A Lipid-Sensitive Spider Peptide Toxin Exhibits Selective Anti-Leukemia Efficacy through Multimodal Mechanisms.

Anti-cancer peptides (ACPs) represent a promising potential for cancer treatment, although their mechanisms need to be further elucidated to improve their application in cancer therapy. Lycosin-I, a linear amphipathic peptide isolated from the venom of Lycosa singorensis, shows significant anticancer potential. Herein, it is found that Lycosin-I, which can self-assemble into a nanosphere structure, has a multimodal mechanism of action involving lipid binding for the selective and effective treatment of leukemia. Mechanistically, Lycosin-I selectively binds to the K562 cell membrane, likely due to its preferential interaction with negatively charged phosphatidylserine, and rapidly triggers membrane lysis, particularly at high concentrations. In addition, Lycosin-I induces apoptosis, cell cycle arrest in the G1 phase and ferroptosis in K562 cells by suppressing the PI3K-AKT-mTOR signaling pathway and activating cell autophagy at low concentrations. Furthermore, intraperitoneal injection of Lycosin-I inhibits tumor growth of K562 cells in a nude mouse xenograft model without causing side effects. Collectively, the multimodal effect of Lycosin-I can provide new insights into the mechanism of ACPs, and Lycosin-I, which is characterized by high potency and specificity, can be a promising lead for the development of anti-leukemia drugs.

Targeting TRIM40 signaling reduces esophagus cancer development: A mechanism involving in protection of oroxylin A.

Oroxylin A (OA), a naturally active O-methylated flavone derived from Scutellaria baicalensis, is regarded as a potential drug with strong anticancer effects. Unfortunately, our understanding of the antineoplastic mechanism of oral exposure to such flavonoids is inadequate. Growing evidence has confirmed the important role of OA in the regulation of oxidative stress- and inflammatory-response-induced tissue injury. However, it remains unknown whether OA is capable of mitigating esophagus cancer (EC) progression and its potential molecular mechanism. Furthermore, the tripartite motif containing 40 (TRIM40) is a ubiquitin ligase that mediates the immune response. The potential molecular function of TRIM40 in regulating EC is largely unknown. We confirmed that OA-triggered oxidative stress markedly upregulates TRIM40. During the OA challenge, increased TRIM40 reduced oxidative stress and promoted the ER stress response. Inversely, deletion of TRIM40 facilitated oxidative stress and blocked cancer cell growth in vivo and in vitro. Mechanistically, in response to OA treatment, TRIM40 directly interacts with Keap1 and promotes ubiquitin-proteasome degradation, thus leading to the promotion of Nrf2 nuclear translocation and its downstream cascade activation, which increases antioxidant defense and cell survival. TRIM40 expression was positively correlated with Nrf2 expression and negatively associated with Keap1 expression in EC xenografts and human specimens. In addition, high TRIM40 expression correlates with poor patient survival in EC. The findings suggested that oral exposure to OA significantly mitigates EC development by targeting TRIM40 activity. These findings further elucidated the potential role of TRIM40 in EC progression by mediating Keap1 degradation, which could be considered a therapeutic target for the treatment of such a disease.

Long-term toxicity evaluation of aristolochic acid-IIIa in mice.

Aristolochic acid (AA)-IIIa is an AA analog present in Aristolochiaceae plants. To evaluate the chronic toxicity of AA-IIIa, mice were intragastrically administered with media control, 1 mg/kg AA-IIIa, and 10 mg/kg AA-IIIa, and designated as the control (CTL), AA-IIIa low dose (AA-IIIa-L), and AA-IIIa high dose (AA-IIIa-H) groups, respectively. AA-IIIa was administered three times a week, every other day, for 24 weeks (24-week time point). Thereafter, some mice were sacrificed immediately, while others were sacrificed 29 or 50 weeks after AA-IIIa withdrawal (53- or 74-week time point). Serum and organs were collected for biochemical and pathological analyses, respectively. Whole-genome sequencing was performed on the kidney, liver, and stomach tissues of AA-IIIa-treated mice for single-nucleotide polymorphism (SNP) detection. AA-IIIa-H mice died at 66 weeks, and the remaining mice showed moribund conditions at the 69 weeks. AA-IIIa induced minor kidney tubule injury, fibroblast hyperplasia, and forestomach carcinoma in mice. Bladder, intestine, liver, heart, spleen, lung, and testis tissues were not pathologically altered by AA-IIIa. In addition, AA-IIIa increased the C:G > A:T mutation in the kidney; however, no SNP mutation changes were observed in the liver and forestomach tissues of AA-IIIa-H mice at the 24-week time point compared with control mice. Therefore, we suspect that AA-IIIa is potentially mutagenic for mice after overdose and long-term administration. On the other hand, the forestomach is a unique organ in mice, but it does not exist in humans; thus, we hypothesize that the stomach toxicity induced by AA-IIIa is not a suitable reference for toxicological evaluation in humans. We recommend that Aristolochiaceae plants containing AA-IIIa should be properly supervised, and overdosing and long-term administration of drugs containing AA-IIIa should be avoided.

Long-term oral administration of Kelisha capsule does not cause hepatorenal toxicity in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Kelisha capsules (KLS) are often used to treat acute diarrhoea, bacillary dysentery, heat stroke, and other diseases. One of its components, Asarum, contains aristolochic acid I which is both nephrotoxic and carcinogenic. However, the aristolochic acid (AA) content in KLS and its toxicity remain unclear. AIM OF THE STUDY: The aims of this study were to quantitatively determine the contents of five aristolochic acid analogues (AAAs) in Asarum and KLS, and systematically evaluate the in vivo toxicity of KLS in rats. MATERIALS AND METHODS: Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to determine the content of the five AAAs in Asarum and KLS. Sprague-Dawley rats were administered KLS at 0, 0.75, 1.5, and 3.0 g/kg respectively, and then sacrificed after 4 weeks of administration or after an additional 2 weeks of recovery. The endpoints assessed included body weight measurements, serum biochemistry and haematology indices, and clinical and histopathological observations. RESULTS: The AAAs content in Asarum sieboldii Miq. (HB-ESBJ) were much lower than those of the other Asarums. The contents of AA I, AA IVa, and aristolactam I in KLS were in the ranges of 0.03-0.06 µg/g, 1.89-2.16 µg/g, and 0.55-1.60 µg/g, respectively, whereas AA II and AA IIIa were not detected. None of the rats showed symptoms of toxic reactions and KLS was well tolerated throughout the study. Compared to the control group, the activated partial thromboplastin time values of rats in the 1.5 and 3.0 g/kg groups significantly reduced after administration (P < 0.05). In addition, the serum triglycerides of male rats in the 0.75 and 1.5 g/kg groups after administration, and the 0.75, 1.5, 3.0 g/kg groups after recovery were significantly decreased (P < 0.01 or P < 0.001). No significant drug-related toxicological changes were observed in other serum biochemical indices, haematology, or histopathology. CONCLUSIONS: The AA I content in KLS met the limit requirements (<0.001%) of the Chinese Pharmacopoeia. Therefore, it is safe to use KLS in the short-term. However, for safety considerations, attention should be paid to the effects of long-term KLS administration on coagulation function and triglyceride metabolism.

Value of orthogonal axial MR images in preoperative T staging of gastric cancer.

PURPOSE: To assess the value of orthogonal axial images (OAI) of MRI in gastric cancer T staging. METHODS: This retrospective study enrolled 133 patients (median age, 63 [range, 24-85] years) with gastric adenocarcinoma who underwent both CT and MRI followed by surgery. MRI lacking or incorporating OAI and CT images were evaluated, respectively. Diagnostic performance (accuracy, sensitivity, and specificity) for each T stage, overall diagnostic accuracy and rates of over- and understaging were quantified employing pathological T stage as a reference standard. The McNemar's test was performed to compare the overall accuracy. RESULTS: Among patients with pT1-pT4 disease, MRI with OAI (accuracy: 88.7-94.7%, sensitivity: 66.7-93.0%, specificity: 91.5-100.0%) exhibited superior diagnostic performance compared to MRI without OAI (accuracy: 81.2-88.7%, sensitivity: 46.2-83.1%, specificity: 85.5-99.1%) and CT (accuracy: 88.0-92.5%, sensitivity: 53.3-90.1%, specificity: 88.7-98.1%). The overall accuracy of MRI with OAI was significantly higher (83.5%) than that of MRI without OAI (67.7%) (p < .001). However, there was no significant difference in the overall accuracy of MRI with OAI and CT (78.9%) (p = .35). The over- and understaging rates of MRI with OAI (12.0, 4.5%) were lower than those of MRI without OAI (21.8, 10.5%) and CT (12.8, 8.3%). CONCLUSION: OAI play a pivotal role in the T staging of gastric cancer. MRI incorporating OAI demonstrated commendable performance for gastric cancer T-staging, with a slight tendency toward its superiority over CT.

Polymeric micellar nanoparticles for effective CRISPR/Cas9 genome editing in cancer.

The clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9) gene editing has attracted extensive attentions in various fields, however, its clinical application is hindered by the lack of effective and safe delivery system. Herein, we reported a cationic micelle nanoparticle composed of cholesterol-modified branched small molecular PEI (PEI-CHO) and biodegradable PEG-b-polycarbonate block copolymer (PEG-PC), denoted as PEG-PC/PEI-CHO/pCas9, for the CRISPR/Cas9 delivery to realize genomic editing in cancer. Specifically, PEI-CHO condensed pCas9 into nanocomplexes, which were further encapsulated into PEG-PC nanoparticles (PEG-PC/PEI-CHO/pCas9). PEG-PC/PEI-CHO/pCas9 had a PEG shell, protecting DNA from degradation by nucleases. Enhanced cellular uptake of PEG-PC/PEI-CHO/pCas9 nanoparticles was observed as compared to that mediated by Lipo2k/pCas9 nanoparticles, thus leading to significantly elevated transfection efficiency after escaping from endosomes via the proton sponge effect of PEI. In addition, the presence of PEG shell greatly improved biocompatibility, and significantly enhanced the in vivo tumor retention of pCas9 compared to PEI-CHO/pCas9. Notably, apparent downregulation of GFP expression could be achieved both in vitro and in vivo by using PEG-PC/PEI-CHO/pCas9-sgGFP nanoparticles. Furthermore, PEG-PC/PEI-CHO/pCas9-sgMcl1 induced effective apoptosis and tumor suppression in a HeLa tumor xenograft mouse model by downregulating Mcl1 expression. This work may provide an alternative paradigm for the efficient and safe genome editing in cancer.

A combined nomogram based on radiomics and hematology to predict the pathological complete response of neoadjuvant immunochemotherapy in esophageal squamous cell carcinoma.

BACKGROUND: To predict pathological complete response (pCR) in patients receiving neoadjuvant immunochemotherapy (nICT) for esophageal squamous cell carcinoma (ESCC), we explored the factors that influence pCR after nICT and established a combined nomogram model. METHODS: We retrospectively included 164 ESCC patients treated with nICT. The radiomics signature and hematology model were constructed utilizing least absolute shrinkage and selection operator (LASSO) regression, and the radiomics score (radScore) and hematology score (hemScore) were determined for each patient. Using the radScore, hemScore, and independent influencing factors obtained through univariate and multivariate analyses, a combined nomogram was established. The consistency and prediction ability of the nomogram were assessed utilizing calibration curve and the area under the receiver operating factor curve (AUC), and the clinical benefits were assessed utilizing decision curve analysis (DCA). RESULTS: We constructed three predictive models.The AUC values of the radiomics signature and hematology model reached 0.874 (95% CI: 0.819-0.928) and 0.772 (95% CI: 0.699-0.845), respectively. Tumor length, cN stage, the radScore, and the hemScore were found to be independent factors influencing pCR according to univariate and multivariate analyses (P < 0.05). A combined nomogram was constructed from these factors, and AUC reached 0.934 (95% CI: 0.896-0.972). DCA demonstrated that the clinical benefits brought by the nomogram for patients across an extensive range were greater than those of other individual models. CONCLUSIONS: By combining CT radiomics, hematological factors, and clinicopathological characteristics before treatment, we developed a nomogram model that effectively predicted whether ESCC patients would achieve pCR after nICT, thus identifying patients who are sensitive to nICT and assisting in clinical treatment decision-making.

Design and Characterization of a New Formulation for the Delivery of COVID-19-mRNA Vaccine to the Nasal Mucosa.

Chitosan, a natural polysaccharide derived from chitin, possesses biocompatibility, biodegradability, and mucoadhesive characteristics, making it an attractive material for the delivery of mRNA payloads to the nasal mucosa and promoting their uptake by target cells such as epithelial and immune cells (e.g., dendritic cells and macrophages). In this project, we aimed at developing novel lipid-based nanoformulations for mRNA delivery to counteract the pandemic caused by SARS-CoV-2 virus. The formulations achieved a mRNA encapsulation efficiency of ~80.2% with chitosan-lipid nanoparticles, as measured by the RiboGreen assay. Furthermore, the evaluation of SARS-CoV-2 Spike (S) receptor-binding domain (RBD) expression via ELISA for our vaccine formulations showed transfection levels in human embryonic kidney cells (HEK 293), lung carcinoma cells (A549), and dendritic cells (DC 2.4) equal to 9.9 ± 0.1 ng/mL (174.7 ± 1.1 fold change from untreated cells (UT)), 7.0 ± 0.2 ng/mL (128.1 ± 4.9 fold change from UT), and 0.9 ± 0.0 ng/mL (18.0 ± 0.1 fold change from UT), respectively. Our most promising vaccine formulation was also demonstrated to be amenable to lyophilization with minimal degradation of loaded mRNA, paving the way towards a more accessible and stable vaccine. Preliminary in vivo studies in mice were performed to assess the systemic and local immune responses. Nasal bronchoalveolar lavage fluid (BALF) wash showed that utilizing the optimized formulation resulted in local antibody concentrations and did not trigger any systemic antibody response. However, if further improved and developed, it could potentially contribute to the management of COVID-19 through nasopharyngeal immunization strategies.

Effectiveness of a Teach-Back Education Program on Perioperative Pain in Patients With Lung Cancer: An Intervention Study Using Behavior Change Wheel.

OBJECTIVE: To assess the effect of a teach-back educational intervention using Behavior Change Wheel (BCW) framework on perioperative pain among patients with lung cancer. METHODS: A prospective quasi-experimental study was conducted in 88 patients with lung cancer from a tertiary hospital in China. According to the order of admission, they were allocated to either control group or intervention group, with 44 patients in each group. Patients in the control group received routine nursing care, while patients in the intervention group were given a teach-back education program based on BCW framework. The visual analog scale (VAS) was adopted to evaluate patients' pain on the day of surgery (T0), 1 (T1), 2 (T2), and 3 (T3) days after surgery. We also recorded the use of patient-controlled analgesia (PCA), the length of hospital stay, and the degree of patients' satisfaction. RESULTS: Rest pain, pain when coughing, and pain during activity that patients in the intervention group experienced were significantly less severe than those in the control group on T0 and T1. The pain when coughing in the intervention group was also significantly milder on T2 and T3. In addition, the number of self-control time, use duration, and total dose of PCA were significantly lower in the intervention group. Moreover, patients' satisfaction of nursing service was significantly higher in the intervention group. CONCLUSION: A teach-back education program based on BCW framework was effective in pain management among the perioperative patients with lung cancer. This study demonstrates the application of teach-back method and the BCW in the development of patient education intervention to mitigate perioperative pain.

Clinical efficacy and safety of composite non-cross-linked hyaluronic acid for treating tear trough-lower eyelid bag deformity.

BACKGROUND: Tear trough-eye bag deformities may appear in young Asian patients due to the weak support of their facial skeletons. For these patients with better periorbital skin elasticity, the injection may be more suitable than surgery for treating tear trough-lower eyelid bag deformity. AIMS: Identify the clinical efficacy and safety of non-cross-linked HA in the treatment of tear trough-lower eyelid bag deformity. METHODS: In this study, we analyzed pre- and postinjection photographs of 55 patients treated with non-cross-linked hyaluronic acid (HA) for tear trough-lower eyelid bag deformity. RESULTS: The mean [SD] scores of modified Goldberg score suggested that the most significant improvement of preoperative and postoperative scores was in tear trough depression, followed by infraorbital triangular depression, orbital fat prolapse, loss of skin elasticity, and skin transparency. Only transient localized complications were observed, including bruising, swelling, and erythema. There were no serious complications, such as skin necrosis or visual impairment. CONCLUSIONS: Our study confirmed the beneficial efficacy and minor complications of composite non-cross-linked HA for the treatment of tear trough-lower eyelid bag deformity.

A Phase 1b Clinical Trial of Neoadjuvant Radio-immunotherapy for Esophageal Squamous Cell Cancer.

PURPOSE: Neoadjuvant chemoradiotherapy is the recommended treatment for patients with resectable esophageal cancer but is associated with a higher incidence of adverse effects. Given the efficacy of immunotherapy, we propose a chemotherapy-free regimen of neoadjuvant radio-immunotherapy (NRIT) to balance therapeutic efficacy and potential side effects or overtreatment. METHODS AND MATERIALS: In this phase 1b clinical trial, we assessed the safety and efficacy of NRIT in esophageal squamous cell cancer. The enrolled patients received 41.4 Gy of radiation and 4 cycles of 240 mg of toripalimab injection before surgery. The primary endpoint was treatment-related adverse events and the secondary endpoints were pathologic complete response and major pathologic response. Immunohistochemistry and multiplex immunofluorescence staining were used to evaluate the tumor microenvironment before and after neoadjuvant treatment. RESULTS: Of the 22 patients enrolled, 19 underwent R0 surgery. One patient discontinued neoadjuvant immune therapy due to experiencing a grade 3 treatment-related adverse event. Three patients did not undergo surgery due to tumor progression or side effects. Among the patients who underwent surgery, 3 patients experienced serious complications shortly after surgery. Upon pathologic evaluation, the pathologic complete response and major pathologic response rates were 47.4% and 68.4%, respectively. CONCLUSIONS: The NRIT regimen is safe and feasible for patients with esophageal squamous cell cancer.

Radix Sanguisorbae Improves Intestinal Barrier in Septic Rats via HIF-1 α/HO-1/Fe2+ Axis.

OBJECTIVE: To investigate whether Radix Sanguisorbae (RS, Diyu) could restore intestinal barrier function following sepsis using a cecal ligation and puncture (CLP)-induced septic rat model and lipopolysaccharide (LPS)-challenged IEC-6 cell model, respectively. METHODS: Totally 224 rats were divided into 4 groups including a control, sham, CLP and RS group according to a random number table. The rats in the control group were administrated with Ringer's lactate solution (30 mL/kg) with additional dopamine [10 µ g/(kg·min)] and given intramuscular injections of cefuroxime sodium (10 mg/kg) 12 h following CLP. The rats in the RS group were administrated with RS (10 mg/kg) through tail vein 1 h before CLP and treated with RS (10 mg/kg) 12 h following CLP. The rats in the sham group were only performed abdominal surgery without CLP. The rats in the CLP group were performed with CLP without any treatment. The other steps were same as control group. The effects of RS on intestinal barrier function, mesenteric microvessels barrier function, multi-organ function indicators, inflammatory response and 72 h survival window following sepsis were observed. In vitro, the effects of RS on LPS-challenged IEC-6 cell viability, the expressions of zona occludens-1 (ZO-1) and ferroptosis index were evaluated by cell counting kit-8, immunofluorescence and Western blot analysis. Bioinformatic tools were applied to investigate the pharmacological network of RS in sepsis to predict the active compounds and potential protein targets and pathways. RESULTS: The sepsis caused severe intestinal barrier dysfunction, multi-organ injury, lipid peroxidation accumulation, and ferroptosis in vivo. RS treatment significantly prolonged the survival time to 56 h and increased 72-h survival rate to 7/16 (43.75%). RS also improved intestinal barrier function and relieved intestinal inflammation. Moreover, RS significantly decreased lipid peroxidation and inhibited ferroptosis (P<0.05 or P<0.01). Administration of RS significantly worked better than Ringer's solution used alone. Using network pharmacology prediction, we found that ferroptosis and hypoxia inducible factor-1 (HIF-1 α) signaling pathways might be involved in RS effects on sepsis. Subsequent Western blot, ferrous iron measurements, and FerroOrange fluorescence of ferrous iron verified the network pharmacology predictions. CONCLUSION: RS improved the intestinal barrier function and alleviated intestinal injury by inhibiting ferroptosis, which was related in part to HIF-1 α/heme oxygenase-1/Fe2+ axis.

Chemical Proteomics and Morphological Profiling Revealing MYDGF as a Target for Synthetic Anticancer Macromolecules.

Biodegradable guanidinium-functionalized polycarbonates kill cancer cells via membrane translocation without causing resistance after repeated use, but the exact molecular targets of the polycarbonates are unknown. Here, we investigate the protein targets of the polycarbonates through affinity-based protein profiling and report myeloid-derived growth factor (MYDGF) as the main protein target. Direct binding of the polycarbonates to MYDGF protein is validated through biolayer interferometry. MYDGF is overexpressed in a range of cancer cells, and knockdown of MYDGF is shown to reduce cell proliferation in cancer cells. Through morphological profiling, we also identify similarities in phenotypic effects of the functionalized polycarbonates with topoisomerase I inhibitors, MDM2 inhibitors, and phosphatidylinositol 3kinase inhibitors against cancer cells, suggesting a common mechanism through the PIK3/AKT pathway leading to apoptosis. These findings present the first macromolecular compound targeting MYDGF and may serve as an example for MYDGF modulation as a potential new target for macromolecular chemotherapeutic development.

Injectable Hydrogels Prepared Using Novel Synthetic Short Peptides with Defined Structure and Gelatin as Scaffolds to Support Cell and Tissue Growth.

Animal-derived basement-membrane matrices such as Geltrex are used to grow cells and tissues. Particularly, these are commonly applied to support tumor growth in animals for cancer research. However, a material derived from an animal source has an undefined composition, and may thus have unavoidable batch-to-batch variation in properties. To overcome these issues, a series of synthetic short peptides to form hydrogels is designed in combination with gelatin to promote cell adhesion and growth. The peptides have sequences of (X1Y1X2Y2)2 , where X1 and X2 are hydrophobic residues, while Y1 and Y2 are hydrophilic residues. The peptides spontaneously fold and self-assemble into a ß-sheet secondary structure upon contact with salts, and then aggregate to form hydrophilic networks of hydrogels. Hybrid hydrogels formed by mixing the peptide IEVEIRVK (IVK8) with gelatin are injectable and enzymatically degradable. The hybrid hydrogels at optimal compositions support SW480 and HepG2 tumor spheroid growth in vitro as effectively as Geltrex. More importantly, the peptide/gelatin hydrogels support tumor growth in a SW480 human colorectal adenocarcinoma xenograft mouse model. Altogether, the results illustrate that the synthetic peptide/gelatin hybrid hydrogel is a promising scaffold that can be used to support cell and tissue growth both in vitro and in vivo.

Role of dynamic contrast-enhanced MRI in predicting severe acute radiation-induced rectal injury in patients with rectal cancer.

OBJECTIVES: To explore the potential of dynamic contrast-enhanced MRI (DCE-MRI) quantitative parameters in predicting severe acute radiation-induced rectal injury (RRI) in rectal cancer. METHODS: This retrospective study enrolled 49 patients with rectal cancer who underwent neoadjuvant chemoradiotherapy and rectal MRI including a DCE-MRI sequence from November 2014 to March 2021. Two radiologists independently measured DCE-MRI quantitative parameters, including the forward volume transfer constant (Ktrans), rate constant (kep), fractional extravascular extracellular space volume (ve), and the thickness of the rectal wall farthest away from the tumor. These parameters were compared between mild and severe acute RRI groups based on histopathological assessment. Receiver operating characteristic curve analysis was performed to analyze statistically significant parameters. RESULTS: Forty-nine patients (mean age, 54 years ± 12 [standard deviation]; 37 men) were enrolled, including 25 patients with severe acute RRI. Ktrans was lower in severe acute RRI group than mild acute RRI group (0.032 min-1 vs 0.054 min-1; p = 0.008), but difference of other parameters (kep, ve and rectal wall thickness) was not significant between these two groups (all p > 0.05). The area under the receiver operating characteristic curve of Ktrans was 0.72 (95% confidence interval: 0.57, 0.84). With a Ktrans cutoff value of 0.047 min-1, the sensitivity and specificity for severe acute RRI prediction were 80% and 54%, respectively. CONCLUSION: Ktrans demonstrated moderate diagnostic performance in predicting severe acute RRI. CLINICAL RELEVANCE STATEMENT: Dynamic contrast-enhanced MRI can provide non-invasive and objective evidence for perioperative management and treatment strategies in rectal cancer patients with acute radiation-induced rectal injury. KEY POINTS: • To our knowledge, this study is the first to evaluate the predictive value of contrast-enhanced MRI (DCE-MRI) quantitative parameters for severe acute radiation-induced rectal injury (RRI) in patients with rectal cancer. • Forward volume transfer constant (Ktrans), derived from DCE-MRI, exhibited moderate diagnostic performance (AUC = 0.72) in predicting severe acute RRI of rectal cancer, with a sensitivity of 80% and specificity of 54%. • DCE-MRI is a promising imaging marker for distinguishing the severity of acute RRI in patients with rectal cancer.

Age at Natural Menopause, Reproductive Lifespan, and the Risk of Late-Onset Psoriasis and Psoriatic Arthritis in Women: A Prospective Cohort Study.

Although a peak incidence of psoriasis in women aged around 60 years has been observed, the link between reproductive lifespan and late-onset psoriatic diseases is underexplored. This study aims to elucidate the association between reproductive lifespan and the risk of late-onset psoriasis and psoriatic arthritis (PsA). Utilizing the UK Biobank data, we conducted a prospective cohort study in postmenopausal women without baseline psoriatic diseases. The exposure variables included age at natural menopause (ANM) and duration from menarche to menopause, termed reproductive years. The outcome variables were incident psoriasis and PsA. We employed Cox regression analysis, factoring in polygenic risk scores for psoriatic diseases and recognized risk factors. We found that later ANM and longer reproductive years were significantly associated with decreased risks of late-onset psoriasis and PsA in a dose-dependent manner (P<.05). ANM after age 55 years led to a 34 and 46% risk reduction in late-onset psoriasis and PsA, respectively, compared with ANM before age 45 years (P<.001). The population-attributable risks of ANM were 17.4% for late-onset psoriasis and 21.6% for PsA. In conclusion, reproductive lifespan, with its inherent homeostasis, plays a pivotal yet overlooked role in late-onset psoriatic diseases. Investigations into estrogen-centric causes and sex-specific interventions are imperative.

Hypothyroidism reduces the risk of lung cancer through oxidative stress response and the PI3K/Akt signaling pathway: An RNA-seq and Mendelian randomization study.

Hypothyroidism has been suggested to play a role in tumor progression. However, the causal association between hypothyroidism and lung cancer remains unknow. To elucidate the potential association between hypothyroidism and lung cancer risk, we employ a Mendelian randomization (MR) approach. MR was performed to analyze pooled data from the International Lung Cancer Consortium (11,348 cases and 15,861 controls; European ancestry) to determine the causal relationship between hypothyroidism and lung cancer. We used 36, 83, and 14 single nucleotide polymorphisms as instrumental variables for hypothyroidism/myxoedema, hypothyroidism, and exercise, respectively. We further investigated the mechanisms involved in transcriptome analysis using data from The Cancer Genome Atlas and Genotype-Tissue Expression database. We conducted an initial validation of intermediary factor using a two-step MR analysis. Genetically predicted hypothyroidism was significantly related to the risk of overall lung cancer, specifically the risk of lung squamous cell cancer (LSCC) but not with the risk of lung adenocarcinoma (LUAD) as assessed using the inverse-variance weighted (IVM) method. A similar causal association was found between hypothyroidism/myxoedema and the risk of lung cancer, LSCC, and LUAD. Transcriptome analysis showed that genes associated with hypothyroidism, lung cancer, and LSCC were enriched in the PI3K/Akt signaling pathway and oxidative stress response. However, genes related to hypothyroidism and LUAD did not exhibit enrichment in these pathways. Hypothyroidism was significantly associated with strenuous sports or other exercises. Moreover, genetically predicted exercise was significantly related to the risk of overall lung cancer, and LSCC, but not LUAD. We detected no horizontal pleiotropy using the MR-PRESSO and MR Egger regression intercept. Hypothyroidism was causally associated with a lower risk of lung cancer, and these effects might be mediated by the oxidative stress response and the PI3K/Akt signaling pathway. Therefore, our study suggests that the potential factors and viable etiologies of hypothyroidism that contributed to lung cancer risk deserve further investigation.

MRI-detected tumor deposits in cT3 and cT4 rectal cancer following neoadjuvant chemoradiotherapy.

OBJECTIVES: To evaluate the identification of tumor deposits (TDs) and the prognostic significance of an MRI tumor regression grade for TDs in patients with rectal cancer treated with neoadjuvant chemoradiotherapy (nCRT). METHODS: Ninety-one patients with cT3 or cT4 rectal cancer who underwent surgery following nCRT between August 2014 and June 2020 were retrospectively analyzed. Changes in pre-nCRT MRI-detected TDs (mrTDs) were described as mrTD regression grade. The diagnostic performance of post-nCRT MRI-detected TDs (ymrTDs) was compared with histopathological reference standard. The correlation between ymrTDs, mrTD regression grade, and disease-free survival (DFS) was assessed. RESULTS: The sensitivity and specificity of ymrTDs were 88.00% and 89.39%, respectively. The area under the receiver operating characteristic curve was 0.887 (95% confidence interval [CI]: 0.803-0.944). The 3-year DFS of patients with positive ymrTDs was significantly lower than of the negative group (44.83% vs 82.73%, p < 0.001). The 3-year DFS was 33.33% for patients with poor regression of mrTDs following nCRT and 55.56% for those with moderate regression, compared to 69.23% in good responders and 83.97% in patients without mrTDs (p < 0.001). On multivariable Cox regression, mrTD regression grade was the only independent MRI factor associated with DFS (p = 0.042). CONCLUSIONS: Diagnostic performance of ymrTDs was moderate. The mrTD regression grade was independently correlated with DFS, which may have a prognostic implication for treatment and follow-up. CLINICAL RELEVANCE STATEMENT: Patients with poor regression of MRI-detected tumor deposits may benefit from more aggressive treatments, such as chemoradiation therapy plus induction or consolidation chemotherapy. KEY POINTS: • MRI provides a preoperative and noninvasive way to visualize tumor deposits (TDs) after neoadjuvant chemoradiotherapy (nCRT). • Post-nCRT MRI-detected TDs are a poor prognostic marker in cT3 and cT4 rectal cancer patients. • The regression of MRI-detected TDs after nCRT is associated with an improved disease-free survival.

pH-Responsive Polymeric Micelle Dynamic Complexes for Selective Killing of Helicobacter pylori.

Helicobacter pylori, the world's most common chronic infection-causing pathogen, is responsible for causing gastric ulcers, the fourth-leading cause of cancer-related death globally in 2020. In recent years, the effectiveness of the current treatment regimen (two antibiotics and one proton pump inhibitor) has often been plagued with problems such as resistance and the undesired elimination of commensal bacteria. Herein, we report the synthesis of block and random copolycarbonates, functionalized with cationic guanidinium and anionic acetate functional groups, aimed at selectively killing H. pylori in the acidic environment of the stomach, while remaining nontoxic to the commensal bacteria in the gut. The compositions of the polymers were fine-tuned so that the polymers were readily dispersed in water without any difficulty at both pH 3.0 and 7.4. The self-assembly behavior of the polymers at different pH values by dynamic light scattering showed that the random and block copolymers formed stable micelles in a simulated gastric environment (pH 3.0) while aggregated at pH 7.4. Both polymers demonstrated stronger antibacterial activity against H. pylori than the guanidinium-functionalized homopolymer without any acetate functional group at pH 3.0. The block copolymer was significantly more bactericidal at pH 3.0 across the concentrations tested, as compared to the random copolymer, while it did not show significant toxicity toward rat red blood cells (rRBCs) and HK-2 cells or bactericidal effect toward E. coli (a common gut bacterium) and nor caused aggregation of rRBCs at its effective concentration and at physiological pH of 7.4. Additionally, both the block and random copolymers were much more stable against hydrolysis at pH 3.0 than at pH 7.4. This study provides insight into the influence of both polymer architecture and dynamic assembly on the bioactivities of antimicrobial polymers, where the disassembly of coacervates into narrowly dispersed micelles at pH 3 make them potent antimicrobials aided by the protonated carboxylic acid block.