of Sox9 in YAP-induced hepatocarcinogenesis in vivo, we used several genetic mouse models of inducible hepatocyte-specific YAP activation with simultaneous Sox9 removal. Cell fate reprogramming was determined by lineage tracing and immunohistochemistry. The molecular mechanism underlying Yap and Sox9 function in hepatocyte plasticity was investigated by transcription and transcriptomic analyses of mouse and human liver tumors. RESULTS: Sox9, a marker of liver progenitor cells (LPCs) and BECs, is differentially required in YAP-induced stepwise hepatocyte programming. While Sox9 has a limited role in hepatocyte dedifferentiation to LPCs, it is required for BEC differentiation from LPCs. YAP activation in Sox9-deficient hepatocytes resulted in more aggressive HCC with enhanced Yap activity at the expense of iCCA-like tumors. Furthermore, we showed that 20% of primary human liver tumors were associated with a YAP activation signature, and tumor plasticity is highly correlated with YAP activation and SOX9 expression. CONCLUSION: Our data demonstrated that Yap-Sox9 signaling determines hepatocyte plasticity and tumor heterogeneity in hepatocarcinogenesis in both mouse and human liver tumors. We identified Sox9 as a critical transcription factor required for Yap-induced hepatocyte cell fate reprogramming during hepatocarcinogenesis. LAY SUMMARY: Sox9, a marker of liver progenitor cells and bile duct lining cells, is a downstream target of YAP protein activation. Herein, we found that YAP activation in hepatocytes leads to a transition from mature hepatocytes to liver progenitor cells and then to bile duct lining cells. Sox9 is required in the second step during mouse hepatocarcinogenesis. We also found that human YAP and SOX9 may play similar roles in liver cancers.

Insertional activation of STAT3 and LCK by HIV-1 proviruses in T cell lymphomas.

Retroviruses cause cancers in animals by integrating in or near oncogenes. Although HIV-1 infection increases the risk of cancer, most of the risk is associated with immunodeficiency and coinfection by oncogenic virus (Epstein-Barr virus, Kaposi sarcoma herpesvirus, and human papillomavirus). HIV-1 proviruses integrated in some oncogenes cause clonal expansion of infected T cells in vivo; however, the infected cells are not transformed, and it is generally believed that HIV-1 does not cause cancer directly. We show that HIV-1 proviruses integrated in the first introns of signal transducer and activator of transcription 3 (STAT3) and lymphocyte-specific protein tyrosine kinase (LCK) can play an important role in the development of T cell lymphomas. The development of these cancers appears to be a multistep process involving additional nonviral mutations, which could help explain why T cell lymphomas are rare in persons with HIV-1 infection.

NLRP3 Inhibition Ameliorates Severe Cutaneous Autoimmune Manifestations in a Mouse Model of Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy-Like Disease.

Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy show diverse endocrine and nonendocrine manifestations initiated by self-reactive T cells because of AIRE mutation-induced defective central tolerance. A large number of American patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy suffer from early-onset cutaneous inflammatory lesions accompanied by an infiltration of T cells and myeloid cells. The role of myeloid cells in this setting remains to be fully investigated. In this study, we characterize the autoinflammatory phenotypes in the skin of both autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy-like kinase-dead Ikkα knockin mice and patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. We found a marked infiltration of autoreactive CD4 T cells, macrophages, and neutrophils; elevated uric acid; and increased NLRP3, a major inflammasome component. Depleting autoreactive CD4 T cells or ablating Ccl2/Cxcr2 genes significantly attenuated the inflammasome activity, inflammation, and skin phenotypes in kinase-dead Ikkα knockin mice. Importantly, treatment with an NLRP3 inhibitor reduced skin phenotypes and decreased infiltration of CD4 T cells, macrophages, and neutrophils. These results suggest that increased myeloid cell infiltration contributes to autoreactive CD4 T cell-mediated skin autoinflammation. Thus, our findings reveal that the combined infiltration of macrophages and neutrophils is required for autoreactive CD4 T cell-mediated skin disease pathogenesis and that the NLRP3-dependent inflammasome is a potential therapeutic target for the cutaneous manifestations of autoimmune diseases.

Characteristics of Breast Ducts in Normal-Risk and High-risk Women and Their Relationship to Ductal Cytologic Atypia.

Breast ductal cytologic atypia is an important risk factor for sporadic breast cancer. Characterization of the associated normal breast tissue is needed to develop additional methods of risk assessment and new targets for breast cancer prevention. We conducted a prospective clinical trial evaluating women at normal-risk or at high-risk for sporadic breast cancer. Breast ductal cells were collected and studied cytologically and by gene expression profiling, and breast ductal architectural changes were studied by breast ductal endoscopy (BDE) and breast MRI. One hundred and forty subjects were studied, 70 at high risk (RR, 2.0-4.6) and 70 at normal risk. Cytologic atypia was present in 22.9% of high-risk and 25.7% of normal-risk subjects. Ductal endoscopy was performed in 89 subjects and revealed benign intraductal abnormalities, primarily intraductal fibrous webbing suggesting chronic inflammation, in 40.4% of high-risk and 5.4% of normal-risk subjects, respectively (P 2 = 0.0002). Two high-risk subjects with atypia and no normal-risk subjects with atypia developed invasive breast cancer. Gene expression profiling of ductal cells showed comparable gene expression profiles without enriched expression of previously defined oncogenic signatures in subjects with cellular atypia compared with those without atypia, and in high-risk subjects compared with normal-risk subjects (FDR > 0.5). Cytologic ductal atypia in normal-risk subjects does not appear to be of clinical significance. Atypia in women at high risk may be associated with benign and malignant breast ductal abnormalities; these characteristics of high-risk ductal cells may not be reflected in gene expression profiles.

Spindle-like and telophase-like self-assemblies mediated by complementary nucleobase molecular recognition.

Inspired by nature, supramolecular nanoparticles based on complementary nucleobase interactions have aroused wide interest. In our study, two kinds of fluorophores were conjugated at the end of nucleobase containing homopolymers, which can be used to confirm the binding state and calculate the binding constants among different nucleobase pairs. Furthermore, we describe a facile synthesis of nucleobase-functionalized amphiphilic polymers with rigid and flexible backbones using RAFT polymerization. Spindle-like or telophase-like supramolecular self-assemblies were formed by different components of such synthetic amphiphilic polymers.

IKKα inactivation promotes Kras-initiated lung adenocarcinoma development through disrupting major redox regulatory pathways.

Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are two distinct and predominant types of human lung cancer. IκB kinase α (IKKα) has been shown to suppress lung SCC development, but its role in ADC is unknown. We found inactivating mutations and homologous or hemizygous deletions in the CHUK locus, which encodes IKKα, in human lung ADCs. The CHUK deletions significantly reduced the survival time of patients with lung ADCs harboring KRAS mutations. In mice, lung-specific Ikkα ablation (IkkαΔLu ) induces spontaneous ADCs and promotes KrasG12D-initiated ADC development, accompanied by increased cell proliferation, decreased cell senescence, and reactive oxygen species (ROS) accumulation. IKKα deletion up-regulates NOX2 and down-regulates NRF2, leading to ROS accumulation and blockade of cell senescence induction, which together accelerate ADC development. Pharmacologic inhibition of NADPH oxidase or ROS impairs KrasG12D-mediated ADC development in IkkαΔLu mice. Therefore, IKKα modulates lung ADC development by controlling redox regulatory pathways. This study demonstrates that IKKα functions as a suppressor of lung ADC in human and mice through a unique mechanism that regulates tumor cell-associated ROS metabolism.

Autoreactive T Cells and Chronic Fungal Infection Drive Esophageal Carcinogenesis.

Humans with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a T cell-driven autoimmune disease caused by impaired central tolerance, are susceptible to chronic fungal infection and esophageal squamous cell carcinoma (ESCC). However, the relationship between autoreactive T cells and chronic fungal infection in ESCC development remains unclear. We find that kinase-dead Ikkα knockin mice develop APECED-like phenotypes, including impaired central tolerance, autoreactive T cells, chronic fungal infection, and ESCCs expressing specific human ESCC markers. Using this model, we investigated the link between ESCC and fungal infection. Autoreactive CD4 T cells permit fungal infection and incite tissue injury and inflammation. Antifungal treatment or autoreactive CD4 T cell depletion rescues, whereas oral fungal administration promotes, ESCC development. Inhibition of inflammation or epidermal growth factor receptor (EGFR) activity decreases fungal burden. Fungal infection is highly associated with ESCCs in non-autoimmune human patients. Therefore, autoreactive T cells and chronic fungal infection, fostered by inflammation and epithelial injury, promote ESCC development.