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Most investigations on heat exchanger network (HEN) synthesis which plays an important role in improving the efficiency of industrial plants, focus on deterministic conditions whereas operational flexibility and feasibility are less concerned. In the real industrial world, each system experiences various disturbances due to changes in stream temperature, flow rate, and other uncertain factors. An approach for flexible HEN synthesis under severe operation uncertainty is proposed, which is represented by the Probability bounds analysis (PBA) theory and is sampled by a double-loop sampling method. A case study, which generates a better solution with less total annual cost and good flexibility under severe uncertainty, demonstrates the capability of this simplified approach.

higher than that in carcinoid. Mutations in TP53 and RB1 occurred concurrently in 83% (29/35) SCLC patients, whereas in only 32.3% (10/31) LCNECs. (Fig.1) We further investigated the distribution of mutations across KEGG pathways and found that mutation frequencies in both HIF-1 and Notch signaling pathways were lower in LCNEC than SCLC (p¼0.032, p¼0.025). Copy number variation (CNV) analysis revealed that LCNEC and SCLC had comparable CNVs which were significantly higher than carcinoid (p<0.001, p<0.001) and atypical carcinoid (p¼0.010, p¼0.028). TMB analysis also revealed a comparable TMB status of LCNEC (12.7/Mb) and SCLC (11.9/Mb), and relatively lower TMB in both carcinoid (2.4/Mb, p<0.001, p<0.001) and atypical carcinoid (5.6/Mb, p¼0.003, p¼0.009) than LCNEC and SCLC. Conclusion: We demonstrated the differential genomic characteristics in the four subtypes of neuroendocrine carcinomas. Compared with SCLC, LCNEC has lower mutation frequencies in RB1, PIK3CA, as well as HIF-1 and Notch signaling pathways. In addition, LCNEC and SCLC had comparable CNV and TMB status, which significantly higher than that of carcinoids and atypical carcinoid.

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