Colorectal cancer initiation: Understanding early-stage disease for intervention.

How tumors arise or the cause of precancerous lesions is a fundamental question in cancer biology. It is generally accepted that tumors originate from normal cells that undergo uncontrolled proliferation owing to genetic alterations. At the onset of adenoma formation, cancer driver mutations confer clonal growth advantage, enabling mutant cells to outcompete and eliminate the surrounding healthy cells. Hence, the development of precancerous lesions is not only attributed to the expansion of pre-malignant clones, but also relies on the relative fitness of mutated cells compared to the neighboring cells. Colorectal cancer (CRC) is an excellent model to investigate cancer origin as it follows a stereotypical process from mutant cell hyperplasia to adenoma formation and progression. Here, we review the evolving understanding of colonic tumor development, focusing on how cell intrinsic and extrinsic factors impact cell competition and the "clone war" between cancer-initiating cells and normal stem cells. We also discuss the promises and limitations of targeting cell competitiveness in cancer prevention and early intervention. The field of tumor initiation is currently in its infancy, elucidating the adenoma origin is crucial for designing effective prevention strategies and early treatments before cancer becomes incurable.

S2DA-Net: Spatial and spectral-learning double-branch aggregation network for liver tumor segmentation in CT images.

Accurate liver tumor segmentation is crucial for aiding radiologists in hepatocellular carcinoma evaluation and surgical planning. While convolutional neural networks (CNNs) have been successful in medical image segmentation, they face challenges in capturing long-term dependencies among pixels. On the other hand, Transformer-based models demand a high number of parameters and involve significant computational costs. To address these issues, we propose the Spatial and Spectral-learning Double-branched Aggregation Network (S2DA-Net) for liver tumor segmentation. S2DA-Net consists of a double-branched encoder and a decoder with a Group Multi-Head Cross-Attention Aggregation (GMCA) module, Two branches in the encoder consist of a Fourier Spectral-learning Multi-scale Fusion (FSMF) branch and a Multi-axis Aggregation Hadamard Attention (MAHA) branch. The FSMF branch employs a Fourier-based network to learn amplitude and phase information, capturing richer features and detailed information without introducing an excessive number of parameters. The FSMF branch utilizes a Fourier-based network to capture amplitude and phase information, enriching features without introducing excessive parameters. The MAHA branch incorporates spatial information, enhancing discriminative features while minimizing computational costs. In the decoding path, a GMCA module extracts local information and establishes long-term dependencies, improving localization capabilities by amalgamating features from diverse branches. Experimental results on the public LiTS2017 liver tumor datasets show that the proposed segmentation model achieves significant improvements compared to the state-of-the-art methods, obtaining dice per case (DPC) 69.4 % and global dice (DG) 80.0 % for liver tumor segmentation on the LiTS2017 dataset. Meanwhile, the pre-trained model based on the LiTS2017 datasets obtain, DPC 73.4 % and an DG 82.2 % on the 3DIRCADb dataset.

Clinical outcomes of treatment-naïve HBeAg-negative patients with chronic hepatitis B virus infection with low serum HBsAg and undetectable HBV DNA.

Serum hepatitis B surface antigen (HBsAg) level < 100 IU/ml and undetectable hepatitis B virus (HBV) DNA have been recently proposed as an alternate endpoint of "partial cure" in chronic hepatitis B (CHB). We investigated clinical outcomes of hepatitis B e antigen (HBeAg)-negative CHB patients with HBsAg <100 IU/ml and undetectable HBV DNA. Treatment-naïve HBeAg-negative CHB patients with undetectable HBV DNA and normal alanine aminotransferase were retrospectively included from three institutions. Patients were classified into the low HBsAg group (<100 IU/ml) and the high HBsAg group (≥100 IU/ml). Liver fibrosis was evaluated by noninvasive tests (NITs). A total of 1218 patients were included and the median age was 41.5 years. Patients with low HBsAg were older (45.0 vs. 40.0 years, P < 0.001) than those in the high HBsAg group, while the NIT parameters were comparable between groups. During a median follow-up of 25.7 months, patients with low HBsAg achieved a higher HBsAg clearance rate (13.0% vs. 0%, P < 0.001) and a lower rate of significant fibrosis development (2.2% vs. 7.0%, P = 0.049) compared to patients with high HBsAg. No patient developed HCC in either group. HBsAg level was negatively associated with HBsAg clearance (HR 0.213, P < 0.001) and patients with HBsAg < 100 IU/ml had a low risk of significant fibrosis development (HR 0.010, P = 0.002). The optimal cutoff value of HBsAg for predicting HBsAg clearance was 1.1 Log10 IU/ml. Treatment-naïve HBeAg-negative CHB patients with HBsAg <100 IU/ml and undetectable HBV DNA had favourable outcomes with a high rate of HBsAg clearance and a low risk of fibrosis progression.

Association of Cantonese dietary patterns with mortality risk in older Chinese: a 16-year follow-up of a Guangzhou Biobank cohort study.

Background: Evidence about the associations between Cantonese dietary patterns and mortality is scarce. We examined the prospective association of the dietary pattern with all-cause, cancer and cardiovascular disease (CVD) mortality in older Chinese. Methods: We included 19 598 participants of a Guangzhou Biobank cohort study aged 50+ years, who were recruited from 2003 to 2006 and followed up until July, 2022. The diet was assessed by using a 300-item validated food frequency questionnaire. The food items were collapsed into 27 food groups. Factor analysis (FA) was used to identify dietary patterns. Multivariable Cox regression produced hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality. Results: During 305 410 person-years, 4966 deaths including 1971 CVD, 1565 cancer and 1436 other-causes occurred. Four dietary patterns were identified by FA. No association of the vegetable-based dietary pattern with all-cause, CVD and cancer mortality was found. Compared with the lowest quartile of the healthy Cantonese dietary pattern score, the highest quartile showed lower risks of all-cause (HR 0.86, 95% CI 0.80-0.94) and CVD mortality (HR 0.84, 95% CI 0.72-0.97). The highest quartile of the nut and fruit dietary pattern showed lower risks of all-cause (HR 0.92, 95% CI 0.85-0.99) and CVD mortality (HR 0.82, 95% CI 0.72-0.93), while the unhealthy western dietary pattern was associated with a higher risk of all-cause (HR 1.10, 95% CI 1.01-1.19) and cerebrovascular disease mortality (HR 1.28, 95% CI 1.03-1.58). Conclusion: We have first identified four dietary patterns based on the Cantonese cuisine and found that healthy Cantonese and nut and fruit dietary patterns were associated with lower risks of all-cause and CVD mortality, whereas the unhealthy western dietary pattern was associated with a higher risk of all-cause and cerebrovascular disease mortality.

Hollow microsphere probes formed by hollow core optical fiber discharging for monitoring gas pressure and temperature.

A hollow core fiber (HCF) is spliced with a single-mode fiber, and then, the end face of the HCF is etched to form a microsphere interferometer for measuring gas pressure and environmental temperature. The total length of each microsphere is less than 200 µm. We fabricated two such structures and used femtosecond laser pulses to drill micro-holes on the HCF walls of both structures. One of the structures is directly used to measure air pressure, achieving a sensitivity of up to 2.857 nm/MPa while being almost insensitive to temperature. This structure is capable of assessing pressure down to 3.4 kPa within the range of 0-0.5 MPa. Another structure is filled with thermally sensitive material dimethyl silicone oil through a micro-hole, and then, it is sealed with AB adhesive to form a harmonic Vernier effect temperature sensor, with a sensitivity of up to -5.16 nm/°C. This structure is capable of assessing temperature down to 0.38 °C within the range of 30-60 °C. Additionally, the sensors have good repeatability and stability and compact structure and simple manufacturing and can be used as a sensing probe for monitoring gas pressure and temperature under extreme environments.

Pre- and intra-operative risk factors predict postoperative respiratory failure after minimally invasive oesophagectomy.

OBJECTIVES: Severe pulmonary complications such as postoperative respiratory failure can occur after minimally invasive oesophagectomy. However, the risk factors have not been well identified. The goal of this study was to develop a predictive model for the occurrence of postoperative respiratory failure with a large sample. METHODS: We collected data from patients with oesophageal cancer who had a minimally invasive oesophagectomy at Shanghai Chest Hospital from 2019 to 2022. Univariable and backward stepwise logistic regression analysis of 19 pre- and intra-operative factors was used before model fitting, and its performance was evaluated with the receiver operating characteristic curve. Internal validation was assessed with a calibration plot, decision curve analysis and area under the curve with 95% confidence intervals, obtained from 1000 resamples set by the bootstrap method. RESULTS: This study enrolled 2,386 patients, 57 (2.4%) of whom developed postoperative respiratory failure. Backward stepwise logistic regression analysis revealed that age, body mass index, cardiovascular disease, diabetes, diffusion capacity of the lungs for carbon monoxide, tumour location and duration of chest surgery ≥101.5 min were predictive factors. A predictive model was constructed and showed acceptable performance (area under the curve: 0.755). The internal validation with the bootstrap method proves the good agreement for prediction and reality. CONCLUSIONS: Obesity, severe diffusion dysfunction and upper segment oesophageal cancer were strong predictive factors. The established predictive model has acceptable predictive validity for postoperative respiratory failure after minimally invasive oesophagectomy, which may improve the identification of high-risk patients and enable health-care professionals to perform risk assessment for postoperative respiratory failure at the initial consultation.

Enzyme-labeled liquid-based cytology (ELLBC): a new noninvasive diagnostic method for bladder cancers.

BACKGROUND: Based on liquid-based cytology, we performed an enzyme histochemical staining using acid phosphatase as a marker and termed it ELLBC. The aim of this study was to investigate the value of ELLBC in the diagnosis of bladder cancer. METHODS: Fifty patients who were initially diagnosed with suspected bladder cancers (hematuria or bladder irritation symptoms, urinary ultrasound suggestive of bladder mass) at the Second Affiliated Hospital of Anhui Medical University (Anhui, China) from January 2022 to December 2022 were selected as the study subjects, all of whom underwent ELLBC, CC, and histopathology Histopathology was used as the gold standard to calculate the diagnostic efficacy of ELLBC, CC and ELLBC combined with CC in bladder cancer. RESULTS: Histopathological examination revealed 35 positive cases in 50 patients, including 15 cases of high-grade uroepithelial carcinoma (HGUC) and 20 cases of low-grade uroepithelial carcinoma (LGUC.) The sensitivity of ELLBC was 82.86%, the specificity was 93.33%, the positive predictive value (PPV) was 96.67%, the negative predictive value (NPV) was 70.00%, and the accuracy was 86.00%; CC had a sensitivity of 37.14%, specificity of 80.00%, PPV of 81.25%, NPV of 35.29%, and accuracy of 50%; ELLBC combined with CC had a sensitivity of 88.57%, specificity of 73.33%, PPV of 88.57%, NPV of 73.33%, and accuracy of 84.00%. The sensitivity and specificity of ELLBC were higher than that of CC, and the difference was statistically significant (p < 0.05), ELLBC combined with CC achieved higher sensitivity, but the diagnostic accuracy decreased. For clinical staging, the diagnostic accuracy was 86.36% for ELLBC and 40.91% for CC in patients in Stage I, and 90.91% for ELLBC and 36.36% for CC in patients in Stage II. CONCLUSION: ELLBC has high clinical application value for the diagnosis of bladder cancer and can provide new options and methods for the early screening of bladder cancer.

Case report: Successful treatment of a rare HER2-positive advanced breast squamous cell carcinoma.

Background: Breast squamous cell carcinoma (SCC) is an uncommon and highly aggressive variant of metaplastic breast cancer. Despite its rarity, there is currently no consensus on treatment guidelines for this specific subtype. Previous studies have demonstrated that chemotherapy alone has limited efficacy in treating breast SCC. However, the potential for targeted therapy in combination with chemotherapy holds promise for future treatment options. Case presentation: In this case report, we present a patient with advanced HER2-positive breast SCC, exhibiting a prominent breast mass, localized ulcers, and metastases in the lungs and brain. Our treatment approach involved the administration of HER2-targeted drugs in conjunction with paclitaxel, resulting in a sustained control of tumor growth. Conclusion: This case represents a rare occurrence of HER2-positive breast SCC, with limited available data on the efficacy of previous HER2-targeted drugs in treating such patients. Our study presents the first application of HER2-targeted drugs in this particular case, offering novel therapeutic insights for future considerations. Additionally, it is imperative to conduct further investigations to assess the feasibility of treatment options in a larger cohort of patients.

Associations of soy product intake with all-cause, cardiovascular disease and cancer mortality: Guangzhou Biobank Cohort Study and updated meta-analyses.

PURPOSE: We examined the associations of soy product intake with all-cause, cardiovascular disease (CVD), and cancer mortality and mediations through CVD risk factors based on the Guangzhou Biobank Cohort Study (GBCS), and conducted updated meta-analyses. METHODS: A total of 29,825 participants aged 50 + years were included. Causes of death were identified through record linkage. Soy product intake was assessed by food frequency questionnaire. Cox proportional hazards regression was used to analyze the associations between soy product intake and mortality, yielding hazard ratios (HRs) and 95% confidence intervals (CIs). Mediation analyses with CVD risk factors as mediators, and updated meta-analyses were conducted. RESULTS: During 454,689 person-years of follow-up, 6899 deaths occurred, including 2694 CVD and 2236 cancer. Participants who consumed soy product of 1-6 portions/week, versus no consumption, had significantly lower risks of all-cause and CVD mortality (adjusted HR (95% CI) 0.91 (0.86, 0.97) and 0.87 (0.79, 0.96), respectively). In participants who consumed soy product of ≥ 7 portions/week, the association of higher intake with lower CVD mortality was modestly mediated by total cholesterol (4.2%, 95% CI 1.0-16.6%). Updated meta-analyses showed that the highest level of soy product intake, versus the lowest, was associated with lower risks of all-cause and CVD mortality (pooled HR (95% CI) 0.92 (0.88, 0.96) and 0.92 (0.87, 0.98), respectively). CONCLUSION: Moderate and high soy product intake were associated with lower risks of all-cause and CVD mortality. Our findings provide support for current dietary guidelines recommending moderate soy product intake, and contribute additional evidence regarding the potential protective effects of high soy product intake.

Methionyl-Methionine Dipeptide Enhances Mammogenesis and Lactogenesis by Suppressing the Expression of a Novel Long Noncoding RNA MGPNCR to Inhibit eIF4B Dephosphorylation.

Previous research has demonstrated that in pregnant mice deficient in l-methionine (Met), the mixture of the dipeptide l-methionyl-l-methionine (Met-Met) with Met was more effective than Met alone in promoting mammogenesis and lactogenesis. This study aimed to investigate the role of a novel long noncoding RNA (lncRNA), named mammary gland proliferation-associated lncRNA (MGPNCR), in these processes. Transcriptomic analysis of mammary tissues from Met-deficient mice, supplemented either with a Met-Met/Met mixture or with Met alone, revealed significantly higher MGPNCR expression in the Met group compared to the mixture group, a finding recapitulated in a mammary epithelial cell model. Our findings suggested that MGPNCR hindered mammogenesis and milk protein synthesis by binding to eukaryotic initiation factor 4B (eIF4B). This interaction promoted the dephosphorylation of eIF4B at serine-422 by enhancing its association with protein phosphatase 2A (PP2A). Our study sheds light on the regulatory mechanisms of lncRNA-mediated dipeptide effects on mammary cell proliferation and milk protein synthesis. These insights underscore the potential benefits of utilizing dipeptides to improve milk protein in animals and potentially in humans.

Comparative prognosis and risk assessment in gallbladder neuroendocrine neoplasms versus adenocarcinomas.

Background: Gallbladder neuroendocrine neoplasms (GB-NENs) are a rare malignant disease, with most cases diagnosed at advanced stages, often resulting in poor prognosis. However, studies regarding the prognosis of this condition and its comparison with gallbladder adenocarcinomas (GB-ADCs) have yet to yield convincing conclusions. Methods: We extracted cases of GB-NENs and GB-ADCs from the Surveillance, Epidemiology, and End Results (SEER) database in the United States. Firstly, we corrected differences in clinical characteristics between the two groups using propensity score matching (PSM). Subsequently, we visualized and compared the survival outcomes of the two groups using the Kaplan-Meier method. Next, we employed the least absolute shrinkage and selection operator (LASSO) regression and Cox regression to identify prognostic factors for GB-NENs and constructed two nomograms for predicting prognosis. These nomograms were validated with an internal validation dataset from the SEER database and an external validation dataset from a hospital. Finally, we categorized patients into high-risk and low-risk groups based on their overall survival (OS) scores. Results: A total of 7,105 patients were enrolled in the study, comprising 287 GB-NENs patients and, 6,818 GB-ADCs patients. There were substantial differences in clinical characteristics between patients, and GB-NENs exhibited a significantly better prognosis. Even after balancing these differences using PSM, the superior prognosis of GB-NENs remained evident. Independent prognostic factors selected through LASSO and Cox regression were age, histology type, first primary malignancy, tumor size, and surgery. Two nomograms for prognosis were developed based on these factors, and their performance was verified from three perspectives: discrimination, calibration, and clinical applicability using training, internal validation, and external validation datasets, all of which exhibited excellent validation results. Using a cutoff value of 166.5 for the OS nomogram score, patient mortality risk can be identified effectively. Conclusion: Patients with GB-NENs have a better overall prognosis compared to those with GB-ADCs. Nomograms for GB-NENs prognosis have been effectively established and validated, making them a valuable tool for assessing the risk of mortality in clinical practice.

From pixels to patient care: deep learning-enabled pathomics signature offers precise outcome predictions for immunotherapy in esophageal squamous cell cancer.

BACKGROUND: Immunotherapy has significantly improved survival of esophageal squamous cell cancer (ESCC) patients, however the clinical benefit was limited to only a small portion of patients. This study aimed to perform a deep learning signature based on H&E-stained pathological specimens to accurately predict the clinical benefit of PD-1 inhibitors in ESCC patients. METHODS: ESCC patients receiving PD-1 inhibitors from Shandong Cancer Hospital were included. WSI images of H&E-stained histological specimens of included patients were collected, and randomly divided into training (70%) and validation (30%) sets. The labels of images were defined by the progression-free survival (PFS) with the interval of 4 months. The pretrained ViT model was used for patch-level model training, and all patches were projected into probabilities after linear classifier. Then the most predictive patches were passed to RNN for final patient-level prediction to construct ESCC-pathomics signature (ESCC-PS). Accuracy rate and survival analysis were performed to evaluate the performance of ViT-RNN survival model in validation cohort. RESULTS: 163 ESCC patients receiving PD-1 inhibitors were included for model training. There were 486,188 patches of 1024*1024 pixels from 324 WSI images of H&E-stained histological specimens after image pre-processing. There were 120 patients with 227 images in training cohort and 43 patients with 97 images in validation cohort, with balanced baseline characteristics between two groups. The ESCC-PS achieved an accuracy of 84.5% in the validation cohort, and could distinguish patients into three risk groups with the median PFS of 2.6, 4.5 and 12.9 months (P < 0.001). The multivariate cox analysis revealed ESCC-PS could act as an independent predictor of survival from PD-1 inhibitors (P < 0.001). A combined signature incorporating ESCC-PS and expression of PD-L1 shows significantly improved accuracy in outcome prediction of PD-1 inhibitors compared to ESCC-PS and PD-L1 anlone, with the area under curve value of 0.904, 0.924, 0.610 for 6-month PFS and C-index of 0.814, 0.806, 0.601, respectively. CONCLUSIONS: The outcome supervised pathomics signature based on deep learning has the potential to enable superior prognostic stratification of ESCC patients receiving PD-1 inhibitors, which convert the images pixels to an effective and labour-saving tool to optimize clinical management of ESCC patients.

Effect of Intensive Blood Pressure Control on Cardiovascular Outcomes in Cancer Survivors.

BACKGROUND: To evaluate whether cancer modifies the effect of intensive blood pressure control on major cardiovascular outcomes. METHODS: Using data of the SPRINT (Systolic Blood Pressure Intervention Trial), we compared the risk of the composite outcomes of myocardial infarction, other acute coronary syndromes, stroke, heart failure, and cardiovascular death in patients with and without a history of cancer. Using Cox proportional hazards regression, we tested interactions between history of cancer and intensive blood pressure control on major cardiovascular outcomes. RESULTS: The study included a total of 9336 patients, with a mean age of 67.9±9.4 years, among whom 2066 (22.2%) were cancer survivors. Over a median follow-up of 3.2 years, 561 primary cardiovascular outcomes were observed. Cancer survivors had a similar risk of experiencing the primary outcome compared with patients without cancer after multivariable adjustment (adjusted hazard ratio, 0.94 [95% CI, 0.77-1.15]). Intensive blood pressure control reduced risk of the primary cardiovascular outcome similarly for cancer survivors (hazard ratio, 0.70 [95% CI, 0.51-0.97]) and patients without cancer (HR, 0.76 [95% CI, 0.63-0.93]; P for interaction 0.74). CONCLUSIONS: In SPRINT study, intensive blood pressure treatment reduced the risk of major cardiovascular events in cancer survivors to a similar extent to that of patients without cancer. Cancer history not requiring active treatment in last 2 years should not be an obstacle to intensive treatment of hypertension. This post hoc analysis should be considered as hypothesis-generating and merit further clinical trial. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.

Biphasic release of betamethasone from an injectable HA hydrogel implant for alleviating lumbar disc herniation induced sciatica.

Epidural steroid injection (ESI) is a common therapeutic approach for managing sciatica caused by lumbar disc herniation (LDH). However, the short duration of therapeutic efficacy and the need for repeated injections pose challenges in LDH treatment. The development of a controlled delivery system capable of prolonging the effectiveness of ESI and reducing the frequency of injections, is highly significant in LDH clinical practice. In this study, we utilized a thiol-ene click chemistry to create a series of injectable hyaluronic acid (HA) based release systems loaded with diphasic betamethasone, including betamethasone dipropionate (BD) and betamethasone 21-phosphate disodium (BP) (BD/BP@HA). BD/BP@HA hydrogel implants demonstrated biocompatibility and biodegradability to matched neuronal tissues, avoiding artificial compression following injection. The sustained release of betamethasone from BD/BP@HA hydrogels effectively inhibited both acute and chronic neuroinflammation by suppressing the nuclear factor kappa-B (NF-κB) pathway. In a mouse model of LDH, the epidural administration of BD/BP@HA efficiently alleviated LDH-induced sciatica for at least 10 days by inhibiting the activation of macrophages and microglia in dorsal root ganglion and spinal dorsal horn, respectively. The newly developed HA hydrogels represent a valuable platform for achieving sustained drug release. Additionally, we provide a simple paradigm for fabricating BD/BP@HA for epidural injection, demonstrating greater and sustained efficiency in alleviating LDH-induced sciatica compared to traditional ESI and displaying potentials for clinical translation. This system has the potential to revolutionize drug delivery for co-delivery of both soluble and insoluble drugs, thereby making a significant impact in the pharmaceutical industry. STATEMENT OF SIGNIFICANCE: Lumbar disc herniation (LDH) is a common degenerative disorder leading to sciatica and spine surgery. Although epidural steroid injection (ESI) is routinely used to alleviate sciatica, the efficacy is short and repeated injections are required. There remains challenging to prolong the efficacy of ESI. Herein, an injectable hyaluronic acid (HA) hydrogel implant by crosslinking acrylated-modified HA (HA-A) with thiol-modified HA (HA-SH) was designed to achieve a biphasic release of betamethasone. The hydrogel showed biocompatibility and biodegradability to match neuronal tissues. Notably, compared to traditional ESI, the hydrogel better alleviated sciatica in vivo by synergistically inhibiting the neuroinflammation in central and peripheral nervous systems. We anticipate the injectable HA hydrogel implant has the potential for clinical translation in treating LDH-induced sciatica.

Association of Measures of Glucose Metabolism with Colorectal Cancer Risk in Older Chinese: A 13-Year Follow-up of the Guangzhou Biobank Cohort Study-Cardiovascular Disease Substudy and Meta-Analysis.

BACKGRUOUND: Abnormal glucose metabolism is a risk factor for colorectal cancer (CRC). However, association of glycosylated hemoglobin (HbA1c) with CRC risk remains under-reported. We examined the association between glycemic indicators (HbA1c, fasting plasma glucose, fasting insulin, 2-hour glucose, 2-hour insulin, and homeostasis model of risk assessment-insulin resistance index) and CRC risk using prospective analysis and meta-analysis. METHODS: Participants (n=1,915) from the Guangzhou Biobank Cohort Study-Cardiovascular Disease Substudy were included. CRC events were identified through record linkage. Cox regression was used to assess the associations of glycemic indicators with CRC risk. A meta-analysis was performed to investigate the association between HbA1c and CRC risk. RESULTS: During an average of 12.9 years follow-up (standard deviation, 2.8), 42 incident CRC cases occurred. After adjusting for potential confounders, the hazard ratio (95% confidence interval [CI]) of CRC for per % increment in HbA1c was 1.28 (95% CI, 1.01 to 1.63) in overall population, 1.51 (95% CI, 1.13 to 2.02) in women and 1.06 (95% CI, 0.68 to 1.68) in men. No significant association of other measures of glycemic indicators and baseline diabetes with CRC risk was found. Meta-analyses of 523,857 participants including our results showed that per % increment of HbA1c was associated with 13% higher risk of CRC, with the pooled risk ratio being 1.13 (95% CI, 1.01 to 1.27). Subgroupanalyses found stronger associations in women, colon cancer, Asians, and case-control studies. CONCLUSION: Higher HbA1c was a significant predictor of CRC in the general population. Our findings shed light on the pathology of glucose metabolism and CRC, which warrants more in-depth investigation.

A combination of PD-L1-targeted IL-15 mRNA nanotherapy and ultrasound-targeted microbubble destruction for tumor immunotherapy.

PD-1/PD-L1-based immune checkpoint blockade therapy has shown limited benefits in tumor patients, partially attributed to the inadequate infiltration of immune effector cells within tumors. Here, we established a nanoplatform named DPPA/IL-15 NPs to target PD-L1 for the tumor delivery of IL-15 messenger RNA (mRNA). DPPA/IL-15 NPs were endowed with ultrasound responsiveness and contrast-enhanced ultrasound (CEUS) imaging performance. They effectively protected IL-15 mRNA from degradation and specifically transfected it into tumor cells through the utilization of ultrasound-targeted microbubble destruction (UTMD). This resulted in the activation of IL-15-related immune effector cells while blocking the PD-1/PD-L1 pathway. In addition, UTMD could generate reactive oxygen species (ROS) that induce endoplasmic reticulum (ER) stress-driven immunogenic cell death (ICD), initiating anti-tumor immunity. In vitro and in vivo studies revealed that this combination therapy could induce a robust systemic immune response and enhance anti-tumor efficacy. Thus, this combination therapy has the potential for clinical translation through enhanced immunotherapy and provides real-time ultrasound imaging guidance.

Analysis of risk factors for stenosis after laparoscopic pyeloplasty in the treatment of ureteropelvic junction obstruction.

BACKGROUND: Laparoscopic ureteroplasty is an effective method for managing ureteropelvic junction obstruction. Despite its high success rate, there remains a subset of patients who do not experience improvement in the hydrops. METHODS: The study retrospectively analyzed the data of 143 patients with ureteropelvic junction obstruction (UPJO) who underwent laparoscopic pyeloplasty (LP) in our hospital from January 2015 to May 2022. Logistic regression was used to analyze the risk factors of recurrence stenosis after UPJO. RESULTS: Out of these patients, 119 had complete clinical data and follow-up records. Among these patients, restenosis occurred in nine cases after the operation. There was a significant statistical difference in blood loss (P < 0.05). Univariate and multivariate logistic regression analysis revealed that the preoperative separation degree of the renal pelvis, cystatin C, and intraoperative blood loss were potential risk factors for recurrent stenosis after primary LP. When divided by split renal function (SRF), the odds ratio (OR) was 7.850 (P = 0.044), indicating that it was an independent risk factor for postoperative restenosis. Similarly, the OR for stenotic segment length was 0.025 (P = 0.011), also indicating it as an independent risk factor for restenosis. The areas under the receiver operating characteristic curve for stenotic segment length and SRF were 0.9056 and 0.7697, respectively. CONCLUSION: In our study, we identified that preoperative renal pelvis separation, cystatin C, and intraoperative blood loss were potential risk factors for postoperative restenosis. SRF and stenosis segment length were independent risk factors for postoperative restenosis.

Efficacy and Safety of a Pharmaco-Invasive Strategy Using Half-Dose Recombinant Human Prourokinase in Patients with ST-Segment Elevation Myocardial Infarction During Hospitalization.

This study investigated the efficacy and safety of pharmaco-invasive strategy with half-dose recombinant human prourokinase (PHDP) during hospitalization for patients with ST-segment elevation myocardial infarction (STEMI) to provide references for the treatment of STEMI. Patients with STEMI who fulfilled the inclusion and exclusion criteria and attended Chengde Central Hospital, Hebei Province, China, between September 3, 2019, and December 28, 2021, were included in this study. The experimental group received PHDP and the control group underwent primary percutaneous coronary intervention (PPCI). This study enrolled 150 patients with STEMI, 75 in the experimental group and 75 in the control group. Coronary angiography revealed successful thrombolysis in 64 (85.33%) patients. Compared with the control group, the experimental group had shorter first medical contact-reperfusion time (P < 0.001), less slow flow/no-reflow (P < 0.001), and a lower utilization rate of Tirofiban (P < 0.001). Validity endpoints: no statistically significant differences between the two groups. Safety endpoints: no statistically significant differences between bleeding and major adverse cardiovascular and cerebrovascular events (MACCEs), but the experimental group was more prone to arrhythmias (P = 0.040), particularly premature ventricular beats (PVB) (P = 0.008). In conclusion, the efficacy and safety of PHDP in the treatment of patients with STEMI were positive. Complete epicardial and myocardial reperfusion rates, risk for bleeding during hospitalization, and incidence of MACCEs were similar to those of the PPCI strategy. Although the PHDP group has a higher incidence of PVB, it does not increase the incidence of malignant arrhythmia. This study aimed to provide a new therapeutic strategy for the treatment of STEMI in hospitals without adequate PPCI resources condition.

FOXO1 regulates bovine skeletal muscle cells differentiation by targeting MYH3.

The growth and development of bovine skeletal muscle and beef yield is closely intertwined. Our previous research found that forkhead box O1 (FOXO1) plays an important role in the regulation of beef muscle formation, but its specific mechanism is still unknown. In this study, we aimed to clarify the regulatory mechanism of FOXO1 in proliferation and differentiation of bovine skeletal muscle cells (BSMCs). The results showed that interfering with FOXO1 can promote proliferation and the cell G1/S phase of BSMCs by up-regulating the expression of PCNA, CDK1, CDK2, CCNA2, CCNB1, CCND1 and CCNE2. Besides, interfering with FOXO1 inhibited the apoptosis of BSMCs by up-regulating the expression of anti-apoptosis gene BCL2, while simultaneously down-regulating the expression of the pro-apoptosis genes BAD and BAX. Inversely, interfering with FOXO1 can promote the differentiation of BSMCs by up-regulating the expression of myogenic differentiation marker genes MYOD, MYOG, MYF5, MYF6 and MYHC. Furthermore, RNA-seq combined with western bolt, immunofluorescence and chromatin immunoprecipitation analysis showed that FOXO1 could regulate BSMCs differentiation process by influencing PI3K-Akt, Relaxin and TGF-beta signaling pathways, and target MYH3 for transcriptional inhibition. In conclusion, this study provides a basis for studying the role and molecular mechanism of FOXO1 in BSMCs.

Surgery for bronchiectasis-destroyed lung: feasibility of video-assisted thoracoscopic surgery, and surgical outcomes.

OBJECTIVES: To provide the experience of surgical treatment for bronchiectasis-destroyed lung (BDL) and evaluate the feasibility of video-assisted thoracoscopic surgery (VATS). METHODS: BDL patients underwent surgical treatment between January 2013 and June 2018 were included. Logistic regression was performed to assess factors for major complications, and Cox's regression was performed to assess factors affected symptomatic outcome. RESULTS: Totally, 143 patients were treated by VATS (n = 64) and thoracotomy (n = 79). Nine (14.1%) cases scheduled for VATS were converted to thoracotomy for dense adhesions (n = 6) and frozen hilum (n = 3). The VATS group had a median chest tube duration, hospitalization and a time of returning to full activity of 4 days, 5 days and 1.5 months, respectively. Major complications occurred in 28 (19.6%) of all patients, 50.0% after pneumonectomy and 13.4% after lobectomy/extensive lobectomy. Multivariable analysis identified pneumonectomy [odds ratio, 3.64; 95% confidence interval (CI), 1.18-11.21] as a significant predictor for major complications. Overall, 141 (98.6%) patients benefitted from surgery (completely asymptomatic, n = 109; acceptable alleviation, n = 32). Thirty-four patients experienced relapse of the disease, including 13 with productive cough, 11 with haemoptysis and 10 with recurrent infections. Pseudomonas aeruginosa infection [hazard ratio (HR), 3.07; 95% CI, 1.38-6.83] and extent of remanent bronchiectatic areas (HR, 1.03; 95% CI, 1.00-1.05) were independent risk factors for shorter relapse free interval. CONCLUSIONS: VATS for BDL is feasible in well-selected patients. Pneumonectomy increased the risk of postoperative major complications. Removing all BDL lesions contributed to satisfactory prognosis.