Improving the accuracy of mechanistic models for dynamic batch distillation enabled by neural network:An industrial plant case

Neural networks are often viewed as pure‘black box’models,lacking interpretability and extrapolation capabilities of pure mechanistic models.This work proposes a new approach that,with the help of neural networks,improves the conformity of the first-principal model to the actual plant.The final result is still a first-principal model rather than a hybrid model,which maintains the advantage of the high interpretability of first-principal model.This work better simulates industrial batch distillation which separates four components:water,ethylene glycol,diethylene glycol,and triethylene glycol.GRU(gated recurrent neural network)and LSTM(long short-term memory)were used to obtain empirical parameters of mechanistic model that are difficult to measure directly.These were used to improve the empirical processes in mechanistic model,thus correcting unreasonable model assumptions and achieving better predictability for batch distillation.The proposed method was verified using a case study from one industrial plant case,and the results show its advancement in improving model predictions and the potential to extend to other similar systems.

miR-124 suppresses multiple steps of breast cancer metastasis by targeting a cohort of pro-metastatic genes in vitro

Metastasis is a multistep process involving modification of morphology to suit migration, reduction of tumor cell adhesion to the extracellular matrix, increase of cell mobility, tumor cell resistance to anoikis, and other steps. MicroRNAs are well-suited to regulate tumor metastasis due to their capacity to repress numerous target genes in a coordinated manner, thereby enabling their intervention at multiple steps of the invasion-metastasis cascade. In this study, we identified a microRNA exemplifying these attributes, miR-124, whose expression was reduced in aggressive MDA-MB-231 and SK-3rd breast cancer cells. Down-regulation of miR-124 expression in highly aggressive breast cancer cells contributed in part to DNA hypermethylation around the promoters of the three genes encoding miR-124. Ectopic expression of miR-124 in MDA-MB-231 cells suppressed metastasis-related traits including formation of spindle-like morphology, migratory capacity, adhesion to fibronectin, and anoikis. These findings indicate that miR-124 suppresses multiple steps of metastasis by diverse mechanisms in breast cancer cells and suggest a potential application of miR-124 in breast cancer treatment.

A novel kind of multiple steady states characteristics in the dividing wall column

In this article, one kind of multiple steady states(MSS) phenomenon was investigated for a dividing wall column(DWC). The four-section model constructed in Aspen Plus was employed to simulate two DWC cases: mixture of n-hexane, n-heptane and n-octane;system of methanol, ethanol and n-propanol. It can be seen that there is a range of vapor split ratio in which multiple solutions of reflux ratio exist for fixed DWC configuration with the same feed and product streams. The width and the curve shapes of the MSS region, and the number of solutions change with the liquid split ratio. This MSS phenomenon was further explained using the component recovery around the prefractionator and the component recycling flow inside the DWC. This MSS phenomenon is helpful for DWC design by knowing the probable existence of multiple solutions in advance.

Comparison of breast-conserving surgery and mastectomy in early breast cancer using observational data revisited:a propensity score-matched analysis

Recent observational studies showed that breast-conserving surgery(BCS) resulted in superior survival compared to mastectomy in breast cancer patients. This study compared the clinical outcomes of BCS and mastectomy using propensity score(PS)matching analysis, which had advantages over conventional methods in reducing bias. Nonmetastatic breast cancer patients who underwent BCS and mastectomy were matched 1:1 based on their PS. We used the Kaplan-Meier method and Cox-regression model to estimate the treatment effects. A total of 2,866 patients with a median follow-up time of 67 months were included in the original study population. Although the mastectomy cohort(N=1,219) had more advanced disease compared to the BCS cohort(N=1,647), LRFS was similar between the two groups(93.8% vs. 92.4%, P>0.05). BCS(vs. mastectomy) was associated with improved DFS(73.8% vs. 58.7%, P<0.01) and CSS(91% vs. 78.2%, P<0.01) in the original population. In the PS-matched population(N=1,668), clinicopathological features were equally distributed between the two cohorts. BCS(vs. mastectomy) was not associated with improved DFS(70.7% vs. 66.9%, P>0.05) or CSS(87.5% vs. 84.9%, P>0.05). We found that PS methods reduce bias when estimating treatment effects using observational data. BCS and mastectomy show equivalent outcomes in nonmetastatic breast cancer patients.

Challenges and strategies for next-generation bispecific antibody-based antitumor therapeutics

Bispecific antibodies(bsAbs)refer to a large family of molecules that recognize two different epitopes or antigens.Although a series of challenges,especially immunogenicity and chain mispairing issues,once hindered the development of bsAbs,they have been gradually overcome with the help of rapidly developing technologies in the past 5 decades.In the meantime,an increasing number of bsAb platforms have been designed to satisfy different clinical demands.Currently,numerous preclinical and clinical trials are underway,portraying a promising future for bsAb-based cancer treatment.Nevertheless,bsAb drugs still face enormous challenges in their application as cancer therapeutics,including tumor heterogeneity and mutational burden,intractable tumor microenvironment(TME),insufficient costimulatory signals to activate T cells,the necessity for continuous injection,fatal systemic side effects,and off-target toxicities to adjacent normal cells.Therefore,we provide several strategies as solutions to these issues,which comprise generating multispecific bsAbs,discovering neoantigens,combining bsAbs with other anticancer therapies,exploiting natural killer(NK)-cell-based bsAbs and producing bsAbs in situ.In this review,we mainly discuss previous and current challenges in bsAb development and underscore corresponding strategies,with a brief introduction of several typical bsAb formats.

A 10-miRNA risk score-based prediction model for pathological complete response to neoadjuvant chemotherapy in hormone receptor-positive breast cancer

Patients with hormone receptor(HR)-positive tumors breast cancer usually experience a relatively low pathological complete response(p CR)to neoadjuvant chemotherapy(NAC).Here,we derived a 10-micro RNA risk score(10-mi RNA RS)-based model with better performance in the prediction of p CR and validated its relation with the disease-free survival(DFS)in 755 HRpositive breast cancer patients(273,265,and 217 in the training,internal,and external validation sets,respectively).This model,presented as a nomogram,included four parameters:the 10-mi RNA RS found in our previous study,progesterone receptor(PR),human epidermal growth factor receptor 2(HER2)status,and volume transfer constant(K).Favorable calibration and discrimination of 10-mi RNA RS-based model with areas under the curve(AUC)of 0.865,0.811,and 0.804 were shown in the training,internal,and external validation sets,respectively.Patients who have higher nomogram score(>92.2)with NAC treatment would have longer DFS(hazard ratio=0.57;95%CI:0.39–0.83;P=0.004).In summary,our data showed the 10-mi RNA RS-based model could precisely identify more patients who can attain p CR to NAC,which may help clinicians formulate the personalized initial treatment strategy and consequently achieves better clinical prognosis for patients with HRpositive breast cancer.

The roles of ncRNAs and histone-modifiers in regulating breast cancer stem cells

Cancer stem cells （CSCs）, a subpopulation of cancer cells with ability of initiating tumorigenesis, exist in many kinds of tumors including breast cancer. Cancer stem cells contribute to treatment resistance and relapse. Conventional treatments only kill differentiated cancer cells, but spare CSCs. Combining conventional treatments with therapeutic drugs targeting to CSCs will eradicate cancer cells more efficiently. Studying the molecular mechanisms of CSCs regulation is essential for developing new therapeutic strategies. Growing evidences showed CSCs are regulated by non-coding RNA （ncRNA） including microRNAs and long non-coding RNAs （IncRNAs）, and histone-modifiers, such as let- 7, miR-93, miR-100, HOTAIR, Bmi-1 and EZH2. Herein we review the roles of microRNAs, IncRNAs and histone- modifiers especially Polycomb family proteins in regulating breast cancer stem cells （BCSCs）.

The theory of tumor ecosystem

Cancer cells can be conceived as“living organisms”interacting with cellular or non-cellular components in the host internal environment,not only the local tumor microenvironment but also the distant organ niches,as well as the immune,nervous and endocrine systems,to construct a self-sustainable tumor ecosystem.With increasing evidence for the systemic tumor-host interplay,we predict that a new era of cancer therapy targeting the ecosystemic vulnerability of human malignancies has come.Revolving around the tumor ecosystem scoped as different hierarchies of primary,regional,distal and systemic onco-spheres,we comprehensively review the tumor-host interaction among cancer cells and their local microenvironment,distant organ niches,immune,nervous and endocrine systems,highlighting material and energy flow with tumor ecological homeostasis as an internal driving force.We also substantiate the knowledge of visualizing,modelling and subtyping this dynamically intertwined networkwith recent technological advances,and discuss ecologically rational strategies formore effective cancer therapies.

Overexpression of PITPNM3 promotes hepatocellular carcinoma cell metastasis

A previous study indicated that C–C chemokine(C–C motif)ligand 18(CCL18)is capable of inducing tumor cell invasion and metastasis by interacting with receptor membrane-associated phosphatidylinositol transfer protein 3(PITPNM3)in breast cancer cells.The present study aims to investigate the correlation between the PITPNM3 expression and metastasis in hepatocellular carcinoma(HCC).Real-time quantitative polymerase chain reaction and Western blot were performed to detect the expression pattern of PITPNM3 in patient samples and HCC cell lines.Wound-healing and transwell chamber assays were performed to assess the migration and invasiveness of HCC cells,and the activation of the signaling protein downstream of PITPNM3 was also detected by Western blot and immunofluorescence.The results revealed that PITPNM3 was upregulated in HCC tissue compared to matched normal liver tissue.Silencing the expression of PITPNM3 by specific siRNAs markedly attenuated the invasive and metastatic abilities of HCC cells,whereas the upregulation of PITPNM3 significantly increased HCC cell mobility.Furthermore,inhibiting the expression of PITPNM3 suppressed the activation of Pyk2,FAK,and Src,while overexpression of PITPNM3enhanced the phosphorylation of FAK and Src in HCC cells.Besides,suppression of Pyk2 can also impair the clustering of integrin.These results imply that PITPNM3 is a vital determinant of HCC migration and invasion.

Introduction of a multicenter online database for non-metastatic breast cancer in China

Dear Editor,Breast cancer is now the most frequently diagnosed cancer and is the fifth leading cause of cancer-related death in Chinese women. Therefore, the burden of breast cancer in China is gradually increasing. According to figures released by the Chinese Cancer Center in 2018, the number of newly diagnostic breast cancer is about 278,900 cases, accounting for 16.51%of all women who were diagnosed with the first primary malignant tumors;and 66,000 cases of breast cancer died in 2014 (Chen et al., 2016).

In pursuit of a flawless aphrodite:paving the way to scarless oncoplastic breast surgery

Introduction Breast cancer is the most commonly diagnosed malig-nancy in women worldwide[1,2]and in the twentieth century,mastectomy was the primary surgical treatment for breast cancer patients.Advances in breast-conserving surgery(BCS)propelled a change in treatment rational from“maximum tolerable”to“minimum effective”ther-apy.Oncoplastic breast surgery aims to restore the shape of the breast and has been widely adopted since the past decade.Although the cosmetic outcome has been sig-nificantly improved,the scar remaining on the surgeried breast skin is still a major pitfall that urges urgent consid-eration.In this editorial,we review a series of techniques that can be incorporated in oncoplastic breast surgery to minimize scarring,signifying the beginning of an era for scarless oncoplastic surgery.

CD146 promotes malignant progression of breast phyllodes tumor through suppressing DCBLD2 degradation and activating the AKT pathway

Background As a rapid-progressing tumor,breast malignant phyllodes tumors(PTs)are challenged by the lack of effective therapeutic strategies and suitable prognostic markers.This study aimed to clarify the role and mechanism of CD146 on promoting PTs malignant progression,and to identify a novel prognosis marker and treatment target of breast malignant PTs.Methods The expression and prognostic significance of CD146 in PTs was detected through single-cell RNA-sequencing(scRNA-seq),immunostaining,real-time PCR and other methodologies.Functional experiments including proliferation assay,colony formation assay,transwell assay,and collagen contraction assay were conducted to validate the role of CD146 in malignant progression of PTs.The efficacy of anti-CD146 monoclonal antibody AA98 against malignant PTs was corroborated by a malignant PT organoid model and a PT patient-derived xenograft(PDX)model.Transcriptome sequencing,proteomic analysis,co-immunoprecipitation,and pull-down assay was employed to identify the modulating pathway and additional molecular mechanism.Results In this study,the scRNA-seq analysis of PTs disclosed a CD146-positive characteristic in theα-SMA+fibroblast subset.Furthermore,a progressive elevation in the level of CD146 was observed with the malignant progression of PTs.More importantly,CD146 was found to serve as an independent predictor for recurrence in PT patients.Furthermore,CD146 was found to augment the viability and invasion of PTs.Mechanistically,CD146 acted as a protective“shield”to prevent the degradation of Discoidin,CUB,and LCCL domain-containing protein 2(DCBLD2),thereby activating the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway and enhancing malignant behaviors of PT cells.In the malignant PT organoid and PDX model,a significant suppression of malignant PT growth was observed after the application of AA98.Conclusions These findings suggested that CD146 served as an efficacious marker for predicting PT malignant progression and showed promise as a prognosis marker and treatment target of breast malignant PTs.The study further unveiled the essential role of the CD146-DCBLD2/PI3K/AKT axis in the malignant progression of PTs.

Insights into artificial intelligence in clinical oncology:opportunities and challenges

Cancer continues to be a major public health issue worldwide.Given the complexity of the etiology and pathophysiology of cancer,challenges always exist at every step of cancer management,including early screening,diagnosis,treatment selection,and surveillance.Emerging novel technologies hold promise in addressing a wide range of healthcare problems.Artificial intelligence(AI),which is capable of learning of features from given datasets.

Mammary stem cells:angels or demons in mammary gland?

A highly dynamic development process exits within the epithelia of mammary gland,featuring morphogenetic variation during puberty,pregnancy,lactation,and regression.The identification of mammary stem cells(MaSCs)via lineage-tracing studies has substantiated a hierarchical organization of the mammary epithelia.A single MaSC is capable of reconstituting the entirely functional mammary gland upon orthotopic transplantation.Although different mammary cell subpopulations can be candidate cells-of-origin for distinct breast tumor subtypes,it still lacks experimental proofs whether MaSCs,the most primitive cells,are the‘seeds’of malignant transformation during most,if not all,tumorigenesis in the breast.Here,we review current knowledge of mammary epithelial hierarchy,highlighting the roles of mammary stem/progenitor cells and breast cancer stem cells(BCSCs)along with their key molecular regulators in organ development and cancer evolution.Clarifying these issues will pave the way for developing novel interventions toward stem/progenitor cells in either prevention or treatment of breast cancer(BrCa).