MYH6 suppresses tumor progression by downregulating KIT expression in human prostate cancer.

Prostate cancer (PRAD) is one of the leading malignancies in men all around the world. Here, we identified Myosin Heavy Chain 6 (MYH6) as a potential tumor suppressor gene in the development of prostate cancer. We found lower expression of MYH6 in prostate cancer tissues, and its lower gene expression was also associated with worse clinical outcomes. In vitro and in vivo assays indicated that overexpressed MYH6 could suppress the proliferation and migration progression of prostate cancer cells. RNA-seq was employed to investigate the mechanism, and KIT Proto-Oncogen (KIT) was determined as the downstream gene of MYH6, which was further confirmed using rescue assays. In all, we provide the evidence that MYH6 could serve as a tumor suppressor in prostate cancer. Our results highlight the potential role of MYH6 in the development of prostate cancer.

Immunotherapeutic hydrogel for co-delivery of STAT3 siRNA liposomes and lidocaine hydrochloride for postoperative comprehensive management of NSCLC in a single application.

Despite standard treatment for non-small cell lung cancer (NSCLC) being surgical resection, cancer recurrence and complications, such as induction of malignant pleural effusion (MPE) and significant postoperative pain, usually result in treatment failure. In this study, an alginate-based hybrid hydrogel (SOG) is developed that can be injected into the resection surface of the lungs during surgery. Briefly, endoplasmic reticulum-modified liposomes (MSLs) pre-loaded with the signal transducer and activator of transcription 3 (STAT3) small interfering RNA and lidocaine hydrochloride are encapsulated in SOG. Once applied, MSLs strongly downregulated STAT3 expression in the tumor microenvironment, resulting in the apoptosis of lung cancer cells and polarization of tumor-associated macrophages towards the M1-like phenotype. Meanwhile, the release of lidocaine hydrochloride (LID) was beneficial for pain relief and natural killer cell activation. Our data demonstrated MSL@LID@SOG not only efficiently inhibited tumor growth but also potently improved the quality of life, including reduced MPE volume and pain relief in orthotopic NSCLC mouse models, even with a single administration. MSL@LID@SOG shows potential for comprehensive clinical management upon tumor resection in NSCLC, and may alter the treatment paradigms for other cancers.

Risk factors for COVID-19 and their association with mortality in Ecuadorian patients admitted to the ICU: A retrospective cohort multicentric study.

Several risk factors were associated with mortality in patients with coronavirus disease 2019 (COVID-19) infection in intensive care units (ICU). We assessed the effect of risk factors related to the characteristics and clinical history of the population, laboratory test results, drug management, and type of ventilation on the probability of survival/discharge from the ICU. A retrospective cohort multicentric study of adults with COVID-19 admitted to the ICU between March 2020 and December 2021. Data were collected from 6 hospitals in 5 cities in Ecuador. The primary outcome was ICU survival/discharge. Survival analysis was conducted using semi-parametric Cox proportional hazards models. Of those admitted to the ICU with COVID-19, (n = 991), mean age was 56.76 ±â€…13.14, and 65.9% were male. Regarding the primary outcome, 51.1% (n = 506) died and 48.9% (n = 485) survived. Of the group that died, their mean age was higher than the survivors (60.7 vs 52.60 years, respectively), and they had a higher prevalence of comorbidities such as arterial hypertension (37.2% vs 20.4%, respectively) and diabetes mellitus (26.9% vs 15.7%, respectively), with P < .001. In ventilatory management, 32.7% of patients used noninvasive ventilation and high-flow nasal cannula, and 67.3% required invasive ventilatory support. After adjusting for confounders, Cox regression analysis showed that patients were less likely to be discharged alive from the ICU if they met the following conditions: arterial hypertension (hazard ratio [HR] = 0.83 95% CI 0.723-0.964), diabetes mellitus (HR = 0.80 95% CI 0.696-0.938), older than 62 years (HR = 0.86 95% CI 0.790-0.956), obese (body mass index ≥ 30) (HR = 0.78 95% CI 0.697-0.887), 1 unit increase in SOFA score (HR = 0.94 95% CI 0.937-0.961), PaO2/FiO2 ratio <100 mm Hg (HR = 0.84 95% CI 0.786-0.914), and the use of invasive mechanical ventilation (HR = 0.68 95% CI 0.614-0.769). Risk factors associated with increased mortality were older age, obesity, arterial hypertension, and diabetes. Factors such as male gender, chronic obstructive pulmonary disease, acute kidney injury, and cancer reported in other investigations did not have the same effect on mortality in our study.

GAS6-AS1 drives bladder cancer progression by increasing MMP7 expression in a ceRNA- and RBP-dependent manner.

Numerous recent studies have underscored the indispensable roles of long non-coding RNAs (lncRNAs) in various diseases. However, their precise mechanisms in urinary bladder cancer (UBC) remain to be further elucidated. To delve into this inquiry, online databases were analyzed to identify differentially expressed lncRNAs in UBC, followed by the functional experiments in vivo and in vitro functional experiments. GAS6-AS1 exhibited high expression levels in UBC tissues and was shown to regulate the proliferation, migration, invasion, and cell cycle progression of UBC cells in vitro and in vivo. Then, a series of molecular biology experiments, including RNA pull-down, dual-luciferase reporter gene assays, RNA immunoprecipitation (RIP) assays, fluorescent in situ hybridization (FISH), and the triplex-capture assay demonstrated its interaction with miR-367-3p and PRC1. Mechanistically, GAS6-AS1 was found to enhance MMP7 expression by sequestering miR-367-3p. Moreover, GAS6-AS1 inhibited APC transcription by binding with PRC1, thereby activating several oncogenes downstream of the WNT pathway. To sum up, GAS6-AS1 promotes UBC progression through two distinct axes: the GAS6-AS1/miR-367-3p/MMP7 axis and the GAS6-AS1/PRC1/APC/Wnt/MMP7 axis, respectively. As a potential biomarker for UBC, GAS6-AS1 holds promising prospects for the diagnosis, treatment, and prognosis of UBC.

Comparative efficacy of totally thoracoscopic, mini-thoracotomy, and mini-sternotomy approaches in aortic valve replacement.

Aortic valve replacement (AVR) is a critical procedure for patients with aortic valve diseases. This study compares the effectiveness of three minimally-invasive surgical approaches for AVR: totally thoracoscopic (TT), right anterior mini-thoracotomy, and upper mini-sternotomy. We analyzed retrospective data from 130 patients who underwent one of these surgeries, focusing on various factors such as duration of hospital stay, operation time, times for cardiopulmonary bypass and aortic cross-clamping, postoperative complications, levels of cardiac biomarkers, pain intensity using the Visual Analog Scale, and mid-term survival rates. Results show that while the TT method had the longest operation times, it also had the shortest hospital stays and faster pain reduction post-surgery. Although the TT group initially showed higher cardiac biomarker levels after surgery, these levels normalized by the third day, similar to the other groups. There were no significant differences in mid-term survival and major adverse cardiac and cerebrovascular event (MACCE) rates among the groups. These findings suggest that the TT method, despite longer surgical times, offers a quicker initial recovery, making it a viable option for AVR.

Synthesis, Screening, and Evaluation of Theranostic Molecular CPCR4-Based Probe Targeting CXCR4.

Chemokines and chemokine receptors are indispensable to play a key role in the development of malignant tumors. As one of the most widely expressed chemokine receptors, chemokine (C-X-C motif) receptor 4 (CXCR4) has been a popular research focus. In most tumors, CXCR4 expression is significantly upregulated. Moreover, integrated nuclide diagnosis and therapy targeting CXCR4 show great potential. [68Ga]Ga-pentixafor, a radioligand targeting CXCR4, exhibits a strong affinity for CXCR4 both in vivo and in vitro. However, [177Lu]Lu-pentixather, the therapeutic companion of [68Ga]Ga-pentixafor, requires significant refinement to mitigate its pronounced hepatic biodistribution. The objective of this study was to synthesize theranostic molecular tracers with superior CXCR4 targeting functions. The Daudi cell line, which highly expressed CXCR4, and the MM.1S cell line, which weakly expressed CXCR4, were used in this study. Based on the pharmacophore cyclo (-d-Tyr-n-me-d-Orn-l-Arg-L-2-NAL-Gly-) (CPCR4) of pentixafor, six tracers were synthesized: [124I]I-1 ([124I]I-CPCR4), [99mTc]Tc-2 ([99mTc]Tc-HYNIC-CPCR4), [124I]I-3 ([124I]I-pentixafor), [18F]AlF-4 ([18F]AlF-NETA-CPCR4), [99mTc]Tc-5 ([99mTc]Tc-MAG3-CPCR4) and [124I]I-6 ([124I]I-pentixafor-Ga) and their radiochemical purities were all higher than 95%. After positron emission tomography (PET)/single-photon emission computed tomography (SPECT) imaging, the [124I]I-6 group exhibited the best target-nontarget ratio. At the same time, comparing the [68Ga]Ga-pentixafor group with the [124I]I-6 group, we found that the [124I]I-6 group had a better target-nontarget ratio and lower uptake in nontarget organs. Therefore, compound 6 was selected for therapeutic radionuclide (131I) labeling, and the tumor-bearing animal models were treated with [131I]I-6. The volume of the tumor site was significantly reduced in the treatment group compared with the control group, and no significant side effects were found. [124I]I-6 and [131I]I-6 showed excellent affinity for targeting CXCR4, and they showed great potential for the integrated diagnosis and treatment of tumors with high CXCR4 expression.

Mid-term clinical outcomes of totally endoscopic repair for mitral regurgitation in Barlow's disease.

OBJECTIVE: This study aimed to confirm the safety and feasibility of totally endoscopic repair for mitral regurgitation (MR) in Barlow's disease. METHODS: From June 2018 to December 2022, 21 consecutive Barlow's disease patients (aged 33 ± 12 years; 57.1% male) underwent totally endoscopic mitral valve (MV) repair with leaflets folding, multiple artificial chordae implantation and ring annuloplasty. The safety and feasibility of this technique was evaluated by its mid-term clinical outcomes. RESULTS: There was no operative death or complications. The mean cardiopulmonary bypass (CPB) time was 190 ± 41 (128-267) min, and the aortic cross-clamp time was 145 ± 32 (66-200) min. The average number of artificial chordae implantation was 2.9 ± 0.7 (1-4) pairs. The mean MV coaptation length was 1.4 ± 0.3 (0.8-1.8) cm, and the median transvalvular gradient was 1 [interquartile range (IQR), 1-2] mmHg. During a median follow-up time of 24 (IQR, 10-38) months, all patients showed persistent effective valve function with no significant MR or systolic anterior motion. CONCLUSIONS: Totally endoscopic repair was a safe, effective, and reproducible procedure with satisfied mid-term clinical outcomes for MR in Barlow's disease. However, further randomized and long-term follow-up studies were warranted to determine its clinical effects.

A WeChat-based nursing intervention program improves the postoperative rehabilitation of breast cancer patients: results from a randomized controlled trial.

Background: In postoperative setting, breast cancer (BC) patients can experience adverse effects, including fatigue, sleep disorders, and pain, which substantially affect their health-related quality of life (HRQoL). This study sought to assess the effectiveness of a WeChat-based multimodal nursing program (WCBMNP) that was specifically designed for the rehabilitation of women following BC surgery. Methods: BC patients were randomly, single-blinded allocated to either the intervention (n=62) or control (n=63) cohorts. Over a period of 6 months (24 weeks), the intervention cohort received a WCBMNP in addition to routine nursing care, while the control cohort received routine nursing care only. To evaluate patients' fear of cancer recurrence (FCR), their overall fear score was assessed using the Japanese version of the Concerns About Recurrence Scale (CARS-J) for primary outcome. The initial outcome (HRQoL) and secondary results, such as fatigue, sleep, and pain, were examined using the Functional Assessment of Cancer Therapy-Breast (FACT-B, version 4.0) and Nursing Rating Scale (NRS), respectively. Results: Two hundred and ten participants, 85 participants were excluded. Compared to the controls (n=63), the intervention cohort (n=62) showed statistically significant improvements in their CARS-J scores. The intervention cohort aggregate scores on the FACT-B improved significantly but were affected by the compounding influences of cohort dynamics, temporal progression, and their interaction. Similar improvements were observed in the social/family and functional well-being domains. Emotional well-being was improved based on the effects of time and group-time interaction. In the intervention cohort, the "BC-specific subscale for additional concerns" was affected by group and time, whereas physical well-being was only affected by time. Conversely, there were no statistically significant changes in the variables of fatigue, sleep, and pain. Conclusions: The WCBMNP reduced FCR and significantly increased the HRQoL of female patients with BC postoperatively. The WCBMNP could be implemented as a postoperative rehabilitation intervention in this patient population to improve outcomes. Trial Registration: Chinese Clinical Trial Registry (ChiCTR2400081557).

Genome-scale CRISPR-Cas9 screen identifies PAICS as a therapeutic target for EGFR wild-type non-small cell lung cancer.

Epidermal growth factor receptor-targeted (EGFR-targeted) therapies show promise for non-small cell lung cancer (NSCLC), but they are ineffective in a third of patients who lack EGFR mutations. This underlines the need for personalized treatments for patients with EGFR wild-type NSCLC. A genome-wide CRISPR/Cas9 screen has identified the enzyme phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), which is vital in de novo purine biosynthesis and tumor development, as a potential drug target for EGFR wild-type NSCLC. We have further confirmed that PAICS expression is significantly increased in NSCLC tissues and correlates with poor patient prognosis. Knockdown of PAICS resulted in a marked reduction in both in vitro and in vivo proliferation of EGFR wild-type NSCLC cells. Additionally, PAICS silencing led to cell-cycle arrest in these cells, with genes involved in the cell cycle pathway being differentially expressed. Consistently, an increase in cell proliferation ability and colony number was observed in cells with upregulated PAICS in EGFR wild-type NSCLC. PAICS silencing also caused DNA damage and cell-cycle arrest by interacting with DNA repair genes. Moreover, decreased IMPDH2 activity and activated PI3K-AKT signaling were observed in NSCLC cells with EGFR mutations, which may compromise the effectiveness of PAICS knockdown. Therefore, PAICS plays an oncogenic role in EGFR wild-type NSCLC and represents a potential therapeutic target for this disease.

Inhibiting G6PD by quercetin promotes degradation of EGFR T790M mutation.

EGFRT790M mutation causes resistance to the first-generation tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). However, the therapeutic options for sensitizing first TKIs and delaying the emergence of EGFRT790M mutant are limited. In this study, we show that quercetin directly binds with glucose-6-phosphate dehydrogenase (G6PD) and inhibits its enzymatic activity through competitively abrogating NADP+ binding in the catalytic domain. This inhibition subsequently reduces intracellular NADPH levels, resulting in insufficient substrate for methionine reductase A (MsrA) to reduce M790 oxidization of EGFRT790M and inducing the degradation of EGFRT790M. Quercetin synergistically enhances the therapeutic effect of gefitinib on EGFRT790M-harboring NSCLCs and delays the acquisition of the EGFRT790M mutation. Notably, high levels of G6PD expression are correlated with poor prognosis and the emerging time of EGFRT790M mutation in patients with NSCLC. These findings highlight the potential implication of quercetin in overcoming EGFRT790M-driven TKI resistance by directly targeting G6PD.

Alveolar type I cells can give rise to KRAS-induced lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and presents clinically with a high degree of biological heterogeneity and distinct clinical outcomes. The current paradigm of LUAD etiology posits alveolar epithelial type II (AT2) cells as the primary cell of origin, while the role of AT1 cells in LUAD oncogenesis remains unknown. Here, we examine oncogenic transformation in mouse Gram-domain containing 2 (Gramd2)+ AT1 cells via oncogenic KRASG12D. Activation of KRASG12D in AT1 cells induces multifocal LUAD, primarily of papillary histology. Furthermore, KRT8+ intermediate cell states were observed in both AT2- and AT1-derived LUAD, but SCGB3A2+, another intermediate cell marker, was primarily associated with AT1 cells, suggesting different mechanisms of tumor evolution. Collectively, our study reveals that Gramd2+ AT1 cells can serve as a cell of origin for LUAD and suggests that distinct subtypes of LUAD based on cell of origin be considered in the development of therapeutics.

CYP19A1 promotes gastric cancer as part of a lipid metabolism-related gene signature related to the response of immunotherapy and prognosis.

BACKGROUND: Increasing evidence suggests that the metabolism of lipids plays a crucial role in the progression of gastric cancer. However, the expression of lipid metabolism-related genes (LMGs) still does not serve as a prognostic biomarker in gastric cancer. METHODS: We obtained transcriptome data for 751 LMGs and divided STAD patients into two subtypes based on differences in LMGs expression. Then, we analyzed genetic changes in two subtypes as well as immune features to determine their differences. We also constructed a prognostic risk model related to LMGs for individualized comprehensive evaluations. RESULTS: In this study, two lipid metabolic (LM) subtypes were identified anchored in the expression profiles of LMGs. Clinical information, genomic alterations, immune features, and immunotherapy response varied significantly between the two LM subtypes. A risk model based on LMGs was also developed to assess prognosis and distinguish patients with high risk from those at low risk. The prognosis differed significantly between the two risk groups of patients. In STAD patients, the risk score was strongly correlated with genomic alterations and immune profile scores. Also, the risk score was an excellent predictor of immune checkpoint inhibitors (ICIs) response. Anchored in preliminary results derived from the aforementioned bioinformatic analysis, we chose CYP19A1 as our target gene and the expression of CYP19A1 was verified in several common gastric cancer cell lines. Then, we carried out the Western blotting, CCK-8 assay, colony formation assay, wound healing assay, and transwell assay to explore the effects of CYP19A1 on malignant biological behavior, and positive consequences were obtained. CONCLUSIONS: In this study, STAD patients were divided into two subtypes based on LMGs expression. It is possible to assess the prognosis of a patient and the response to immunotherapy using the established prognostic risk model. A series of basic laboratory experiments also verified the functional role of CYP19A1 in gastric cancer.

Preoperative expectations, postoperative satisfaction and patient directed priorities for clinical burn research.

INTRODUCTION: Burn patients receiving split thickness skin grafting are left with scarring and chronically dysfunctional grafted skin. Given evidence that patients' preoperative expectations mediate postoperative outcomes and satisfaction, we described burn patients' experience, expectations, and satisfaction with their skin graft, their views towards a cell based clinical trial to improve their graft and identified graft outcome measures for use in future studies. METHODS: Data were collected via questionnaires preoperatively, one, and three months postoperatively. Longitudinal analyses assessed change over time. RESULTS: Expectations of graft function were consistent pre- and postoperatively. Expectations of graft appearance showed significant decrease over time (ß1 = -0.290, p = 0.008). Significant improvements in skin function (ß1 = 0.579, p = 0.000) and appearance (ß1 = 0.247, p = 0.025) at the wound site during recovery were observed. Patients noted great difference between grafted and normal skin. Patient satisfaction with their graft did not change significantly over time. Patients were willing to participate in a cell based clinical trial to improve graft symptomology and prioritized improvements in scarring, redness, sensation, and elasticity. CONCLUSIONS: Outcome measures in trials advancing skin grafting should reflect chronic, patient prioritized limitations. We recommend preoperative educational interventions for burn patients receiving grafting to improve postoperative satisfaction.

New advances in circulating tumor cell­mediated metastasis of breast cancer (Review).

Breast cancer stands as the most prevalent form of cancer affecting women, with metastasis serving as a leading cause of mortality among patients with breast cancer. Gaining a comprehensive understanding of the metastatic mechanism in breast cancer is essential for early detection and precision treatment of the disease. Circulating tumor cells (CTCs) play a vital role in this context, representing cancer cells that detach from tumor tissues and enter the bloodstream of cancer patients. These cells travel in the blood circulation as single cells or clusters. Recent research has shed light on the enhanced metastatic potential of CTC clusters compared to single CTCs, despite their limited occurrence. The aim of the present review was to explore recent findings on CTCs with a particular focus on the clustering phenomenon of CTCs observed in breast cancer. Additionally, the present review delved into the comparison between single CTCs and CTC clusters regarding their implications for the treatment and prognosis of patients diagnosed with metastatic breast cancer. By examining the role and mechanisms of CTCs in breast cancer metastasis, the present review provided an improved understanding of CTCs and their significance in early detection of breast cancer metastasis through peripheral blood analysis. Moreover, it contributed to the comprehension of cancer prognosis and prediction by highlighting the implications of CTCs in these aspects. Ultimately, the present study seeks to advance knowledge in the field and pave the way for improved approaches to breast cancer management.

Abnormal adenosine metabolism of neutrophils inhibits airway inflammation and remodeling in asthma model induced by Aspergillus fumigatus.

BACKGROUND: Neutrophils consume a large amount of energy when performing their functions. Compared with other white blood cells, neutrophils contain few mitochondria and mainly rely on glycolysis and gluconeogenesis to produce ATP. The inflammatory site is hypoxic and nutrient poor. Our aim is to study the role of abnormal adenosine metabolism of neutrophils in the asthmatic airway inflammation microenvironment. METHOD: In this study, an asthma model was established by intratracheal instillation of Aspergillus fumigatus extract in Ecto-5'-Nucleotidase (CD73) gene-knockout and wild-type mice. Multiple analyses from bronchoalveolar lavage fluid (BALF) were used to determine the levels of cytokines and chemokines. Immunohistochemistry was used to detect subcutaneous fibrosis and inflammatory cell infiltration. Finally, adenosine 5'-(α, ß-methylene) diphosphate (APCP), a CD73 inhibitor, was pumped subcutaneously before Aspergillus attack to observe the infiltration of inflammatory cells and subcutaneous fibrosis to clarify its therapeutic effect. RESULT: PAS staining showed that CD73 knockout inhibited pulmonary epithelial cell proliferation and bronchial fibrosis induced by Aspergillus extract. The genetic knockdownof CD73 significantly reduced the production of Th2 cytokines, interleukin (IL)-4, IL-6, IL-13, chemokine (C-C motif) ligand 5 (CCL5), eosinophil chemokine, neutrophil IL-17, and granulocyte colony-stimulating factor (G-CSF). In addition, exogenous adenosine supplementation increased airway inflammation. Finally, the CD73 inhibitor APCP was administered to reduce inflammation and subcutaneous fibrosis. CONCLUSION: Elevated adenosine metabolism plays an inflammatory role in asthma, and CD73 could be a potential therapeutic target for asthma.

Reconsidering N component of cancer staging for T1-2N0-2M0 small-cell lung cancer: a retrospective study based on multicenter cohort.

BACKGROUND: The current nodal (pN) classification still has limitations in stratifying the prognosis of small cell lung cancer (SCLC) patients with pathological classifications T1-2N0-2M0. Thus. This study aimed to develop and validate a modified nodal classification based on a multicenter cohort. MATERIALS AND METHODS: We collected 1156 SCLC patients with pathological classifications T1-2N0-2M0 from the Surveillance, Epidemiology, and End Results database and a multicenter database in China. The X-tile software was conducted to determine the optimal cutoff points of the number of examined lymph nodes (ELNs) and lymph node ratio (LNR). The Kaplan-Meier method, the Log-rank test, and the Cox regression method were used in this study. We classified patients into three pathological N modification categories, new pN#1 (pN0-#ELNs > 3), new pN#2 (pN0-#ELNs ≤ 3 or pN1-2-#LNR ≤ 0.14), and new pN#3 (N1-2-#LNR > 0.14). The Akaike information criterion (AIC), Bayesian Information Criterion, and Concordance index (C-index) were used to compare the prognostic, predictive ability between the current pN classification and the new pN component. RESULTS: The new pN classification had a satisfactory effect on survival curves (Log-rank P < 0.001). After adjusting for other confounders, the new pN classification could be an independent prognostic indicator. Besides, the new pN component had a much more accurate predictive ability in the prognostic assessment for SCLC patients of pathological classifications T1-2N0-2M0 compared with the current pN classification in the SEER database (AIC: 4705.544 vs. 4731.775; C-index: 0.654 vs. 0.617, P < 0.001). Those results were validated in the MCDB from China. CONCLUSIONS: The multicenter cohort developed and validated a modified nodal classification for SCLC patients with pathological category T1-2N0-2M0 after surgery. Besides, we propose that an adequate lymph node dissection is essential; surgeons should perform and consider the situation of ELNs and LNR when they evaluate postoperative prognoses of SCLC patients.

Targeted deprivation of methionine with engineered Salmonella leads to oncolysis and suppression of metastasis in broad types of animal tumor models.

The strong dependency of almost all malignant tumors on methionine potentially offers a pathway for cancer treatment. We engineer an attenuated strain of Salmonella typhimurium to overexpress an L-methioninase with the aim of specifically depriving tumor tissues of methionine. The engineered microbes target solid tumors and induce a sharp regression in several very divergent animal models of human carcinomas, cause a significant decrease in tumor cell invasion, and essentially eliminate the growth and metastasis of these tumors. RNA sequencing analyses reveal that the engineered Salmonella reduce the expression of a series of genes promoting cell growth, cell migration, and invasion. These findings point to a potential treatment modality for many metastatic solid tumors, which warrants further tests in clinical trials.

Correlation analysis of the expression of mesenchymal circulating tumor cells and CD133 with the prognosis of colorectal cancer.

OBJECTIVE: To evaluate the expression of tumor stem cell marker CD133 in peripheral blood circulating tumor cells (CTC) and the value of CD133 in prognosis of patients with colorectal cancer (CRC). METHODS: Preoperative/pre-chemotherapy peripheral blood samples of 63 patients with CRC from January 2016 to January 2021 were selected to detect peripheral blood CTC by CanPatrol CTC enrichment technology. Expression of CD133 in different epithelial-mesenchymal transition (EMT) typing CTC was analyzed. Clinical data (including tumor size, tumor stage, pathological typing, molecular typing, lymph node metastasis, distant metastasis, carcinoembryonic antigen (CEA), and CA-199 expression), PFS time and OS time were followed up. The expression of CD133 in different CTCs was compared, and the correlation between CD133 and patient survival time was compared. RESULTS: The positive rate of E-CTC in patients with tumor diameter ≥5 cm was significantly higher than that of patients with tumor diameter <5 cm (P=0.035). The positive rate of M-CTC in patients with diabetes was significantly higher than that of patients without diabetes (P=0.006). The CD133-positive M-CTCs were significantly higher in DM and CEA>5 ng/mL patients than in non-DM and CEA≤5 ng/mL patients (P<0.001, P=0.0195). Fifty-five patients were followed up for a median of 14 months. During follow-up, 19 had disease progression and five died. According to the cutoff point obtained by ROC analysis, the PFS of M-CTC>2.5/5 ml patients (0%) was lower than that of ≤2.5/5 ml patients (76.5%), P<0.05. PFS in patients with CD133-positive M-CTC>0.5/5 mL (18.6%) was lower than in patients with ≤0.5/5 ml (76.5%), P<0.05. However, thedifference in the OS between patients with CD133-positive M-CTC>0.5/5 ml (71.7%) and those with ≤0.5/5 ml (93.8%), was not significant, P=0.054. CONCLUSION: CD133 positive M-CTC is closely related to distant metastasis in CRC. The expression of CD133 in CTC, especially in M-CTC, can be used as a prognostic indicator for colorectal cancer.

Establishment and validation of a prognostic risk classification for patients with stage T1-3N0M0 esophageal squamous cell carcinoma.

INTRODUCTION: At present, clinical factors and hematological indicators have been proved to have great potential in predicting the prognosis of cancer patients, and no one has combined these two valuable indicators to establish a prognostic model for esophageal squamous cell carcinoma (ESCC) patients with stage T1-3N0M0 after R0 resection. To verify, we aimed to combine these potential indicators to establish a prognostic model. METHODS: Stage T1-3N0M0 ESCC patients from two cancer centers (including training cohort: N = 819, and an external validation cohort: N = 177)-who had undergone esophagectomy in 1995-2015 were included. We integrated significant risk factors for death events by multivariable logistic regression methods and applied them to the training cohort to build Esorisk. The parsimonious aggregate Esorisk score was calculated for each patient; the training set was divided into three prognostic risk classes according to the 33rd and 66th percentiles of the Esorisk score. The association of Esorisk with cancer-specific survival (CSS) was assessed using Cox regression analyses. RESULTS: The Esorisk model was: [10 + 0.023 × age + 0.517 × drinking history - 0.012 × hemoglobin-0.042 × albumin - 0.032 × lymph nodes]. Patients were grouped into three classes-Class A (5.14-7.26, low risk), Class B (7.27-7.70, middle risk), and Class C (7.71-9.29, high risk). In the training group, five-year CSS decreased across the categories (A: 63%; B: 52%; C: 30%, Log-rank P < 0.001). Similar findings were observed in the validation group. Additionally, Cox regression analysis showed that Esorisk aggregate score remained significantly associated with CSS in the training cohort and validation cohort after adjusting for other confounders. CONCLUSIONS: We combined the data of two large clinical centers, and comprehensively considered their valuable clinical factors and hematological indicators, established and verified a new prognostic risk classification that can predict CSS of stage T1-3N0M0 ESCC patients.

Toward the next generation EGFR inhibitors: an overview of osimertinib resistance mediated by EGFR mutations in non-small cell lung cancer.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is currently the standard first-line therapy for EGFR-mutated advanced non-small cell lung cancer (NSCLC). The life quality and survival of this subgroup of patients were constantly improving owing to the continuous iteration and optimization of EGFR-TKI. Osimertinib, an oral, third-generation, irreversible EGFR-TKI, was initially approved for the treatment of NSCLC patients carrying EGFR T790M mutations, and has currently become the dominant first-line targeted therapy for most EGFR mutant lung cancer. Unfortunately, resistance to osimertinib inevitably develops during the treatment and therefore limits its long-term effectiveness. For both fundamental and clinical researchers, it stands for a major challenge to reveal the mechanism, and a dire need to develop novel therapeutics to overcome the resistance. In this article, we focus on the acquired resistance to osimertinib caused by EGFR mutations which account for approximately 1/3 of all reported resistance mechanisms. We also review the proposed therapeutic strategies for each type of mutation conferring resistance to osimertinib and give an outlook to the development of the next generation EGFR inhibitors. Video Abstract.