Long-term survivals of immune checkpoint inhibitors as neoadjuvant and adjuvant therapy in dMMR/MSI-H colorectal and gastric cancers.

BACKGROUND: The long-term survival benefit of immune checkpoint inhibitors (ICIs) in neoadjuvant and adjuvant settings is unclear for colorectal cancers (CRC) and gastric cancers (GC) with deficiency of mismatch repair (dMMR) or microsatellite instability-high (MSI-H). METHODS: This retrospective study enrolled patients with dMMR/MSI-H CRC and GC who received at least one dose of neoadjuvant ICIs (neoadjuvant cohort, NAC) or adjuvant ICIs (adjuvant cohort, AC) at 17 centers in China. Patients with stage IV disease were also eligible if all tumor lesions were radically resectable. RESULTS: In NAC (n = 124), objective response rates were 75.7% and 55.4%, respectively, in CRC and GC, and pathological complete response rates were 73.4% and 47.7%, respectively. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 96% (95%CI 90-100%) and 100% for CRC (median follow-up [mFU] 29.4 months), respectively, and were 84% (72-96%) and 93% (85-100%) for GC (mFU 33.0 months), respectively. In AC (n = 48), the 3-year DFS and OS rates were 94% (84-100%) and 100% for CRC (mFU 35.5 months), respectively, and were 92% (82-100%) and 96% (88-100%) for GC (mFU 40.4 months), respectively. Among the seven patients with distant relapse, four received dual blockade of PD1 and CTLA4 combined with or without chemo- and targeted drugs, with three partial response and one progressive disease. CONCLUSION: With a relatively long follow-up, this study demonstrated that neoadjuvant and adjuvant ICIs might be both associated with promising DFS and OS in dMMR/MSI-H CRC and GC, which should be confirmed in further randomized clinical trials.

Deep Learning Radiomics Nomogram Based on Enhanced CT to Predict the Response of Metastatic Lymph Nodes to Neoadjuvant Chemotherapy in Locally Advanced Gastric Cancer.

BACKGROUND: We aimed to construct and validate a deep learning (DL) radiomics nomogram using baseline and restage enhanced computed tomography (CT) images and clinical characteristics to predict the response of metastatic lymph nodes to neoadjuvant chemotherapy (NACT) in locally advanced gastric cancer (LAGC). METHODS: We prospectively enrolled 112 patients with LAGC who received NACT from January 2021 to August 2022. After applying the inclusion and exclusion criteria, 98 patients were randomized 7:3 to the training cohort (n = 68) and validation cohort (n = 30). We established and compared three radiomics signatures based on three phases of CT images before and after NACT, namely radiomics-baseline, radiomics-delta, and radiomics-restage. Then, we developed a clinical model, DL model, and a nomogram to predict the response of LAGC after NACT. We evaluated the predictive accuracy and clinical validity of each model using the receiver operating characteristic curve and decision curve analysis, respectively. RESULTS: The radiomics-delta signature was the best predictor among the three radiomics signatures. So, we developed and validated a DL delta radiomics nomogram (DLDRN). In the validation cohort, the DLDRN produced an area under the receiver operating curve of 0.94 (95% confidence interval, 0.82-0.96) and demonstrated adequate differentiation of good response to NACT. Furthermore, the DLDRN significantly outperformed the clinical model and DL model (p < 0.001). The clinical utility of the DLDRN was confirmed through decision curve analysis. CONCLUSIONS: In patients with LAGC, the DLDRN effectively predicted a therapeutic response in metastatic lymph nodes, which could provide valuable information for individualized treatment.

Regorafenib monotherapy or combined with an immune-checkpoint inhibitor as later-line treatment for metastatic colorectal cancer: a multicenter, real-world retrospective study in China.

OBJECTIVE: To evaluate the efficacy and safety of regorafenib monotherapy or in combination with immune-checkpoint inhibitor while treating Chinese patients with metastatic colorectal cancer (mCRC): a real-world study. METHODS: The data of patients with metastatic colorectal cancer who received regorafenib-containing regimen as the third or later line treatment at ten Chinese hospitals from Aug 2017 to Jun 2020 were retrospectively analyzed, including dosing details, survival data as well as adverse events. Survival analysis was further performed for patients administrated with regorafenib monotherapy and combined with an immune-checkpoint inhibitor based on Kaplan-Meier and Cox regression methods. The primary endpoint was overall survival. RESULTS: A total of 537 patients were included with a median age of 61, among whom 376 received regorafenib monotherapy and 245 received regorafenib combined with immune-checkpoint inhibitors. The clinicopathological characteristics of the two groups at baseline were mainly balanced. No significant difference in progression-free survival (PFS) was observed in patients receiving regorafenib monotherapy or combination therapy (3.8 vs. 5.5 months, p = 0.170). In contrast, patients receiving combination therapy had a more prolonged overall survival (OS) than those receiving regorafenib monotherapy (13.5 vs. 10.0 months, p = 0.001). The treatment regimen and regorafenib dosage were significant prognostic factors in the multivariate analysis. Significant benefits in PFS and OS were achieved in KRAS mutant and anti-angiogenesis treatment-naïve subgroups receiving combination therapy compared to monotherapy. No apparent increase was recorded in treatment-related adverse events in patients receiving combination therapy. CONCLUSION: Regorafenib plus an immune-checkpoint inhibitor has already been a widely adopted strategy in the later-line treatment for mCRC in the real world. The combination therapy yielded a significantly prolonged overall survival than regorafenib alone, with a manageable safety profile in Chinese patients, and warrants further investigation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04835324. Registered 6th April 2021.

Activity of Anlotinib in the Second-Line Therapy of Metastatic Gastrointestinal Stromal Tumors: A Prospective, Multicenter, In Vitro Study.

BACKGROUND: Anlotinib is a multi-target tyrosine kinase inhibitor that can effectively inhibit tumor cell proliferation after receptor kinase activation caused by KIT gene mutation. METHODS: We tested the inhibitory effect of anlotinib in GIST cell lines with different gene mutations and evaluated the efficacy of anlotinib for patients with metastatic GIST after imatinib failure in a multicenter, single-arm, phase II study. RESULTS: In vitro, V654A mutation encoded by KIT exon 13 was intermediately sensitive to anlotinib. Moreover, anlotinib was able to partly suppress the activation loop mutation D820A from exon 17 while another activation loop mutation N822K, also from exon 17, was resistant to anlotinib. From September 2018 to October 2020, 64 patients from 9 Chinese medical centers were enrolled in this study. Seven patients had partial response and 39 patients had stable disease. The median PFS was 8.0 months. There was no statistical significance comparing with PFS of sunitinib second-line therapy at the same period. The most common adverse events related to anlotinib treatment were hypertension, neutropenia, and fatigue. CONCLUSION: Anlotinib showed moderate antitumor activity in drug-resistant GIST cell lines in vitro, and good PFS and better tolerance in second-line therapy study.

Investigation Driven by Network Pharmacology on Potential Components and Mechanism of DGS, a Natural Vasoprotective Combination, for the Phytotherapy of Coronary Artery Disease.

Phytotherapy offers obvious advantages in the intervention of Coronary Artery Disease (CAD), but it is difficult to clarify the working mechanisms of the medicinal materials it uses. DGS is a natural vasoprotective combination that was screened out in our previous research, yet its potential components and mechanisms are unknown. Therefore, in this study, HPLC-MS and network pharmacology were employed to identify the active components and key signaling pathways of DGS. Transgenic zebrafish and HUVECs cell assays were used to evaluate the effectiveness of DGS. A total of 37 potentially active compounds were identified that interacted with 112 potential targets of CAD. Furthermore, PI3K-Akt, MAPK, relaxin, VEGF, and other signal pathways were determined to be the most promising DGS-mediated pathways. NO kit, ELISA, and Western blot results showed that DGS significantly promoted NO and VEGFA secretion via the upregulation of VEGFR2 expression and the phosphorylation of Akt, Erk1/2, and eNOS to cause angiogenesis and vasodilation. The result of dynamics molecular docking indicated that Salvianolic acid C may be a key active component of DGS in the treatment of CAD. In conclusion, this study has shed light on the network molecular mechanism of DGS for the intervention of CAD using a network pharmacology-driven strategy for the first time to aid in the intervention of CAD.

Concordance Between Watson for Oncology and a Multidisciplinary Clinical Decision-Making Team for Gastric Cancer and the Prognostic Implications: Retrospective Study.

BACKGROUND: With the increasing number of cancer treatments, the emergence of multidisciplinary teams (MDTs) provides patients with personalized treatment options. In recent years, artificial intelligence (AI) has developed rapidly in the medical field. There has been a gradual tendency to replace traditional diagnosis and treatment with AI. IBM Watson for Oncology (WFO) has been proven to be useful for decision-making in breast cancer and lung cancer, but to date, research on gastric cancer is limited. OBJECTIVE: This study compared the concordance of WFO with MDT and investigated the impact on patient prognosis. METHODS: This study retrospectively analyzed eligible patients (N=235) with gastric cancer who were evaluated by an MDT, received corresponding recommended treatment, and underwent follow-up. Thereafter, physicians inputted the information of all patients into WFO manually, and the results were compared with the treatment programs recommended by the MDT. If the MDT treatment program was classified as "recommended" or "considered" by WFO, we considered the results concordant. All patients were divided into a concordant group and a nonconcordant group according to whether the WFO and MDT treatment programs were concordant. The prognoses of the two groups were analyzed. RESULTS: The overall concordance of WFO and the MDT was 54.5% (128/235) in this study. The subgroup analysis found that concordance was less likely in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors than in patients with HER2-negative tumors (P=.02). Age, Eastern Cooperative Oncology Group performance status, differentiation type, and clinical stage were not found to affect concordance. Among all patients, the survival time was significantly better in concordant patients than in nonconcordant patients (P<.001). Multivariate analysis revealed that concordance was an independent prognostic factor of overall survival in patients with gastric cancer (hazard ratio 0.312 [95% CI 0.187-0.521]). CONCLUSIONS: The treatment recommendations made by WFO and the MDT were mostly concordant in gastric cancer patients. If the WFO options are updated to include local treatment programs, the concordance will greatly improve. The HER2 status of patients with gastric cancer had a strong effect on the likelihood of concordance. Generally, survival was better in concordant patients than in nonconcordant patients.

A multi-center survey on dietary knowledge and behavior among inpatients in oncology department.

OBJECTIVE: To investigate the current associated factors of dietary knowledge and behavior, the intake and nutritional status in malignancy Chinese inpatients, and the malnutrition causes involved in dietary nutrition knowledge level and behavior, providing recommendations to patients for nutrition education and intervention. METHOD: Five hundred and thirty-five participants from 18 hospitals were investigated by a questionnaire related to dietary knowledge and behavior. Physicians asked and recorded the level of dietary intake and appetite scoring of the participants. The nutritional risk screening with the Nutritional Risk Screening 2002 (NRS-2002) and the dietary survey by 24 h dietary recalls were completed by a dietitian. Besides, the target energy intake and the target protein intake were calculated by the "rule of thumb" recommended by ESPEN guideline, comparing the difference between the actual intake and target intake. RESULTS: According to the questionnaire, 95.2% of participants thought it was important to have a good dietetic habit, and nearly half of them have searched for guides on how to diet; 70% of the patients had no clear idea of what was a scientific diet; 82% of patients had contradictory dietary knowledge; 64.2% of patients would listen to the opinion of the attending physician when a contradiction happened. The main three ways of learning about healthy diet were attending physician, network, and TV, respectively, with the values 26.0, 18.5, and 16.1%. Importantly, 99.6% of patients have made mistakes about dietary knowledge, for example, crab, chicken, lamb, fish, and prawns should not be eaten in their concept. In addition, more than 90% of participants have taken Ganoderma lucidum spore powder, sea cucumber, ginseng, Cordyceps sinensis, and so on. Ninety-three percent of the patients never reached a qualified nutrition education. Besides, 15.6% of the participants had nutritional risk (NRS-2002 ≥ 3). The actual daily energy intake was 1169.20 ± 465.97 kcal, which was significantly less than target energy intake (P < 0.01), amounting to 65.3% of the target requirements. The actual daily protein intake was 46.55 ± 21.40 g, which was significantly less than target protein intake (P < 0.01), amounting to 74.44%. On the other hand, 69% of the participants were "Not too bad, Ok, Good, or Very good" according to the records of physicians, while 34% of them did not reach 60%of the target requirements through dietary survey. CONCLUSION: The survey indicated that cancer patients had poor understanding of the scientific dietary nutrition and were in low level of normative nutritional education among Chinese malignancy inpatients. Dietary intake of most cancer patients decreased, and the actual intake cannot be revealed by NRS-2002 score or the physicians' inquiry. It is necessary to enhance the cooperation between dietitians and physicians and develop nutrition education to improve the level of dietary knowledge.

Identification of stage-specific biomarkers in lung adenocarcinoma based on RNA-seq data.

Tumorigenesis is a multistep process that attributes to the sequential accumulation of abnormal expression in key oncogenes or tumor suppressors. We aimed to identify stage-specific biomarkers to distinguish lung adenocarcinoma (LAC) stages in cancer progression. RNA-sequencing data of LAC and matched adjacent non-cancer tissues were downloaded from the Cancer Genome Atlas, including 29 pairs of samples from LAC at stage I, 14 from LAC at stage II, 13 from LAC at stage III, and 1 from LAC at stage IV. Differentially expressed genes (DEGs) were analyzed for each case at different stages of LAC. DEGs were further annotated based on transcription factor data information, tumor-associated gene database, and protein-protein interaction database. Functional annotation was performed for genes in PPI network by DAVID online tool. Our analysis identified 11 high-frequency DEGs in the stage I, 29 in the stage II, and 90 in the stage III of LAC. Among them, eight genes were significantly correlated with LAC stages and identified as biomarkers in LAC progression. ANGPTL5, C7orf16, EDN3, LOC150622, HOXA11AS, IL1F5, and USH1G significantly distinguished stage III from stages I and II. GJB6 was significantly enriched in the gap junction trafficking pathway, while C7orf16 and EDN3 were enriched in Wnt signaling pathway, cell cycle, and G protein-coupled receptor (GPCR) signaling. Up-regulated GJB6 especially in LAC stage II and down-regulated C7orf16 and EDN3 specifically in stage III were identified as biomarkers for distinguishing cancer stage in tumor progression through dysregulating gap junction, Wnt signaling, and GPCR signaling pathways.

Identification of dysfunctional biological pathways and their synergistic mechanism in hepatocellular carcinoma process.

BACKGROUND: Hepatocellular carcinoma (HCC) is a lethal and prevalent cancer worldwide. This study was conducted to investigate dysfunctional pathways and their synergistic mechanism in the HCC process. METHODS: We downloaded transcriptome profiling data (GSE25097) from the Gene Expression Omnibus (GEO) database, including 6 healthy liver samples, 40 cirrhosis samples, 243 adjacent non-tumor samples, and 268 HCC samples. Robust Multi-Array (RMA) in R software was employed to preprocess the downloaded dataset, and Student's t-test (FDR less than 0.001) was performed to identify the differentially expressed genes (DEGs) between 4 sample groups. Then, pathway enrichment analysis (FDR less than 0.05) based on iSubpathwayMiner was performed. Furthermore, we performed collaborative analysis on these pathways through calculating the Jaccard index, and crosstalk networks were constructed and visualized by Cytoscape. RESULTS: Totally, 4617, 9517, and 12,479 DEGs were identified between healthy liver and cirrhosis samples, cirrhosis and adjacent non-tumor samples, and adjacent non-tumor and HCC samples, respectively. Furthermore, a total of 26 crosstalks involving 13 pathways, 78 crosstalks involving 54 pathways, and 86 crosstalks involving 52 pathways were identified through the DEGs between healthy liver and cirrhosis samples, cirrhosis and adjacent non-tumor samples, and adjacent non-tumor and HCC samples, respectively. Moreover, 5 dysfunctional pathways were found to co-exist in the three processes of HCC. Among them, 3 dysfunctional pathways have collaborative relationship, including Staphylococcus aureus infection, leishmaniasis, and Chagas disease. CONCLUSIONS: In this study, dysfunctional pathways in the HCC process and crosstalks between these pathways were investigated for the first time, providing new insight into the potential mechanisms of HCC.

pERK1/2 silencing sensitizes pancreatic cancer BXPC-3 cell to gemcitabine-induced apoptosis via regulating Bax and Bcl-2 expression.

BACKGROUND: Our previous study has demonstrated that knockdown of activated ERK1/2(pERK1/2) sensitizes pancreatic cancer cells to chemotherapeutic drug gemcitabine (Gem) treatment. However, the details of this survival mechanism remain undefined. It has also shown that Bcl-2 confers resistance and Bax sensitizes to gemcitabine-induced apoptosis in pancreatic cancer cells. Furthermore, the extracellular signaling-regulated kinase (ERK) signaling pathway regulates Bcl-2/Bax expression ratio. We therefore tested the hypothesis that pancreatic cancer cells are resistant to gemcitabine and this resistance is due to activation of ERK1/2 and subsequent upregulation of Bcl-2 and downregulation of Bax. METHODS: Pancreatic cancer cell BXPC-3 was used in the study. The effect of pharmacological inhibition of ERK1/2 on resistance of pancreatic cancer cells to apoptosis induced by treatment with gemcitabine was analyzed. The following methods were utilized: TUNEL and ELISA were used to detect apoptosis. Western blot was used to detect the protein expression. RESULTS: Gemcitabine treatment enhanced the activity of ERK1/2 in the BXPC-3 cells. Inhibition of the ERK1/2 by PD98059 could downregulate Bcl-2 and upregulate Bax and was associated with restoration of sensitivity to gemcitabine in BXPC-3 cells. Depletion of endogenous Bcl-2 expression by specific small interfering RNA transfection significantly increased gemcitabine-induced cell apoptosis. Combined treatment with PD98059 and Bax siRNA transfection could decrease gemcitabine-induced ERK1/2 and Bax activation, which subsequently resulted in decreased apoptosis. CONCLUSIONS: The upregulation of ERK1/2-dependent Bcl-2 and downregulation of ERK1/2-dependent Bax can protect human pancreatic cancer cells from gemcitabine-induced apoptosis. Targeting the ERK1/2-Bax/Bcl-2 pathway may in part lead to sensitization of pancreatic cancer to gemcitabine.

Secreted clusterin gene silencing enhances chemosensitivity of a549 cells to cisplatin through AKT and ERK1/2 pathways in vitro.

BACKGROUND/AIMS: Several studies have shown secreted clusterin (sCLU) silencing directed against sCLU mRNA in sCLU-rich lung cancer cell lines sensitized cells to chemotherapy. However, the molecular mechanisms underlying the effect of sCLU silencing on lung cancer cell chemosensitivity is not known. In the present study, we aimed to determine that vector expressing short hairpin RNA against sCLU RNA (sCLU-shRNA) enhances the chemosensitivity in human small cell lung cancer A549 cells in vitro by inhibition of phosphorylated ERK1/2 (p-ERK1/2) and Akt (p-Akt). METHODS: The pCDNA3.1-sCLU and control scrambled pCDNA3.1 plasmid was constructed. We investigated the effects of sCLU overexpression by pCDNA3.1-sCLU transfection on chemosensitivity to cisplatin (DDP) in A549 cells in vitro. We down-regulated sCLU expression by short hairpin RNA against sCLU RNA (sCLU-shRNA) and investigated the effects on chemosensitivity to DDP in A549 cells and A549(DDP)in vitro. In order to confirm the correlation between sCLU and AKT and ERK1/2 signals, cells were treated with wortmannin and U0126. RESULTS: We found the chemotherapeutic agent DDP activated sCLU. Overexpression of sCLU increased cellular DDP chemoresistance in the A549(DDP) and pCDNA3. 1-sCLU transfected A549 cells via inhibition DDP-induced apoptosis. Whereas sCLU knockdown induced chemosensitization in the S549 and A549(DDP) cells via increase of DDP-induced apoptosis. sCLU overexpression activated pAKT Ser(473) and pERK1/2(Thr202/Tyr204), and vice versa. Inhibition of pAKT Ser(473) and pERK1/2(Thr202/Tyr204) was sufficient to induce significant recover y in chemosensitivity to DDP in A549(DDP) in the presence of sCLU overexpression. The DDP activated sCLU, which directly regulated pAKT and pERK1/2. CONCLUSIONS: This novel finding suggests that therapies directed against sCLU and its downstream signaling targets pAKT and pERK1/2 may have the potential to enhance the efficacy of DDP-based chemotherapy.

Clusterin silencing inhibits proliferation and reduces invasion in human laryngeal squamous carcinoma cells.

BACKGROUND: Clusterin is, in its major form, a secreted heterodimeric disulfide-linked glycoprotein (sCLU), which plays important roles in cell survival and death. In laryngeal squamous cell carcinomas (LSCC), sCLU is up-regulated and its expression is related to the invasiveness of these tumors. The purpose of this study was to explore the inhibiting role of sCLU gene silence in the invasive ability and growth of Hep-2 human laryngeal squamous carcinoma cells (Hep-2) by transfection of short hairpin RNA expression plasmids against sCLU (sCLU-shRNA) (in vivo) or small interference RNA (sCLU-siRNA) (in vitro). METHODS: sCLU-siRNA and the control siRNA were transfected into Hep-2 cells using Lipofectamine 2000. RT-PCR and Western blot were used to detect the effect of siRNA transfection on sCLU mRNA and sCLU protein expression. The invasive activity of sCLU-siRNA-transfected Hep-2 cells was measured with the modified Boyden chamber assay and wound healing assay. The effects of sCLU-siRNA on cell proliferation were evaluated by MTT assay. Apoptosis was measured by Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) double-staining methods. We next evaluated the effects of sCLU silencing by sCLU-shRNA transfection in vivo on tumor growth and metastatic properties to the lung. Terminal deoxytransferase-mediated dUTP nick end labeling (TUNEL) staining was used to observe the apoptosis in the xenografts. RESULTS: It showed that siRNA-mediated down-regulation of sCLU expression in Hep-2 cells significantly inhibited cell proliferation and promoted apoptosis in vitro. Furthermore, siRNA-mediated down-regulation of sCLU expression decreases in vitro cell migration and invasion ability. In vivo, the average volume of tumors in the sCLU-shRNA transfected group was significantly lower than in the control group (P<0.01), and the significant apoptosis detected with TUNEL was indicated in the sCLU-shRNA transfected groups (P<0.05). Significantly, we found that sCLU-shRNA could exert marked inhibition of the lung metastasis of Hep-2 cells in nude mice in vivo. CONCLUSIONS: sCLU gene silence can inhibit invasion and growth of LSCC. sCLU may provide a potential therapeutic target against human LSCC.

Aromatic amino acid mutagenesis at the substrate binding pocket of Yarrowia lipolytica lipase Lip2 affects its activity and thermostability.

The lipase2 from Yarrowia lipolytica (YLLip2) is a yeast lipase exhibiting high homologous to filamentous fungal lipase family. Though its crystal structure has been resolved, its structure-function relationship has rarely been reported. By contrast, there are two amino acid residues (V94 and I100) with significant difference in the substrate binding pocket of YLLip2; they were subjected to site-directed mutagenesis (SDM) to introduce aromatic amino acid mutations. Two mutants (V94W and I100F) were created. The enzymatic properties of the mutant lipases were detected and compared with the wild-type. The activities of mutant enzymes dropped to some extent towards p-nitrophenyl palmitate (pNPC16) and their optimum temperature was 35°C, which was 5°C lower than that of the wild-type. However, the thermostability of I100F increased 22.44% after incubation for 1 h at 40°C and its optimum substrate shifted from p-nitrophenyl laurate (pNPC12) to p-nitrophenyl caprate (pNPC10). The above results demonstrated that the two substituted amino acid residuals have close relationship with such enzymatic properties as thermostability and substrate selectivity.

Trends in smoking among adults with mental illness and association between mental health treatment and smoking cessation.

IMPORTANCE: Significant progress has been made in reducing the prevalence of tobacco use in the United States. However, tobacco cessation efforts have focused on the general population rather than individuals with mental illness, who demonstrate greater rates of tobacco use and nicotine dependence. OBJECTIVES: To assess whether declines in tobacco use have been realized among individuals with mental illness and examine the association between mental health treatment and smoking cessation. DESIGN, SETTING, AND PARTICIPANTS: Use of nationally representative surveys of noninstitutionalized US residents to compare trends in smoking rates between adults with and without mental illness and across multiple disorders (2004-2011 Medical Expenditure Panel Survey [MEPS]) and to compare rates of smoking cessation among adults with mental illness who did and did not receive mental health treatment (2009-2011 National Survey of Drug Use and Health [NSDUH]).The MEPS sample included 32,156 respondents with mental illness (operationalized as reporting severe psychological distress, probable depression, or receiving treatment for mental illness) and 133,113 without mental illness. The NSDUH sample included 14,057 lifetime smokers with mental illness. MAIN OUTCOMES AND MEASURES: Current smoking status (primary analysis; MEPS sample) and smoking cessation, operationalized as a lifetime smoker who did not smoke in the last 30 days (secondary analysis; NSDUH sample). RESULTS: Adjusted smoking rates declined significantly among individuals without mental illness (19.2% [95% CI, 18.7-19.7%] to 16.5% [95% CI, 16.0%-17.0%]; P < .001) but changed only slightly among those with mental illness (25.3% [95% CI, 24.2%-26.3%] to 24.9% [95% CI, 23.8%- 26.0%]; P = .50), a significant difference in difference of 2.3% (95% CI, 0.7%-3.9%) (P = .005). Individuals with mental illness who received mental health treatment within the previous year were more likely to have quit smoking (37.2% [95% CI, 35.1%-39.4%]) than those not receiving treatment (33.1% [95% CI, 31.5%-34.7%]) (P = .005). CONCLUSIONS AND RELEVANCE: Between 2004 and 2011, the decline in smoking among individuals with mental illness was significantly less than among those without mental illness, although quit rates were greater among those receiving mental health treatment. This suggests that tobacco control policies and cessation interventions targeting the general population have not worked as effectively for persons with mental illness.

Case report: Acute pancreatitis in lung adenocarcinoma with small cell transformation after multiple line targeted therapy.

In lung cancer, metastasis to the liver, bones, brain, and adrenal glands is more commonly observed, whereas pancreatic metastasis from lung cancer is relatively rare. We present a case of a patient with an 8-year history of lung adenocarcinoma (LUAD) who was admitted to our institution exhibiting symptoms consistent with acute pancreatitis. Subsequent histopathological examination through puncture confirmed the occurrence of pancreatic metastasis originating from small cell lung cancer (SCLC). During a multidisciplinary team discussion, we reached a consensus in diagnosing the patient with post-transformation small cell carcinoma alongside moderately severe pancreatitis, which was determined to be a consequence of pancreatic metastasis. The patient received a regimen of etoposide and cisplatin chemotherapy. This unique clinical case highlights the importance of further investigating the factors contributing to pancreatic metastasis in patients with lung cancer, as the underlying mechanisms remain unclear. Understanding these exceptional metastatic events is vital in devising effective therapeutic strategies and improving patient prognosis. Our findings emphasize the need for continued surveillance and comprehensive management of lung cancer patients, particularly those with resistant forms of the disease, to promptly identify and address the progression of metastatic events to uncommon sites such as the pancreas.

Sheng Mai Yin shows anti-fatigue, anti-hypoxia and cardioprotective potential in an experimental joint model of fatigue and acute myocardial infarction.

ETHNOPHARMACOLOGICAL RELEVANCE: Cardiovascular disease (CVD) and fatigue are two common diseases endangering human life and health that may interact and reinforce one another. Myocardial infarction survivors frequently experience fatigue, and acute myocardial infarction (AMI) is one of the most common cardiovascular diseases that cause fatigue-induced sudden death. Sheng Mai Yin (SMY), a Chinese medicine prescription, is traditionally used for the treatment of diabetes and cardiovascular disease, and has been demonstrated to reduce fatigue and safeguard cardiac function. AIM OF THE STUDY: This study aims to investigate the effects and underlying mechanisms of SMY in treating fatigue and AMI. MATERIALS AND METHODS: The pharmacological mechanisms of SMY in treating fatigue and AMI were predicted by bioinformatics and network pharmacology methods. After administering SMY at high, medium and low doses, the swimming time to exhaustion, hemoglobin level, serological parameters and hypoxia tolerance time were detected in C57BL/6N mice, and the left ventricular ejection fractions (LVEF), left ventricular fractional shortening (LVFS), grasp strength, cardiac histopathology, serological parameters and the expression of PINK1 and Parkin proteins were examined in Wistar rats. RESULTS: 371 core targets for SMY and 282 disease targets for fatigue and AMI were obtained using bioinformatics and network pharmacology methods. Enrichment analysis of target genes revealed that SMY might interfere with fatigue and AMI through biological processes such as mitochondrial autophagy, apoptosis, and oxidative stress. For in vivo experiments, SMY showed significant anti-fatigue and hypoxia tolerance effects in mice; It also improved the cardiac function and grasp strength, decreased their cardiac index, myocardial injury and fibrosis degree, and induced serological parameters levels and the expression of PTEN-induced putative kinase 1 (PINK1) and Parkin proteins in myocardium, suggesting that SMY may exert cardioprotective effects in a joint rat model of fatigue and AMI by inhibiting excessive mitochondrial autophagy. CONCLUSION: This study revealed the anti-fatigue, anti-hypoxia and cardioprotective effects of SMY in a joint model of fatigue-AMI, and the pharmacological mechanism may be related to the inhibition of mitochondrial autophagy in cardiomyocytes through the PINK1/Parkin pathway. The discoveries may provide new ideas for the mechanism study of traditional Chinese medicine, especially complex prescriptions, in treating fatigue and AMI.

A randomized phase 2 study of HLX22 plus trastuzumab biosimilar HLX02 and XELOX as first-line therapy for HER2-positive advanced gastric cancer.

BACKGROUND: Gastric cancer is the fifth most common cancer and the fourth most common cause of cancer death worldwide, yet the prognosis of advanced disease remains poor. METHODS: This was a randomized, double-blinded, phase 2 trial (ClinicalTrials.gov: NCT04908813). Patients with locally advanced/metastatic HER2-positive gastric/gastroesophageal junction cancer and no prior systemic antitumor therapy were randomized 1:1:1 to 25 mg/kg HLX22 (a novel anti-HER2 antibody) + HLX02 (trastuzumab biosimilar) + oxaliplatin and capecitabine (XELOX) (group A), 15 mg/kg HLX22 + HLX02 + XELOX (group B), or placebo + HLX02 + XELOX (group C) in 3-week cycles. Primary endpoints were progression-free survival (PFS) and objective response rate (ORR) assessed by independent radiological review committee (IRRC). FINDINGS: Between November 29, 2021, and June 6, 2022, 82 patients were screened; 53 were randomized to group A (n = 18), B (n = 17), and C (n = 18). With 14.3 months of median follow-up, IRRC-assessed median PFS was prolonged with the addition of HLX22 (A vs. C, 15.1 vs. 8.2 months, hazard ratio [HR] 0.5 [95% confidence interval (CI) 0.17-1.27]; B vs. C, not reached vs. 8.2 months, HR 0.1 [95% CI 0.04-0.52]). Confirmed ORR was comparable among groups (A vs. B vs. C, 77.8% vs. 82.4% vs. 88.9%). Treatment-related adverse events (TRAEs) were observed in 18 (100%), 16 (94.1%), and 17 (94.4%) patients, respectively. One (5.6%) patient in group C reported a grade 5 TRAE. CONCLUSIONS: Adding HLX22 to HLX02 and XELOX prolonged PFS and enhanced antitumor response in the first-line treatment of HER2-positive gastric cancer, with manageable safety. FUNDING: Shanghai Henlius Biotech, Inc.

A novel melittin-MhIL-2 fusion protein inhibits the growth of human ovarian cancer SKOV3 cells in vitro and in vivo tumor growth.

In the current study, we produced a novel fusion protein (melittin-mutant human interleukin 2, melittin-MhIL-2) comprising a mutant human interleukin 2 (Arg88/Ala125) genetically linked to melittin. The plasmid pET15b-melittin-MhIL-2 (Arg88/Ala125) was transformed into E. coli for protein expression. The expressed melittin-MhIL-2 protein was purified using a series of purification steps. The interleukin 2 (IL-2) activity of melittin-MhIL-2 fusion protein was compared with recombinant human interleukin 2 (rhIL-2) for its ability to induce CTLL-2 proliferation. Moreover, the fusion protein directly inhibits the growth of human ovarian cancer SKOV3 cells in vitro. In an in vivo initial experiment, the fusion protein inhibited tumor growth in ovarian cancer mice. In conclusion, we generated a novel melittin-MhIL-2 fusion protein that retained functional activity of IL-2 and melittin and inhibited tumor growth in vivo.

Political uncertainty and high-quality economic development: Evidence from China.

We manually collated data on the turnover of party secretaries and mayors in 285 Chinese cities from 2003 to 2016 and calculated the quality of city economic development represented by environmental total factor productivity growth. We find that the political uncertainty caused by official turnover could significantly promote the improvement of the quality of economic development, and this positive can explained by the progress of production technology and government intervention. Moreover, the political uncertainty caused by the turnover of more educated officials, those with local hukou, promoted officials, and experienced officials could better promote high-quality economic development.