MIST: multiple instance learning network based on Swin Transformer for whole slide image classification of colorectal adenomas.

Colorectal adenoma is a recognized precancerous lesion of colorectal cancer (CRC), and at least 80% of colorectal cancers are malignantly transformed from it. Therefore, it is essential to distinguish benign from malignant adenomas in the early screening of colorectal cancer. Many deep learning computational pathology studies based on whole slide images (WSIs) have been proposed. Most approaches require manual annotation of lesion regions on WSIs, which is time-consuming and labor-intensive. This study proposes a new approach, MIST - Multiple Instance learning network based on the Swin Transformer, which can accurately classify colorectal adenoma WSIs only with slide-level labels. MIST uses the Swin Transformer as the backbone to extract features of images through self-supervised contrastive learning and uses a dual-stream multiple instance learning network to predict the class of slides. We trained and validated MIST on 666 WSIs collected from 480 colorectal adenoma patients in the Department of Pathology, The Affiliated Drum Tower Hospital of Nanjing University Medical School. These slides contained six common types of colorectal adenomas. The accuracy of external validation on 273 newly collected WSIs from Nanjing First Hospital was 0.784, which was superior to the existing methods and reached a level comparable to that of the local pathologist's accuracy of 0.806. Finally, we analyzed the interpretability of MIST and observed that the lesion areas of interest in MIST were generally consistent with those of interest to local pathologists. In conclusion, MIST is a low-burden, interpretable, and effective approach that can be used in colorectal cancer screening and may lead to a potential reduction in the mortality of CRC patients by assisting clinicians in the decision-making process. © 2022 The Pathological Society of Great Britain and Ireland.

FAM134B-induced endoplasmic reticulum (ER)-phagy exacerbates cisplatin-insulted hair cell apoptosis ：Possible relation to excessive ER stress.

AIMS: FAM134B, the initial endoplasmic reticulum (ER)-phagy receptor identified, facilitates ER-phagy during ER stress. The malfunction of FAM134B has been demonstrated to have a crucial role in the pathological mechanisms of diverse human ailments. However, the role of FAM134B-mediated ER-phagy in ototoxicity, particularly in cisplatin-induced ototoxicity, remains unclear. The present study endeavors to investigate whether FAM134B is expressed in House Ear Institute-Organ of Corti 1 (HEI-OC1) and C57BL/6 murine cochlear hair cells (HCs), and to explore its potential function in cisplatin-mediated ototoxicity, with the aim of discovering new insights that can mitigate or forestall the irreversible adverse effect of cisplatin. METHODS: Immunofluorescence (IF) staining was used to test the expression pattern of FAM134B, levels of C/EBP-homologous protein (CHOP), autophagy, and co-localization ratio of lysosomes and ER. Western blotting was employed to measure changes in expression levels of FAM134B, LC3B, ER stress-related proteins, LAMP1 and apoptotic mediators. Cell apoptosis was examined using transferase dUTP nick end labeling (TUNEL) assay and flow cytometry. RESULTS: In the present investigation, it was observed that FAM134B exhibited a diffuse expression pattern in the cytoplasm and nuclei of control HEI-OC1 cells. Following cisplatin administration, FAM134B was found to accumulate and form distinct dots around the nuclei, concomitant with increased levels of ER-phagy, ER stress, unfolded protein response (UPR), and cell apoptosis. Additionally, knockdown of FAM134B resulted in reduced ER-phagy, mitigated ER stress and UPR, and decreased apoptotic activity in HEI-OC1 cells following cisplatin exposure. CONCLUSIONS: Collectively, the findings of this study demonstrate that FAM134B-mediated ER-phagy enhances the susceptibility of HCs to ER stress and apoptosis in response to cisplatin-induced stress. This suggests a sequential progression of ER-phagy, ER stress and apoptosis following cisplatin stimulus, and implies the potential therapeutic benefit of inhibiting of FAM134B-mediated ER-phagy in the prevention of cisplatin-related ototoxicity.

Pilot study of a novel nanobody 68 Ga-NODAGA-SNA006 for instant PET imaging of CD8+ T cells.

PURPOSE: Positron emission tomography (PET) with specific diagnostic probes for quantifying CD8+ T cells has emerged as a powerful technique for monitoring the immune response. However, most CD8+ T cell radiotracers are based on antibodies or antibody fragments, which are slowly cleared from circulation. Herein, we aimed to develop and assess 68 Ga-NODAGA-SNA006 for instant PET (iPET) imaging of CD8+ T cells. METHODS: A novel nanobody without a hexahistidine (His6) tag, SNA006-GSC, was designed, site-specifically conjugated with NODAGA-maleimide and radiolabelled with 68 Ga. The PET imaging profiles of 68 Ga-NODAGA-SNA006 were evaluated in BALB/c MC38-CD8+/CD8- tumour models and cynomolgus monkeys. Three volunteers with lung cancer underwent whole-body PET/CT imaging after 68 Ga-NODAGA-SNA006 administration. The biodistribution, pharmacokinetics and dosimetry of patients were also investigated. In addition, combined with immunohistochemistry (IHC), the quantitative performance of the tracer for monitoring CD8 expression was evaluated in BALB/c MC38-CD8+/CD8- and human subjects. RESULTS: 68 Ga-NODAGA-SNA006 was prepared with RCP > 98% and SA > 100 GBq/µmol. 68 Ga-NODAGA-SNA006 exhibited specific uptake in MC38-CD8+ xenografts tumours, CD8-rich tissues (such as the spleen) in monkeys and CD8+ tumour lesions in patients within 1 h. Fast washout from circulation was observed in three volunteers (t1/2 < 20 min). A preliminary quantitative linear relationship (R2 = 0.9668, p < 0.0001 for xenografts and R2 = 0.7924, p = 0.0013 for lung patients) appeared between 68 Ga-NODAGA-SNA006 uptake and CD8 expression. 68 Ga-NODAGA-SNA006 was well tolerated by all patients. CONCLUSION: 68 Ga-NODAGA-SNA006 PET imaging can instantly quantify CD8 expression with an ideal safety profile and is expected to be important for dynamically tracking CD8+ T cells and monitoring immune responses for individualised cancer immunotherapy. TRIAL REGISTRATION: NCT05126927 (19 November 2021, retrospectively registered).

Automated tumor proportion scoring for PD-L1 expression based on multistage ensemble strategy in non-small cell lung cancer.

INTRODUCTION: Programmed cell death ligand-1 (PD-L1) expression is a promising biomarker for identifying treatment related to non-small cell lung cancer (NSCLC). Automated image analysis served as an aided PD-L1 scoring tool for pathologists to reduce inter- and intrareader variability. We developed a novel automated tumor proportion scoring (TPS) algorithm, and evaluated the concordance of this image analysis algorithm with pathologist scores. METHODS: We included 230 NSCLC samples prepared and stained using the PD-L1(SP263) and PD-L1(22C3) antibodies separately. The scoring algorithm was based on regional segmentation and cellular detection. We used 30 PD-L1(SP263) slides for algorithm training and validation. RESULTS: Overall, 192 SP263 samples and 117 22C3 samples were amenable to image analysis scoring. Automated image analysis and pathologist scores were highly concordant [intraclass correlation coefficient (ICC) = 0.873 and 0.737]. Concordances at moderate and high cutoff values were better than at low cutoff values significantly. For SP263 and 22C3, the concordances in squamous cell carcinomas were better than adenocarcinomas (SP263 ICC = 0.884 vs 0.783; 22C3 ICC = 0.782 vs 0.500). In addition, our automated immune cell proportion scoring (IPS) scores achieved high positive correlation with the pathologists TPS scores. CONCLUSIONS: The novel automated image analysis scoring algorithm permitted quantitative comparison with existing PD-L1 diagnostic assays and demonstrated effectiveness by combining cellular and regional information for image algorithm training. Meanwhile, the fact that concordances vary in different subtypes of NSCLC samples, which should be considered in algorithm development.

Epstein-Barr virus and cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation in patients with non-Hodgkin lymphoma: the prevalence and impacts on outcomes : EBV and CMV reactivation post allo-HCT in NHL.

Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivations are common complications after allogeneic hematopoietic cell transplantation (allo-HCT), but data focusing on non-Hodgkin lymphoma (NHL) are limited. We retrospectively analyzed the prevalence of EBV and CMV reactivation post-allo-HCT and the impacts on transplant outcomes in 160 NHL patients. The 1-year incidences of EBV and CMV reactivation were 22.58% and 25.55%, respectively. Independent impactors for EBV reactivation were more than 6 lines of chemotherapy (P = 0.030), use of rituximab (P = 0.004), and neutrophil recovery within 30 days post-HCT (P = 0.022). For T-cell lymphoblastic lymphoma patients, the International Prognostic Index (IPI) (P = 0.015) and chronic GVHD (P = 0.001) increased the risk of CMV reactivation. CMV reactivation was independently related to a lower risk of relapse (P = 0.027) but higher transplant-related mortality (TRM) (P = 0.038). Although viral reactivation had no significant impact on overall survival (OS) in the whole cohort, it led to an inferior 2-year OS (67.6% versus 92.5%, P = 0.005) and TRM (20.1% versus 4.7%, P = 0.020) in recipients surviving for more than 180 days. We concluded that EBV and CMV reactivation post-allotransplant still deserved concern particularly in NHL patients with high-risk factors, since it is generally related to a deteriorated prognosis. Large-scale studies are warranted to validate our findings.

Molecular heterogeneity in diffuse large B-cell lymphoma and its implications in clinical diagnosis and treatment.

Over half of patients with diffuse large B-cell lymphoma (DLBCL) can be cured by standard R-CHOP treatment (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). However, the remaining patients are refractory and ultimately succumb to progressive or relapsed disease. During the past decade, there has been significant progress in the understanding of molecular mechanisms in DLBCL, largely owing to collaborative efforts in large-scale gene expression profiling and deep sequencing, which have identified genetic alterations critical in lymphomagenesis through activation of key signaling transduction pathways in DLBCL. These discoveries have not only led to the development of targeted therapies, including several currently in clinical trials, but also laid a solid foundation for the future identification of more effective therapies for patients not curable by R-CHOP. This review summarizes the recent advances in our understanding of the molecular characterization and pathogenesis of DLBCL and new treatment directions.

Reduction of air pollutants and associated mortality during and after the COVID-19 lockdown in China: Impacts and implications.

Although strict lockdown measurements implemented during the COVID-19 pandemic have dramatically reduced the anthropogenic-based emissions, changes in air quality and its health impacts remain unclear in China. We comprehensively described air pollution during and after the lockdown periods in 2020 compared with 2018-2019, and estimated the mortality burden indicated by the number of deaths and years of life lost (YLL) related to the air pollution changes. The mean air quality index (AQI), PM10, PM2.5, NO2, SO2 and CO concentrations during the lockdown across China declined by 18.2 (21.2%), 27.0 µg/m3 (28.9%), 10.5 µg/m3 (18.3%), 8.4 µg/m3 (44.2%), 13.1 µg/m3 (38.8%), and 0.3 mg/m3 (27.3%) respectively, when compared to the same periods during 2018-2019. We observed an increase in O3 concentration during the lockdown by 5.5 µg/m3 (10.4%), and a slight decrease after the lockdown by 3.4 µg/m3 (4.4%). As a result, there were 51.3 (95%CI: 32.2, 70.1) thousand fewer premature deaths (16.2 thousand during and 35.1 thousand after the lockdown), and 1066.8 (95%CI: 668.7, 1456.8) thousand fewer YLLs (343.3 thousand during and 723.5 thousand after the lockdown) than these in 2018-2019. Our findings suggest that the COVID-19 lockdown has caused substantial decreases in air pollutants except for O3, and that substantial human health benefits can be achieved when strict control measures for air pollution are taken to reduce emissions from vehicles and industries. Stricter tailored policy solutions of air pollution are urgently needed in China and other countries, especially in well-developed industrial regions, such as upgrading industry structure and promoting green transportation.

Clinical value of high-resolution dynamic contrast-enhanced (DCE) MRI in diagnosis of cutaneous squamous cell carcinoma.

BACKGROUND: While uncomplicated cases of skin squamous cell carcinoma (cSCC) can be treated with surgery topical therapy alone, more objective and non-invasive examination methods are needed to guide clinicians to make more detailed biopsy and surgical plans for lesions with atypical or subcutaneous growth. High-resolution magnetic resonance imaging (HR-MRI) is a novel skin imaging method. MATERIALS AND METHODS: Prospective collection of 19 patients with clinically suspected cSCC. All patients underwent high-resolution DCE-MRI using a 70-mm microscopy coil before operation. The imaging features and results of surgical pathology were recorded. Ktrans , Kep , Ve values, and the time-signal curve (TIC) types were determined using DCE images. RESULTS: 16 cases of cSCC, 3 cases of acanthoma. The subcutaneous invasion of all lesions was clearly displayed, of which 8 lesions invaded the subcutaneous fat layer, 5 invaded the muscle layer, 1 invaded the periosteum, 2 invaded the cap fascia, and the layer of all lesions invasion judged by HR-MR imaging was consistent with the postoperative pathology. The main manifestations of cSCC were ill-defined margin, obvious inhomogeneous enhancement, higher perfusion parameters value and type-III TIC, while acanthoma showed well-defined and type-I TIC. Some imaging findings (such as boundary, enhancement) and DCE perfusion parameters of the two groups overlap. CONCLUSION: High-resolution DCE-MRI can fully and directly display the subcutaneous invasion of cSCC, and more work needs to be done to prove its value. Next, we will expand the sample size, and further explore its value in the differential diagnosis and prognosis evaluation of cSCC from acanthoma or other skin tumors.

The value of preoperative high-resolution MRI with microscopy coil for facial nonmelanoma skin cancers.

BACKGROUND: The extent and depth of facial nonmelanoma skin cancers and the involvement of adjacent structures are critical features for surgical planning, but they are difficult to assess clinically. High-resolution MRI (HR-MRI) with microscopy coil may facilitate detailed evaluation of skin lesions. The authors performed this prospective study to determine the value of high-resolution microscopy coil MRI in the preoperative evaluation of nonmelanoma skin cancer. MATERIALS AND METHODS: Between October 2018 and August 2019, 16 lesions from fifteen consecutive patients with facial nonmelanoma skin cancer were evaluated using high-resolution microscopy coil MRI about tumor extent, depth, margins, characteristic, and their spatial relationship with adjacent structures. The preoperative HR-MRI results were compared with the intraoperative findings and with the histopathology, with special note to the depth of invasion. RESULTS: Among the 16 lesions, HR-MRI imaging was found to provide accurate evaluation of tumor extent, depth, and margins and determine whether there was involvement of adjacent structures. The tumor depth measured on HR-MRI showed good correlation with histopathologic results (CCC: 0.973), and Bland-Altman analysis finding no significant bias existed between the two measurements. All lesions except one were completely resected with primary excision. Only one lesion required further excision. During follow-up for 3-15 months, no tumor recurrence was observed in any case. CONCLUSIONS: HR-MRI is an accurate, noninvasive imaging technique that can be used as preoperative evaluation tool for facial nonmelanoma skin cancer. It can accurate predict tumor depth, margins, and involvement of structure. The valuable information it provided facilitates surgeons optimize surgical planning.

The relationship between ambient temperature and fasting plasma glucose, temperature-adjusted type 2 diabetes prevalence and control rate: a series of cross-sectional studies in Guangdong Province, China.

BACKGROUND: There existed evidence that type 2 diabetes mellitus (T2DM) prevalence and control rate have seasonal variation. Our study aimed to examine the ambient temperature and fasting plasma glucose (FPG) association and estimate temperature-adjusted T2DM prevalence and control rate. METHODS: Four cross-sectional health surveys with 26,350 respondents were conducted in Guangdong Province from 2007 to 2015. Multistage cluster sampling was used to recruit study participants. The data of demographic characteristics, lifestyle factors, diet and use of hypoglycemic medicine, height, weight, FPG and meteorological information were collected. And an inverse distance-weighted method was employed to estimate daily temperature exposures at the individual' s residential district/county. Base on World Health Organization 2006 criteria, participants were divided into normal fasting glucose (NFG) participants (n = 23,877), known T2DM patients (n = 916) and newly detected T2DM patients (n = 1557). Generalized additive mixed model was employed to evaluate the nonlinear associations between temperature and FPG among different T2DM subgroups. The T2DM prevalence and control rate were estimated based on temperature-FPG association. RESULTS: The curves of temperature and FPG were downward parabola for total, NFG and known T2DM groups, while it was "U"-shaped for newly detected T2DM patients. When temperature decreased from 30 °C to 4 °C, the FPG significantly increased 0.24 (95%CI: 0.15, 0.33) mmol/L, 0.10 (95%CI: 0.06, 0.14) mmol/L and 1.34 (95%CI: 0.56, 2.12) mmol/L in total, NFG and known T2DM groups, respectively. Compared to 19 °C, newly detected T2DM patients' FPGs were increased 0.73 (95%CI: 0.13, 1.30) mmol/L at 4 °C and 0.53 (0.00, 1.07) mmol/L at 30 °C. The model-estimated temperature-adjusted T2DM prevalence had a down and up trend, with 9.7% at 5 °C, 8.9% at 20 °C and 9.4% at 30 °C, respectively. At 5, 10, 15, 20, 25 and 30 °C, the model-estimated temperature-adjusted T2DM control rates were 33.2, 35.4, 38.2, 43.6, 49.1 and 55.2%. CONCLUSION: Temperature was negatively associated with FPG for NFG and known T2DM subgroups, while their association was U-shape for newly detected T2DM patients. Hence, the temperature-adjusted T2DM prevalence show a dip/peak pattern and T2DM control rate display a rising trend when temperature increase. Our findings suggest temperature should be considered in T2DM clinic management and epidemiological survey.

Identification of vital genes and pathways associated with mucosal melanoma in Chinese.

Mucosal melanoma is a rare malignant melanoma with more aggressive and poorer outcomes. The incidence of mucosal melanoma varies greatly among different ethnic groups. We herein sought to characterize the vital genes and pathways of Chinese mucosal melanoma patients. By whole-exome sequencing in six patients with mucosal melanoma, we detected a total of 21,733 CNVs and 2372 SNPs. The CNV/SNP burden varies greatly between individuals, including recurrent CNV targeting PIK3 family, KRAS, APC and BRCA1. Significantly mutated genes were NUDT5, ZBTB18, NEURL4, ZNF430, RBM44, GAK, PCDHA13, STK38 and UBR5. Besides, FAT1 gene was identified frequently mutated in anorectal melanoma patients (3/3, 100%). Moreover, our result showed that HPV infection may be associated with mucosal melanoma. In conclusion, this study indicated that mucosal melanomas have a low SNPs burden and a high number of CNVs and expand the spectrum of mucosal melanoma variants, also provided an insight for the pathological mechanism of mucosal melanoma.

[Identifying Molecular Subtypes of Whole-Slide Image in Colorectal Cancer via Deep Learning].

OBJECTIVE: To establish an artificial intelligence-assisted diagnosis system for molecular subtyping of colorectal cancer (CRC). METHODS: 812 whole-slide images (WSIs) of 422 patients were selected from the database of The Cancer Genome Atlas (TCGA) and were put into the training set (75%) and the test set (25%). The slides were stored in the www.paiwsit.com database. We preprocessed and segmented the slides based on the labelling results of experienced pathologists to generate a training set of more than 4 million labeled samples. Finally, deep learning models were adopted for training. RESULTS: After training with several convolutional neural network models, we tested the performance of the trained deep learning model on the test set of 203 WSIs from 110 patients, and our model achieved an accuracy of 53.04% at patch-level and 51.72% at slide-level, while the accuracy of CMS2 (one of a consensus of four subtypes for CRC) at slide-level was as high as 75.00%. CONCLUSION: This study is of great significance to the promotion of colorectal cancer screening and precision treatment.

Identification of a small-molecule compound that inhibits homodimerization of oncogenic NAC1 protein and sensitizes cancer cells to anticancer agents.

Nucleus accumbens-associated protein-1 (NAC1) is a transcriptional repressor encoded by the NACC1 gene, which is amplified and overexpressed in various human cancers and plays critical roles in tumor development, progression, and drug resistance. NAC1 has therefore been explored as a potential therapeutic target for managing malignant tumors. However, effective approaches for effective targeting of this nuclear protein remain elusive. In this study, we identified a core unit consisting of Met7 and Leu90 in NAC1's N-terminal domain (amino acids 1-130), which is critical for its homodimerization and stability. Furthermore, using a combination of computational analysis of the NAC1 dimerization interface and high-throughput screening (HTS) for small molecules that inhibit NAC1 homodimerization, we identified a compound (NIC3) that selectively binds to the conserved Leu-90 of NAC1 and prevents its homodimerization, leading to proteasomal NAC1 degradation. Moreover, we demonstrate that NIC3-mediated down-regulation of NAC1 protein sensitizes drug-resistant tumor cells to conventional chemotherapy and enhances the antimetastatic effect of the antiangiogenic agent bevacizumab both in vitro and in vivo These results suggest that small-molecule inhibitors of NAC1 homodimerization may effectively sensitize cancer cells to some anticancer agents and that NAC1 homodimerization could be further explored as a potential therapeutic target in the development of antineoplastic agents.

The interplay of haze characteristics on mortality in the Pearl River Delta of China.

To estimate the mortality risk from haze and the modifying effects by three characteristics of haze (intensity, duration and timing), data on haze and mortality in the Pearl River Delta region from 2013 to 2016 were collected. We first estimated mortality risk during haze days compared with non-haze days. Then we classified haze into several categories by considering one or any two of the three haze characteristics together, and further calculated the mortality risks separately. The mortality risk increased 5.0% (95% confidence intervals (CI): 3.1%-6.9%) during hazy days compared with non-haze days, with larger effect for the elderly ≥ 85 years old (Excess risk (ER): 8.7%, 95% CI: 3.9%-13.6%) than other age groups. Mortality risk increased in longer haze (ER: 4.4%, 95% CI: 2.9%-6.0%) compared with shorter haze (ER: 1.9%, 95% CI: 0.7%-3.2%). The greatest effect of any two of haze characteristics was observed when haze was intense and long (ER: 4.8%, 95% CI: 3.0%-6.6%). Our study indicates that haze significantly increased mortality risk in the Pearl River Delta. The health effects of haze may be under-estimated when using a single air pollutant concentration during haze periods to assess health risk of haze events. The haze intensity, duration, and time of occurrence should be accounted for in appropriate risk assessment of haze.

Associations of maternal ozone exposures during pregnancy with maternal blood pressure and risk of hypertensive disorders of pregnancy: A birth cohort study in Guangzhou, China.

Although studies have assessed the associations of maternal exposure to ozone (O3) during pregnancy with blood pressure and the risk of hypertensive disorders of pregnancy (HDP), the results were inconsistent. Furthermore, no studies have been conducted in China where the ambient O3 concentration continuedly increased. The present study aimed to estimate the effects of maternal exposure to O3 during pregnancy on the HDP risk, systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP). All participants of pregnant women were selected from the prospective birth cohort study on Prenatal Environments and Offspring Health conducted in Guangzhou, China. A spatiotemporal land-use-regression model was used to estimate individual monthly air pollution exposure from three months before pregnancy to childbirth date. Information on HDP, SBP, DBP and PP was obtained from maternal medical records. A Logistic regression model and a mixed linear model were used to estimate the associations of maternal exposure to O3 with the risk of HDP and blood pressure (SBP, DBP and PP), respectively. We found significant associations of maternal exposure to O3 during the third (OR = 1.31, 95%CI: 1.07, 1.60) and the second month (OR = 1.25, 95%CI: 1.02, 1.51) before pregnancy with the risk of HDP. Observed significantly positive associations of O3 exposures with SBP, DBP and PP during the two months before pregnancy and during the early pregnancy. The peak effects of O3 exposure on SBP, DBP and PP were respectively observed during the second month of pregnancy (ß = 1.07  mmHg, 95%CI: 0.84, 1.31  mmHg), the first month before pregnancy (ß = 0.40  mmHg, 95%CI: 0.21, 0.50  mmHg) and the second month of pregnancy (ß = 0.78  mmHg, 95%CI: 0.59, 0.97  mmHg). Our results suggest that maternal exposure to O3 were positively associated with blood pressure and the risk of HDP, and the period from three months before pregnancy to the first trimester might be the critical exposure window.

Comparison of life loss per death attributable to ambient temperature among various development regions: a nationwide study in 364 locations in China.

BACKGROUND: Several studies have investigated the associations between ambient temperature and years of life lost (YLLs), but few focused on the difference of life loss attributable to temperature among different socioeconomic development levels. OBJECTIVES: We investigated the disparity in temperature-YLL rate relationships and life loss per death attributable to nonoptimal temperature in regions with various development levels. METHODS: Three hundred sixty-four Chinese counties or districts were classified into 92 high-development regions (HDRs) and 272 low-development regions (LDRs) according to socioeconomic factors of each location using K-means clustering approach. We used distributed lag non-linear models (DLNM) and multivariate meta-analysis to estimate the temperature-YLL rate relationships. We calculated attributable fraction (AF) of YLL and temperature-related average life loss per death to compare mortality burden of temperature between HDRs and LDRs. Stratified analyses were conducted by region, age, sex and cause of death. RESULTS: We found that non-optimal temperatures increased YLL rates in both HDRs and LDRs, but all subgroups in LDRs were more vulnerable. The disparity of cold effects between HDRs and LDRs was significant, while the difference in heat effect was insignificant. The overall AF of non-optimal temperature in LDRs [AF = 12.2, 95% empirical confidence interval (eCI):11.0-13.5%] was higher than that in HDRs (AF = 8.9, 95% eCI: 8.3-9.5%). Subgroups analyses found that most groups in LDRs had greater AFs than that in HDRs. The average life loss per death due to non-optimal temperature in LDRs (1.91 years, 95% eCI: 1.72-2.10) was also higher than that in HDRs (1.32 years, 95% eCI: 1.23-1.41). Most of AFs and life loss per death were caused by moderate cold in both HDRs and LDRs. CONCLUSIONS: Mortality burden caused by temperature was more significant in LDRs than that in HDRs, which means that more attention should be paid to vulnerable populations in LDRs in planning adaptive strategies.

HMGA1 in cancer: Cancer classification by location.

The high mobility group A1 (HMGA1) gene plays an important role in numerous malignant cancers. HMGA1 is an oncofoetal gene, and we have a certain understanding of the biological function of HMGA1 based on its activities in various neoplasms. As an architectural transcription factor, HMGA1 remodels the chromatin structure and promotes the interaction between transcriptional regulatory proteins and DNA in different cancers. Through analysis of the molecular mechanism of HMGA1 and clinical studies, emerging evidence indicates that HMGA1 promotes the occurrence and metastasis of cancer. Within a similar location or the same genetic background, the function and role of HMGA1 may have certain similarities. In this paper, to characterize HMGA1 comprehensively, research on various types of tumours is discussed to further understanding of the function and mechanism of HMGA1. The findings provide a more reliable basis for classifying HMGA1 function according to the tumour location. In this review, we summarize recent studies related to HMGA1, including its structure and oncogenic properties, its major functions in each cancer, its upstream and downstream regulation associated with the tumourigenesis and metastasis of cancer, and its potential as a biomarker for clinical diagnosis of cancer.

MicroRNA-143-3p inhibits colorectal cancer metastases by targeting ITGA6 and ASAP3.

MicroRNAs, which regulate mRNAs, operate through a variety of signaling pathways to participate in the development of colorectal cancer (CRC). In this study, we found that microRNA (miR)-143-3p expression was significantly lower in both CRC and liver metastatic CRC tissues from liver compared with normal colonic tissues. Functional assays showed that miR-143-3p inhibited CRC cell invasion and migration in vitro. Using a bioinformatics approach, we identified miR-143-3p target mRNAs. Among the candidate targets, only the expression of integrin alpha 6 (ITGA6) and ArfGAP with the SH3 domain and ankyrin repeat and PH domain 3 (ASAP3) were significantly reduced by miR-143-3p mimics as examined by western blot, and the metastasis potential of CRC cells was attenuated by endogenous ITGA6 and ASAP3 knockdown, determined by migration and invasion assays. Both ITGA6 and ASAP3 were upregulated in CRC tissues compared to normal tissues. Analysis of the relationship between clinicopathological features and ITGA6/ASAP3 protein expression in 200 patients with CRC showed a significant difference in positive ITGA6 expression between the early stage (I + II) and the advanced stage (III + IV), and ASAP3 expression levels positively correlated with metastasis in the lymph nodes. These results indicate that miR-143-3p acts as an anti-oncogene by downregulating ITGA6/ASAP3 protein expression and could offer new insight into potential therapeutic targets for CRC.

Morbidity burden of respiratory diseases attributable to ambient temperature: a case study in a subtropical city in China.

BACKGROUND: There are significant associations between ambient temperature and respiratory disease mortality. However, few studies have assessed the morbidity burdens of various respiratory diseases that are attributable to different temperature ranges in subtropical regions. METHODS: Daily outpatient visits, weather variables, and air pollution data were collected from January 2013 to August 2017 in a hospital in Dongguan city. A standard time series quasi-Poisson regression with a distributed lag non-linear model (DLNM) was applied to estimate the associations between daily mean temperature and morbidity for total respiratory diseases, bronchiectasis, chronic obstructive pulmonary disease (COPD), and asthma. Attributable fractions were then calculated to quantify disease burden relative to different temperature components. Finally, we conducted stratified analysis by age group. RESULTS: Both low and high temperatures were associated with an increased risk of morbidity secondary to respiratory diseases. Compared with the optimum temperature, the accumulated relative risk (RR) during the seven lag days was 1.13 with a 95% confidence interval (CI) of 1.01-1.26 for extreme heat and 1.02 (95% CI: 0.99-1.05) for extreme cold. Heat-related respiratory morbidity risk was higher than cold-related risk for the total population, but an opposite result was observed for the elderly. About 8.4% (95% CI: 2.8-13.3%) of respiratory morbidity was attributable to non-optimal temperatures, and moderate heat was responsible for most of the excess respiratory morbidity (7.5, 95% CI: 2.4-12.2%). CONCLUSIONS: We found that exposure to non-optimal temperatures increased the risk of respiratory morbidity in subtropical region, and moderate heat contributed to most of the temperature-related respiratory morbidities. This indicates a need for further examination of moderate, rather than extreme, heat in subtropical region.

Human Sex Hormone Disrupting Effects of New Flame Retardants and Their Interactions with Polychlorinated Biphenyls, Polybrominated Diphenyl Ethers, a Case Study in South China.

Even though sex hormone disrupting effects of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are widely understood, similar effects associated with new flame retardants (NFRs) have not been so well studied. This study aimed to explore the sex hormone disruption of NFRs and their interactions with PCBs and PBDEs through the conduct of an ecological study in an e-waste dismantling and control region in South China. Questionnaires and blood samples were collected from local adult residents. Results of generalized additive model and linear regression analyses indicate that several species of NFRs showed similar disrupting effects with PBDE congeners on female follicle-stimulating hormone (FSH) and male testosterone. Judged by the curved shape and statistical significance, ΣNFR (sum of 8 species of NFRs) showed stronger disrupting effects on male testosterone and female FSH compared to ΣPBDE (sum of 13 congeners of PBDEs). The interactions induced by NFRs complicated the original sex hormone disruption led by PCBs and PBDEs. The disrupting effects and interactions induced by NFRs decreased female FSH levels in the exposed group. Comprehensive evaluation is needed to provide the evidence base for judging the health risks arising from the increased usage of NFRs.