Development and validation of a model and nomogram for breast cancer diagnosis based on quantitative analysis of serum disease-specific haptoglobin N-glycosylation.

BACKGROUND: A better diagnostic marker is in need to distinguish breast cancer from suspicious breast lesions. The abnormal glycosylation of haptoglobin has been documented to assist cancer diagnosis. This study aims to evaluate disease-specific haptoglobin (DSHp)-ß N-glycosylation as a potential biomarker for breast cancer diagnosis. METHODS: DSHp-ß chains of 497 patients with suspicious breast lesions who underwent breast surgery were separated from serum immunoinflammatory-related protein complexes. DSHp-ß N-glycosylation was quantified by mass spectrometric analysis. After missing data imputation and propensity score matching, patients were randomly assigned to the training set (n = 269) and validation set (n = 113). Logistic regression analysis was employed in model and nomogram construction. The diagnostic performance was analyzed with receiver operating characteristic and calibration curves. RESULTS: 95 N-glycopeptides at glycosylation sites N207/N211, N241, and N184 were identified in 235 patients with benign breast diseases and 262 patients with breast cancer. DSHp-ß N-tetrafucosyl and hexafucosyl were significantly increased in breast cancer compared with benign diseases (p < 0.001 and p = 0.001, respectively). The new diagnostic model and nomogram included GN2F2, G6N3F6, GN2FS at N184, G-N&G2S2, G2&G3NFS, G2N3F, GN3 at N207/N211, CEA, CA153, and could reliably distinguish breast cancer from benign diseases. For the training set, validation set, and training and validation sets, the area under the curves (AUCs) were 0.80 (95% CI: 0.75-0.86, specificity: 87%, sensitivity: 62%), 0.77 (95% CI:0.69-0.86, specificity: 75%, sensitivity: 69%), and 0.80 (95% CI:0.76-0.84, specificity: 77%, sensitivity: 68%), respectively. CEA, CA153, and their combination yielded AUCs of 0.62 (95% CI: 0.56-0.67, specificity: 29%, sensitivity: 90%), 0.65 (95% CI: 0.60-0.71, specificity: 74%, sensitivity: 51%), and 0.67 (95% CI: 0.62-0.73, specificity: 60%, sensitivity: 68%), respectively. CONCLUSIONS: The combination of DSHp-ß N-glycopeptides, CEA, and CA153 might be a better serologic marker to differentiate between breast cancer and benign breast diseases. The dysregulated N-glycosylation of serum DSHp-ß could provide insights into breast tumorigenesis.

Choosing the optimal target area for repeated transcranial magnetic stimulation in treating neuropathic pain in spinal cord injury patients: a comparative analysis.

Objective: The specific target area of repeated transcranial magnetic stimulation (rTMS) in treating neuropathic pain resulting from spinal cord injury (SCI-NP) remains uncertain. Methods: Thirty-four participants with SCI-NP were allocated into three groups, namely, the motor cortex (M1, A) group, the left dorsolateral prefrontal cortex (LDLPFC, B) group, and the control (sham stimulation, C) group. The intervention was administered totally 10 times. Outcome measures assessed pre-(T0) and post-(T1)intervention, including Numerical Rating scale (NRS), anxiety (SAS), depression (SDS), sleep quality (PSQI), brief pain inventory (BPI), and impression of change. Results: All outcomes in groups A and B significantly changed after intervention (p < 0.05), and the delta value (T1-T0) also significantly changed than group C (p < 0.05). The delta value of SDS in the group B was better than the group A, and the change of pain degree in the group B was moderately correlated with the change in PSQI (r = 0.575, p < 0.05). Both patients in the groups A and B showed significant impression of change about their received therapy (p < 0.05). Conclusion: Both targets are effective, but LDLPFC is more effective in reducing depression in SCI-NP. Healthcare providers might select the suitable area according to the specific attributes of their patients.

Self-powered photoelectrochemical immunosensing platform for sensitive CEA detection using dual-photoelectrode synergistic signal amplification.

Self-powered photoelectrochemical (PEC) sensing, as an emerging sensing mode, can effectively solve the problems such as weak anti-interference ability and poor signal response of individual photoanode or photocathode sensing. In this work, an ITO/Co-CuInS2 photocathode and ITO/WO3@CdS photoanode based self-powered cathodic PEC immunosensor was developed, which integrated dual-photoelectrode to synergistic amplify the signal for highly sensitive and specific detection of carcinoembryonic antigen (CEA). The self-powered PEC sensor could drive electrons transfer through the difference in Fermi levels between the two photoelectrodes without an external bias voltage. The photoanode was introduced to amplify the photoelectric signal, and the photocathode was only designed for the construction of sensing interfaces. The proposed sensor quantitatively determined the target CEA with the detection limit of 0.23 pg/mL and a linear correlation confine of 0.1 pg/mL ∼100 ng/mL. The constructed immunosensing platform exhibited high sensitivity, satisfactory stability and great biological detection selectivity, providing a feasible and effective strategy for the manufacture of new self-powered sensors in high-performance PEC bioanalytical applications.

I-scan combined with laryngovideostroboscopy for predicting malignancy in vocal fold leukoplakia.

OBJECTIVE: This study evaluated vocal fold leukoplakia using i-scan combined with laryngovideostroboscopy for risk assessment prediction. METHODS: A total of 141 patients with 218 lesions were enrolled in this study. Morphological characteristics of leukoplakia, assessment of the vascular pattern using i-scan, and vocal fold vibratory function were analyzed. RESULTS: The number of patients with no, mild, moderate, severe dysplasia, and invasive carcinoma were 68, 40, 17, 46 and 47, respectively. The sensitivity of morphological characteristic, vascular pattern, vibratory function and predictive model were 77.4%, 72%, 69.9%, and 82.8%, respectively. Receiver operating characteristic curve analysis of morphological characteristic, vascular pattern, vibratory function and predictive model were 0.771, 0.824, 0.769, and 0.923, respectively. The results of logistic regression analysis showed that rough morphological types, perpendicular vascular pattern, severe decrease and absence of mucosal waves increased the risk of malignancy (OR = 5.531, 4.973, and 16.992, respectively; P < 0.001). CONCLUSIONS: I-scan combined with laryngovideostroboscopy can improve the differential diagnosis of low-risk and high-risk vocal fold leukoplakia.

2D Z-scheme ZnIn2S4/g-C3N4 heterojunction based on photoelectrochemical immunosensor with enhanced carrier separation for sensitive detection of CEA.

Semiconducting materials based on photoelectrochemical (PEC) sensors have been widely utilized for detection. Meanwhile, the sensitivity of the PEC sensor was limited by low-efficiency carrier separation. Thus, a novel sandwich-type PEC bioimmunosensing based on 2D Z-scheme ZnIn2S4/g-C3N4 heterojunction as a photosensitive material and BiVO4 as a photoquencher was designed for the sensitive detection of carcinoembryonic antigen (CEA). Firstly, the 2D ZnIn2S4/g-C3N4 structure provided a multitude of activated sites which facilitated the loading of the capture antibody (Ab1). Secondly, the Z-scheme heterojunction had a high redox capacity while promoting the rapid separation and migration of photogenerated electron-hole pairs (e-/h+). Thus it was able to consume more electron donors to a certain extent, resulting in a higher initial photocurrent. In addition, BiVO4 with large spatial potential resistance was introduced for the first time to realize signal amplification. BiVO4 could not only compete with substrate materials for electron donors, but also effectively prevent electron donors from contacting the substrate, further reducing the photocurrent signal. Under optimized conditions, the sensor had a favorable detection range (0.0001-100 ng/mL) to CEA and a low detection limit of 0.03 pg/mL. With high specificity, excellent stability, and remarkable reproducibility, this sensor provided a new perspective for constructing accurate and convenient PEC immunosensor for bioanalysis and early disease diagnosisdisease diagnosis.

A Wearable Computer Vision System With Gimbal Enables Position-, Speed-, and Phase-Independent Terrain Classification for Lower Limb Prostheses.

Computer vision can provide upcoming walking environment information for lower limb-assisted robots, thereby enabling more accurate and robust decisions for high-level control. However, current computer vision systems in lower extremity devices are still constrained by the disruptions that occur in the interaction between human, machine, and the environment, which hinder optimal performance. In this paper, we propose a gimbal-based terrain classification system that can be adapted to different lower limb movements, different walking speeds, and gait phases. We use a linear active disturbance rejection controller to realize fast response and anti-disturbance control of the gimbal, which allows computer vision to continuously and stably focus on the desired field of view angle during lower limb motion interaction. We also deployed a lightweight MobileNetV2 model in an embedded vision module for real-time and highly accurate inference performance. By using the proposed terrain classification system, it can provide the ability to classify and predict terrain independent of mounting position (thighs and shanks), gait phase, and walking speed. This also makes our system applicable to subjects with different physical conditions (e.g., non-disabled subjects and individuals with transfemoral amputation) without tuning the parameters, which will contribute to the plug-and-play functionality of terrain classification. Finally, our approach is promising to improve the adaptability of lower limb assisted robots in complex terrain, allowing the wearer to walk more safely.

Considerable Long-Term Aesthetic Outcomes and Oncologic Safety of Breast-Conserving Surgery Via a Periareolar Incision: A Retrospective Study.

BACKGROUND: To investigate the application effect of periareolar incision breast-conserving surgery in patients with early breast cancer. METHODS: From January 2017 to November 2021, a clinician in our research center performed a total of 533 breast-conserving surgery. After screening, we collected the information of 209 patients through telephone, online questionnaires, and outpatient follow-up. One hundred seventeen patients with early breast cancer underwent breast-conserving surgery under the periareolar incision, while 92 patients underwent surgery through the tumor surface incision. We compared the differences between the 2 groups in the length of stay, postoperative complications, adjuvant therapy, and other clinical indicators, as well as the subjective and objective evaluation of the long-term postoperative breast aesthetic outcome, local recurrence, distant metastasis, and survival. RESULTS: With a mean follow-up of 3.9 years, patients in the periareolar incision group (PAIG) and tumor surface incision group (TSIG) had no significant differences in clinical indicators, local recurrence, distant metastasis, and survival. However, PAIG patients had better subjective satisfaction with postoperative breast appearance. In the evaluation of objective aesthetic outcomes, PAIG was significantly better than TSIG in texture and elasticity, symmetry, sunken degree of the operative side, skin color, surgical scar, and breast compliance difference. CONCLUSION: By observing and comparing the clinical indicators, postoperative recurrence, and metastasis of the enrolled patients, this study found that periareolar incision surgery could achieve radical therapeutic effects similar to those achieved through tumor surface incision, and had advantages in improving postoperative aesthetic outcomes, which could provide certain references for clinical practice.

COVID-19 vaccination status, side effects, and perceptions among breast cancer survivors: a cross-sectional study in China.

Introduction: Breast cancer is the most prevalent malignancy in patients with coronavirus disease 2019 (COVID-19). However, vaccination data of this population are limited. Methods: A cross-sectional study of COVID-19 vaccination was conducted in China. Multivariate logistic regression models were used to assess factors associated with COVID-19 vaccination status. Results: Of 2,904 participants, 50.2% were vaccinated with acceptable side effects. Most of the participants received inactivated virus vaccines. The most common reason for vaccination was "fear of infection" (56.2%) and "workplace/government requirement" (33.1%). While the most common reason for nonvaccination was "worry that vaccines cause breast cancer progression or interfere with treatment" (72.9%) and "have concerns about side effects or safety" (39.6%). Patients who were employed (odds ratio, OR = 1.783, p = 0.015), had stage I disease at diagnosis (OR = 2.008, p = 0.019), thought vaccines could provide protection (OR = 1.774, p = 0.007), thought COVID-19 vaccines were safe, very safe, not safe, and very unsafe (OR = 2.074, p < 0.001; OR = 4.251, p < 0.001; OR = 2.075, p = 0.011; OR = 5.609, p = 0.003, respectively) were more likely to receive vaccination. Patients who were 1-3 years, 3-5 years, and more than 5 years after surgery (OR = 0.277, p < 0.001; OR = 0.277, p < 0.001, OR = 0.282, p < 0.001, respectively), had a history of food or drug allergies (OR = 0.579, p = 0.001), had recently undergone endocrine therapy (OR = 0.531, p < 0.001) were less likely to receive vaccination. Conclusion: COVID-19 vaccination gap exists in breast cancer survivors, which could be filled by raising awareness and increasing confidence in vaccine safety during cancer treatment, particularly for the unemployed individuals.

Comparison of ultrasound and mammography for early diagnosis of breast cancer among Chinese women with suspected breast lesions: A prospective trial.

BACKGROUND: Ultrasound is more widely used than mammography for early diagnosis of breast cancer in China as most Chinese women have small and dense mammary glands. This study compared the diagnostic performance of ultrasound and mammography for breast cancer among Chinese women with suspected breast lesions. METHODS: From November 2019 to November 2021, we compared the results of ultrasound and mammography for breast lesion diagnosis in 2737 consecutive participants with suspected breast lesions; all patients underwent biopsies. We measured the sensitivity, specificity, and diagnostic accuracy separately. RESULTS: Among the 2737 participants, 2844 breast lesions were detected, including 1935 (68.0%) breast cancers and 909 (32.0%) benign lesions. Of the breast cancers, ultrasound detected 1851 (95.7%), whereas mammography detected 1527 (78.9%). The sensitivity of ultrasound for breast cancer diagnosis was significantly higher than that of mammography (95.7% vs. 78.9%, p < 0.001), whereas the specificity was significantly lower than that of mammography (42.9% vs. 62.3%, p < 0.001). The receiver operating characteristic curves revealed that ultrasound was more accurate in detecting breast cancer than mammography (76.8% vs. 71.3%, p < 0.001). Age, body mass index, and breast density did not influence ultrasound sensitivity and accuracy. CONCLUSIONS: Ultrasound is more sensitive and accurate than mammography and detects more breast cancers with a lower specificity.

High expression of cuproptosis-related SLC31A1 gene in relation to unfavorable outcome and deregulated immune cell infiltration in breast cancer: an analysis based on public databases.

Cuproptosis induction represents a promising alternative for immunotherapies and targeted therapies in breast cancer. This study aimed to investigate the prognostic and biological significance of cuproptosis-related genes in breast cancer. In the current study, we examined the transcriptional and clinical data of 13 cuproptosis-related genes in patients with breast cancer from TCGA database. We found that genes DLAT, SLC31A1, ATP7A and ATP7B were significantly related to the overall survival (OS) of breast cancer patients in univariate Cox regression analysis. Unlike lung or kidney cancers, SLC31A1 expression was upregulated in breast cancer samples compared with normal tissues, and predicted poor prognosis. Univariate and multivariate Cox regression analyses indicated that high SLC31A1 level was an independent prognostic factor for shorter OS. A nomogram integrating SLC31A1, age, T-, N-stage and clinical stage was constructed, and the calibration curves of the 1-, 3-, 5-, 10-year OS fitted well with the ideal model. Furthermore, we found that high SLC31A1 expression was related to deregulated immune response and metabolic pathways. Low SLC31A1 level predicted sensitivity to CTLA4 inhibitors but poor response to paclitaxel. Our study may provide novel insights for copper homeostasis and cuproptosis in breast cancer.

Multifunctional high-Z nanoradiosensitizers for multimodal synergistic cancer therapy.

Radiotherapy (RT) is one of the most common and effective clinical therapies for malignant tumors. However, there are several limitations that undermine the clinical efficacy of cancer RT, including the low X-ray attenuation coefficient of organs, serious damage to normal tissues, and radioresistance in hypoxic tumors. With the rapid development of nanotechnology and nanomedicine, high-Z nanoradiosensitizers provide novel opportunities to overcome radioresistance and improve the efficacy of RT by deposition of radiation energy through photoelectric effects. To date, several types of nanoradiosensitizers have entered clinical trials. Nevertheless, the limitation of the single treatment mode and the unclear mechanism of nanoparticle radiosensitization have hindered the further development of nanoradiosensitizers. In this review, we systematically describe the interaction mechanisms between X-rays and nanomaterials and summarize recent advances in multifunctional high-Z nanomaterials for radiotherapeutic-based multimodal synergistic cancer therapy. Finally, the challenges and prospects are discussed to stimulate the development of nanomedicine-based cancer RT.

Novel immune-related prognostic model and nomogram for breast cancer based on ssGSEA.

This study aimed to construct an immune-related prognostic model and a nomogram to predict the 1-, 3-, and 5-year overall survival (OS) of breast cancer patients. We applied single-sample gene set enrichment analysis to classify 1,053 breast cancer samples from The Cancer Genome Atlas (TCGA) database into high and low immune cell infiltration clusters. In cluster construction and validation, the R packages "GSVA," "hclust," "ESTIMATE," and "CIBERSORT" and GSEA software were utilized. ImmPort, univariate Cox regression analysis, and Venn analysis were then used to identify 42 prognostic immune-related genes. Eventually, the genes TAPBPL, RAC2, IL27RA, ULBP2, PSMB8, SOCS3, NFKBIE, IGLV6-57, CXCL1, IGHD, AIMP1, and CXCL13 were chosen for model construction utilizing least absolute shrinkage and selection operator regression analysis. The Kaplan-Meier curves of both the training and validation sets indicated that the overall survival of patients in the low-risk group was superior to that of patients in the high-risk group (p < .05). The areas under curves (AUCs) of the model at 1, 3, and 5 years were, respectively, .697, .710, and .675 for the training set and .930, .688, and .712 for the validation set. Regarding clinicopathologic characteristics, breast cancer-related genes, and tumor mutational burden, effective differentiation was achieved between high-risk and low-risk groups. A nomogram integrating the risk model and clinicopathologic factors was constructed using the "rms" R software package. The nomogram's 1-, 3-, and 5-year AUCs were .828, .783, and .751, respectively. Overall, our study developed an immune-related model and a nomogram that could reliably predict OS for breast cancer patients, and offered insights into tumor immune and pathological mechanisms.

A naphthalimide-polyamine conjugate preferentially accumulates in hepatic carcinoma metastases as a lysosome-targeted antimetastatic agent.

Disseminated tumors lead to approximately 90% of cancer-associated deaths especially for hepatocellular carcinoma (HCC), indicating the imperative need of antimetastatic drugs and the ineffectiveness of current therapies. Recently polyamine derivatives have been identified as a promising prospect in dealing with metastatic tumors. Herein, a novel class of naphthalimide-polyamine conjugates 8a-8d, 13a-13c, 17 and 21 were synthesized and the mechanism was further determined. The polyamine conjugate 13b displayed remarkably elevated anti-tumor and anti-metastatic effects (76.01% and 75.02%) than the positive control amonafide (46.91% and 55.77%) at 5 mg/kg in vivo. The underlying molecular mechanism indicated that in addition to induce DNA damage by up-regulating p53 and γH2AX, 13b also targeted lysosome to modulate polyamine metabolism and function in a totally different way from that of amonafide. Furthermore, the HMGB1/p62/LC3II/LC3I and p53/SSAT/ß-catenin pathways were mainly involved in the inhibition of 13b-induced HCC metastasis by targeting polyamine transporters (PTs) overexpressed in HCC. At last, 13b down-regulated the concentrations of Put, Spd and Spm by modulating polyamine metabolism key enzymes SSAT and PAO, which favored the suppression of fast growing tumor cells. Taken together, our study implies a promising strategy for naphthalimide conjugates to treat terminal cancer of HCC by targeting autophagy and tumor microenvironment with reduced toxicities and notable activities.

R-CHOP resistance in diffuse large B-cell lymphoma: biological and molecular mechanisms.

ABSTRACT: Although the first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone regimen (R-CHOP) substantially improved outcomes for patients with diffuse large B-cell lymphoma (DLBCL), 40% of the patients suffered from relapsed/refractory disease and had poor survival outcomes. The detailed mechanism underlying R-CHOP resistance has not been well defined. For this review, we conducted a thorough search for literature and clinical trials involving DLBCL resistance. We discussed DLBCL biology, epigenetics, and aberrant signaling of the B-cell receptor (BCR), phosphatidylinositol 3-kinase (PI3K)/Akt, nuclear factor kappa light chain enhancer of activated B-cells (NF-κB), and the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathways as defining mechanisms of DLBCL heterogeneity and R-CHOP resistance. The cell of origin, double- or triple-hit lymphoma and double-protein-expression, clonal evolution, tumor microenvironment, and multi-drug resistance help to contextualize DLBCL resistance in an (epi)genetically and biologically comparative manner. With better understanding of the biological and molecular landscape of DLBCL, a more detailed classification system and tailored treatments will ideally become available to further improve the prognosis of DLBCL patients.

New agents and regimens for diffuse large B cell lymphoma.

As a widely recognized standard regimen, R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is able to cure two-thirds patients with diffuse large B cell lymphoma (DLBCL), and the remaining patients suffer from refractory or relapsed disease due to resistance to R-CHOP and fare poorly. Unsatisfied outcomes for those relapsed/refractory patients prompted efforts to discover new treatment approaches for DLBCL, including chimeric antigen receptor T cells, bispecific T cell engagers, immunomodulatory drugs, immune checkpoint inhibitors, monoclonal antibodies, antibody-drug conjugates, molecular pathway inhibitors, and epigenetic-modifying drugs. Herein, up-to-date data about the most promising treatment approaches for DLBCL are recapitulated, and novel genetic classification systems are introduced to guide individualized treatment for DLBCL.

The landscape of new drugs in extranodal NK/T-cell lymphoma.

To date, much progress has been made in early-stage extranodal NK/T-cell lymphoma (ENKTCL), and risk-adapted therapy with radiotherapy (RT) alone for the low-risk group and RT combined with asparaginase-based chemotherapy (CT) for the high-risk group yields favorable outcomes. However, optimal treatment strategies have not been defined yet for advanced-stage ENKTCL. Historically, ENKTCL responded poorly to conventional anthracycline-based chemotherapy probably because of inherent multidrug resistance (MDR). The fact that ENKTCL cells lack asparagine synthetase (ASNS) activity warranted the use of L-asparaginase or pegaspargase as frontline chemotherapies. Even though, due to high mortality of the disease, approximately 50% patients failing the frontline therapy arrived at dismal clinical outcomes with a median progression-free survival (PFS) less than 8 months. As distinctive molecular and biological subgroups are increasingly discovered within the disease entity of ENKTCL, novel targeted therapies and immunotherapy are of the urgent need for those heterogeneous subgroups. In this review, we sought to summarize the preclinical and clinical results of 6 categories of promising targeted therapy and immunotherapy for the treatment of ENKTCL, including monoclonal antibodies, immune checkpoint inhibitors, small-molecular inhibitors, epigenetic therapy, immunomodulatory drugs, and adoptive T-cell therapy, and these might change the landscape of treatment for ENKTCL in the near future.

A Pt(IV)-based mononitro-naphthalimide conjugate with minimized side-effects targeting DNA damage response via a dual-DNA-damage approach to overcome cisplatin resistance.

Platinum(Pt)(II) drugs and new Pt(IV) agents behave the dysregulation of apoptosis as the result of DNA damage repair and thus, are less effective in the treatment of resistant tumors. Herein, mononitro-naphthalimide Pt(IV) complex 10b with minimized side-effects was reported targeting DNA damage response via a dual-DNA-damage approach to overcome cisplatin resistance. 10b displayed remarkably evaluated antitumor (70.10%) activities in vivo compared to that of cisplatin (52.88%). The highest fold increase (FI) (5.08) for A549cisR cells and the lowest (0.72) for A549 indicated 10b preferentially accumulated in resistant cell lines. The possible molecular mechanism indicates that 10b targets resistant cells in a totally different way from the existing Pt drugs. The cell accumulation and the Pt levels in genomic DNA from 10b is almost 5 folds higher than that of cisplatin and oxaliplatin, indicating the naphthalimide moiety in 10b exhibits preferentially DNA damage. Using 5'-dGMP as a DNA model, the DNA-binding properties of 10b (1 mM) with 5'-dGMP (3 mM) in the presence of ascorbic acid (5 mM) deduced that 10b was generated by the combination of cisplatin with 5'-dGMP after reduction by ascorbic acid. Moreover, 10b promoted the expression of p53 gene and protein more effectively than cisplatin, leading to the increased anticancer activity. The up-regulated γH2A.X and down-regulated RAD51 indicates that 10b not only induced severe DNA damage but also inhibited the DNA damage repair, thus resulting in its higher cytotoxicity in comparison to that of cisplatin. Their preferential accumulation in cancer cells (SMMC-7721) compared to the matched normal cells (HL-7702 cells) demonstrated that they were potentially safe for clinical therapeutic use. In addition, the higher therapeutic indices of 10b for 4T1 cells in vivo indicated that naphthalimide-Pt(IV) conjugates behaved a vital function in the treatment of breast cancer. For the first time, our study implies a significant strategy for Pt drugs to treat resistance cancer targeting DNA damage repair via dual DNA damage mechanism in a totally new field.

Identification of genes associated with gastric cancer survival and construction of a nomogram to improve risk stratification for patients with gastric cancer.

The present study aimed to identify genes associated with gastric cancer survival and improve risk stratification for patients with gastric cancer. Transcriptomic and clinicopathological data from 443 gastric cancer samples were retrieved from The Cancer Genome Atlas database. The DESeq R package was applied to screen for differentially expressed genes between Tumor-Node-Metastasis (TNM) stage (I vs. IV) and histological grade (G3 vs. G1 and G2). A total of seven genes were common to both comparisons; spondin 1 (SPON1); thrombospondin 4 (THBS4); Sushi, Von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1); prickle planar cell polarity protein 1 (PRICKLE1); ATP binding cassette subfamily A member 8 (ABCA8); Slit guidance ligand 2 (SLIT2); and EGF containing fibulin extracellular matrix protein 1 (EFEMP1), were selected as candidate survival-associated genes for further analysis. The prognostic value of these genes was assessed according to a literature review and Kaplan-Meier survival analysis. In addition, a multivariate Cox regression analysis revealed PRICKLE1 expression to be an independent prognostic factor for patients with gastric cancer. Furthermore, a predictive nomogram was generated using PRICKLE1 expression, patient age and TNM stage to assess overall survival (OS) rate at 1, 3 and 5 years, with an internal concordance index of 0.65. External validation was conducted in an independent cohort of 59 patients with gastric cancer, and high consistency between the predicted and observed results for OS was exhibited. Overall, the current findings suggest that PRICKLE1 expression may serve as an independent prognostic factor that can be integrated with age and TNM stage in a nomogram able to predict OS rate in patients with gastric cancer.

A Polyamine-Based Dinitro-Naphthalimide Conjugate as Substrates for Polyamine Transporters Preferentially Accumulates in Cancer Cells and Minimizes Side Effects in vitro and in vivo.

Naphthalimides, such as amonafide and mitonafide in clinical trials, have been developed as antitumor agents for orthotopic tumor. However, the serious side effects in cancer patients limit their applications. Herein, a new class of polyamine-based naphthalimide conjugates 5a-5c, 7a-7b, and 11a-11b with and without the alkylation of the distant nitrogen in the polyamine chain were synthesized and the mechanism was determined. Compared with amonafide, dinitro-naphthalimide conjugate 5c with a 4,3-cyclopropyl motif preferentially accumulates in cancer cells and minimizes side effects in vitro and in vivo. More importantly, 5c at the dosage of as low as 3 mg/kg (57.97%) displays better antitumor effects than the positive control amonafide (53.27%) at 5 mg/kg in vivo. And a remarkably elevated antitumor activity and a reduced toxicity are also observed for 5c at 5 mg/kg (65.90%). The upregulated p53 and the apoptotic cells (73.50%) indicate that the mechanism of 5c to induce apoptosis may result from its enhanced DNA damage. Further investigation indicates that in addition to target DNA, 5c can modulate the polyamine homeostasis by upregulating polyamine oxidase (PAO) in a different way from that of amonafide. And also by targeting PTs overexpressed in most of cancer cells, 5c downregulates the contents of Put, Spd, and Spm, which are in favor of suppressing fast-growing tumor cells. Our study implies a promising strategy for naphthalimide conjugates to treat hepatic carcinoma with notable activities and reduced toxicities at a low dosage.

Characterization of chemical profiles of pH-sensitive cleavable D-gluconhydroximo-1, 5-lactam hydrolysates by LC-MS: A potential agent for promoting tumor-targeted drug delivery.

Currently, controllable linker cleavage at the target site will facilitate the clinical treatment of cancer. Dual-functional prodrugs in combination of carbohydrate as targeting group and pH-sensitive cleavable linker are desired in clinical development. Here, a qualified structure of N-phenylcarbamate-d-gluconhydroximo-1,5-lactam was employed and proved to be a potential candidate prodrug in the drug design. To proof this concept, the possible mechanism of Beckmann rearrangement and the degraded products were confirmed by HPLC and LC-MS under the acid condition mimic lysosome. Hence, the strategy of d-gluconhydroximo-1,5-lactam as a prodrug carrier fabricated with interested drugs will provide a great potential approach for chemotherapy.