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BACKGROUND: Colon adenocarcinoma (COAD) is a globally prevalent cancer, with hormone secretion playing a crucial role in its progression. Despite this, there is limited understanding of the impact of hormone secretion on COAD prognosis. This study aimed to establish a prognostic signature based on hormone secretion-related genes and to elucidate the potential functional mechanisms of these genes in COAD. METHODS: Using data from The Cancer Genome Atlas COAD cohort (TCGA-COAD), six hormone secretion-related genes were identified (CYP19A1, FOXD1, GRP, INHBB, SPP1, and UCN). These genes were used to develop a Hormone secretion score (HSS), which was then evaluated using the Kaplan-Meier curve and multivariable Cox analysis. The HSS model was further validated with external GEO cohorts (GSE41258, GSE39582, and GSE87211). Functional enrichment analyses were performed, and the CIBERSORT and TIDE algorithms were used to assess tumor infiltration. RESULTS: The study developed a prognostic signature, dividing patients into HSS-high and HSS-low groups. The HSS-high group showed a notably worse prognosis within the TCGA-COAD dataset and in three independent datasets: GSE41258, GSE39582, and GSE87211. Moreover, the HSS-high group predicted a shorter overall survival rate in patients maintaining microsatellite stability (MSS). The functional analysis associated HSS-high with the hypoxic, epithelial-mesenchymal transition (EMT), and TGF- β signaling pathways and correlated with distant and lymph node metastases. The tumor immune microenvironment analysis revealed an elevated CIBERSORT score in the HSS-high group, suggesting an association with tumor metastasis. Further, the HSS-high group showed a higher TIDE score, indicating that patients with high HSS scores are less likely to benefit from Immune Checkpoint Inhibitor (ICI) therapy. CONCLUSIONS: This study demonstrated the prognostic significance of a HSS signature based on six hormone secretion-related genes in COAD. The findings suggest that this gene signature may serve as a reliable biomarker for predicting survival outcomes in COAD patients. [ABSTRACT FROM AUTHOR]

Bypass coupling triple-wire gas indirect arc welding (TW-GIA) has been proposed to control the heat input of base metal and consequently improve the weld forming as per the requirement. The influence of the bypass current on arc behavior, welding stability, and weld forming have been investigated. Results showed that the wetting angle and reinforcement reduced gradually, and the weld bead penetration increased with the bypass current increase. The reason was that the workpiece heating mode was changed due to the bypass circuit coupling. It was observed that the heat source was composed of two indirect arcs and two direct arcs, and they were in a coupling state. When the bypass current was 280 A, the electrical parameters of arc fluctuations were at a maximum, and the coupled arc state was not conducive to obtain a stable welding process. Compared to the lack of sidewall fusion and incomplete joint penetration defects of the weld with TW-GIA, the good butt joint of 12 mm thickness steel plates was successfully obtained with bypass coupling TW-GIA under the same energy consumption. [ABSTRACT FROM AUTHOR]

[Display omitted] • This work proposed a laser-offset-TIG hybrid welding method to join Mg-Al dissimilar metals, the joint strength is 1.3 times higher than that with normal laser-TIG hybrid welding. • The laser-offset-TIG hybrid heat source can not only promote the wettability of filler metal, but also inhibit the formation of brittle Mg-Zn IMCs. • The attraction effect of the laser to arc is conducive to reducing the heat input on Mg base metal. This work proposed a laser-offset-TIG hybrid welding method to join AZ31 Mg alloy to 6061 Al alloy with Zn filler in lap configuration. Through the lateral offset of laser and arc, the wettability of filler metal was improved, and the amount of intermetallic compounds (IMCs) was well controlled. The spread width of filler metal increases from 2.13 mm to 3.49 mm and the reaction depth decreases from 0.91 mm to 0.66 mm as the offset distance increases from 0 mm to 2 mm. The major phases formed in joint are Al solid solution, MgZn 2 IMCs, Zn solid solution and Mg 32 (Al,Zn) 49 ternary IMCs. At the appropriate offset distance of 2 mm, the coarse MgZn 2 grains in fusion zone are refined to (Al)+(Zn)+MgZn 2 eutectic, and the brittle Mg 32 (Al,Zn) 49 ternary IMCs in weld corner are eliminated. The maximum joint strength is 1190 N/cm, which is 1.3 times higher than that with normal laser-TIG hybrid welding. [ABSTRACT FROM AUTHOR]

A non-axisymmetric laser-tungsten inert gas (TIG) heat source was designed to join Mg–Al dissimilar metals with pure Zn filler at a series of welding speeds (500–900 mm/min). Laser and TIG heat sources respectively acted on Al and Mg base metals to precisely control their dissolution into the welding pool. The solidification rate of liquid metal was controlled by adjusting the welding speed, then the reaction process of Mg, Al and Zn could be accurately regulated. The results indicated that various microstructures including Al solid solution, Zn solid solution, Mg–Zn intermetallic compounds (IMCs) and eutectic structure formed in the joint produced at different speeds. Lower welding speed (500 mm/min) caused the microstructure coarsening and higher welding speed (900 mm/min) would lead to the enrichment of MgZn2 intermetallic compounds. At the optimal welding speed of 800 mm/min in particular, fine MgZn2 IMCs grains uniformly distributed in the Al and Zn solid solution. The tensile-shear load reached a maximum of 1052.5 N/cm and the joint fractured at the fusion zone near the Al base metal. [ABSTRACT FROM AUTHOR]

Background: Perioperative chemotherapy is the standard of care for patients with locally advanced gastric and gastroesophageal junction cancer. Recent evidence demonstrated the addition of programmed cell death protein 1 (PD-1) inhibitors enhanced therapeutic efficacy. However, the mechanisms of response and resistance remain largely undefined. A detailed multiomic investigation is essential to elucidate these mechanisms., Methods: We performed whole-exome sequencing, whole-transcriptome sequencing, multiplex immunofluorescence and single-cell RNA sequencing on matched pretreatment and post-treatment samples from 30 patients enrolled in an investigator-initiated Phase 2 clinical trial (NCT04908566). All patients received neoadjuvant PD-1 inhibitors in combination with chemotherapy. A major pathologic response (MPR) was defined as the presence of no more than 10% residual viable tumor cells following treatment., Results: Before treatment, the positive ratio of CD3+T cells in both the tumor parenchyma and stroma was significantly higher in the non-MPR group compared with the MPR group (p=0.042 and p=0.013, respectively). Least absolute shrinkage and selection operator regression was employed for feature gene selection and 13 genes were ultimately used to construct a predictive model for identifying MPR after surgery. The model exhibited a perfect area under curve (AUC) of 1.000 (95% CI: 1.000 to 1.000, p<0.001). Post-treatment analysis revealed a significant increase in CD3+T cells, CD8+T cells and NK cells in the tumor stroma of MPR patients. In the tumor parenchyma, aside from a marked increase in CD8+T cells and NK cells, a notable reduction in macrophage was also observed (all p<0.05). Importantly, forkheadbox protein 3 (FOXP3), the principal marker for regulatory T cells (Treg) cells, showed a significant decrease during treatment in MPR patients. FOXP3 expression in the non-MPR group was significantly higher than in the MPR group (p=0.0056) after treatment. Furthermore, single-cell RNA sequencing analysis confirmed that nearly all Treg cells were derived from the non-MPR group., Conclusions: Our study highlights the critical role of dynamic changes within the tumor immune microenvironment in predicting the efficacy of neoadjuvant combined immunochemotherapy. We examined the disparities between MPR/non-MPR groups, shedding light on potential mechanisms of immune response and suppression. In addition to bolstering cytotoxic immune responses, specifically targeting Treg cells may be crucial for enhancing treatment outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

MYC-rearranged high-grade B-cell lymphoma (HGBCL) patients with concurrent BCL2 rearrangements (HGBCL-MYC/BCL2) often have a poor prognosis with standard chemoimmunotherapy and may benefit from more intensified regimens. Conventional fluorescence in situ hybridization (FISH) is the gold standard for detecting rearrangements, but it has several limitations. This study compared DNA- and RNA-sequencing with FISH to detect clinically relevant rearrangements in HGBCL. Archived formalin-fixed, paraffin-embedded samples from 34 patients who underwent FISH testing were analyzed using targeted DNA- and RNA-sequencing. DNA- and RNA-sequencing identified six and five out of the 12 MYC rearrangements detected by FISH, 10 and 6 out of 10 FISH-detectable BCL2 rearrangements, and 13 and 10 out of the 18 FISH-detectable BCL6 rearrangements. When combining DNA- and RNA-sequencing (integrated NGS), the sensitivity for detecting MYC, BCL2, and BCL6 rearrangements was 58.3%, 100%, and 73.7%, respectively. Both DNA- and RNA-sequencing detected the EIF4A2::BCL6 fusion missed by FISH. FISH identified 12 HGBCL-MYC/BCL2 out of 34 cases, while the integrated NGS strategy identified 7 cases, with 5 cases showing discordant results (41.7%). Additionally, patients with DLBCL/HGBCL-MYC/BCL2 had significantly shorter overall survival than other patients. Our results suggest that an integrated NGS strategy should not replace FISH or be routinely used in the workup to detect the clinically relevant rearrangements in HGBCL. It may serve as a complement to FISH testing when FISH shows negative results.