Deciphering the multi- partite mitochondrial genome of Crataegus pinnatifida: insights into the evolution and genetics of cultivated Hawthorn.

Flowering plant (angiosperm) mitochondrial genomes are remarkably dynamic in their structures. We present the complete mitochondrial genome of hawthorn (Crataegus pinnatifida Bunge), a shrub that bears fruit and is celebrated for its extensive medicinal history. We successfully assembled the hawthorn mitogenome utilizing the PacBio long-read sequencing technique, which yielded 799,862 reads, and the Illumina novaseq6000 sequencing platform, which producing 6.6 million raw paired reads. The C. pinnatifida mitochondria sequences encompassed a total length of 440,295 bp with a GC content of 45.42%. The genome annotates 54 genes, including 34 that encode proteins, 17 that encode tRNA, and three genes for rRNA. A fascinating interplay was observed between the chloroplast and mitochondrial genomes, which share 17 homologous sequences sequences that rotal 1,933 bp. A total of 134 SSRs, 22 tandem repeats and 42 dispersed repeats were identified in the mitogenome. Four conformations of C. pinnatifida mitochondria sequences recombination were verified through PCR experiments and Sanger sequencing, and C. pinnatifida mitogenome is more likely to be assembled into three circular-mapping chromosomes. All the RNA editing sites that were identified C-U edits, which predominantly occurred at the first and second positions of the codons. Phylogenetic and collinearity analyses identified the evolutionary trajectory of C. pinnatifida, which reinforced the genetic identity of the hawthorn section. This unveiling of the unique multi-partite structure of the hawthorn mitogenome offers a foundational reference for future study into the evolution and genetics of C. pinnatifida.

SSRI antidepressant citalopram reverses the Warburg effect to inhibit hepatocellular carcinoma by directly targeting GLUT1.

Selective serotonin reuptake inhibitors (SSRIs) have shown promise in cancer therapy, particularly for hepatocellular carcinoma (HCC), but their molecular targets and mechanisms remain unclear. Here, we show that SSRIs exhibit significant anti-HCC effects independent of their classical target, the serotonin reuptake transporter (SERT). Using global inverse gene expression profiling, drug affinity responsive target stability assays, and in silico molecular docking, we demonstrate that citalopram targets glucose transporter 1 (GLUT1), resulting in reduced glycolytic flux. A mutant GLUT1 variant at the citalopram binding site (E380) diminishes the drug's inhibitory effects on the Warburg effect and tumor growth. In preclinical models, citalopram dampens the growth of GLUT1high liver tumors and displays a synergistic effect with anti-PD-1 therapy. Retrospective analysis reveals that SSRI use correlates with a lower risk of metastasis among patients with HCC. Our study describes a role for SSRIs in cancer metabolism, establishing a rationale for their repurposing as potential anti-cancer drugs for HCC.

Serum tumor markers and outcomes in lung cancer patients with brain metastases: a retrospective longitudinal cohort study.

Background: Serum tumor markers (STMs) are recommended for cancer diagnosis and surveillance. However, their role in lung cancer with brain metastases (BM) is not yet clear. We aim to analyze the roles of baseline levels of STMs or ongoing STM surveillance on survival. Methods: This retrospective longitudinal cohort study included 1,169 lung cancer patients with BM. The STM data during disease course were collected. Distinct trajectory groups were identified using the latent class growth mixed model (LCGMM). The roles of STMs on survival were further analyzed using Kaplan-Meier analysis and Cox proportional hazard models. Results: Serum levels of cytokeratin-19 fragment (CYFRA21-1) (P<0.001), carcinoembryonic antigen (CEA) (P=0.005) and neuron-specific enolase (NSE) (P<0.001) at baseline exhibited significant correlation with overall survival (OS) of patients with BM, serving as independent prognostic factors. Further analysis indicated that baseline CYFRA21-1, CEA, NSE as well as status of key driver genes were independent prognostic factors in non-small cell lung cancer (NSCLC) patients with BM, while for small cell lung cancer (SCLC) patients with BM, baseline NSE and receiving chemotherapy show independent correlations with survival. Furthermore, we delineated the dynamic trajectories of STMs based on changes in disease course. More specifically, compared to those showing a baseline-high trend in CEA levels, the survival of patients with either persistently-rising or consistently normal levels seemed to be more promising. For CYFRA21-1, both early-rising and later-rising trends were observed, indicating a prognosis inferior to that of individuals with normal-level trajectory. Likewise, for NSE, patients with persistently-rising or persistently-descending trends showed no significantly survival difference. However, in comparison with the status of driver genes, receiving radiotherapy and targeted therapy, the dynamic changes in STM levels lacked independent prognostic significance. Further analysis indicated that among BM patients lacking key driver genes, NSE trajectory (P<0.05), CYFRA21-1 trajectory (P<0.05) and receiving chemotherapy (P<0.001) were independent prognostic factors. Conclusions: Baseline levels of serum CYFRA21-1, CEA and NSE, as well as status of key driver genes are recommended for evaluating BM patients' outcome. Dynamic changes of STMs during disease course were not significantly associated with the final outcome of BM patients.

A Comparative Study on the Consistency of Ultrasound and X-Ray in Assessing Risser Sign.

OBJECTIVES: Adolescent idiopathic scoliosis (AIS) is a 3-dimensional spinal deformity involving lateral curvature, sagittal plane imbalance, and vertebral rotation. In China, AIS affects over 3 million individuals, with 300,000 new cases annually. AIS impacts physical and psychological well-being, necessitating tailored treatment plans based on growth risk factors. This study evaluates the consistency of ultrasound and X-ray assessments of the Risser sign in AIS patients and explores correlations between iliac crest distance and pelvic rotation degree. METHODS: This prospective study enrolled 80 patients diagnosed with AIS from June to September 2023 at Changzhou Sports Hospital. Eligible participants were aged 10-18 with a Cobb angle >10°. Ultrasonographic examinations were conducted by 3 experienced physicians using the VINNO V10 portable ultrasound system. The primary outcome was the Risser stage determined by X-ray and ultrasound, with secondary outcomes including thoracic and thoracic-lumbar segment rotation angles. Statistical analyses included kappa statistics, correlation analyses, and multiple regression. RESULTS: Among the 77 valid cases, 154 iliac wings were evaluated, with a high concordance rate of 77% between ultrasound and X-ray assessments. kappa values for left and right iliac crests were 0.723 and 0.808, respectively. Grouping Risser grades (0-1, 2-3, and 4-5) into 3 categories yielded kappa values of 0.93, 0.96, and 0.93, indicating high consistency. Significant correlations were found between iliac crest distances and rotation angles (left iliac crest distance and left thoracic rotation angle, r = 0.56, P < .001; right iliac crest distance and right thoracic-lumbar rotation angle, r = 0.69, P < .001; right iliac crest distance and right thoracic rotation angle, r = 0.39, P < .01). CONCLUSIONS: Ultrasound is a reliable, radiation-free alternative to X-ray for assessing the Risser sign in AIS patients. Despite observed inconsistencies in intermediate Risser grades, ultrasound's ability to reduce radiation exposure and provide consistent results makes it a valuable tool in clinical practice. Further research is needed to optimize ultrasound techniques and explore its potential for early detection and intervention in scoliosis management.

Dynamic polysaccharide/platelet-rich plasma hydrogels with synergistic antibacterial activities for accelerating infected wound healing.

Platelet-rich plasma (PRP) has been recognized as an effective therapy in regenerative medicine and surgery, which can reduce the risk of antibiotic abuse and promote the healing of infected wounds. Recent advances in PRP-based treatments have focused on the controlled release of growth factors in PRP with biocompatible hydrogels and antimicrobial promotion by introducing hydrogel components or antibiotics, while the inherent antimicrobial activity of PRP is mostly neglected or sacrificed. Here, we demonstrate the combination of an antimicrobial polysaccharide, carboxymethyl chitosan, and PRP to construct an antimicrobial hydrogel via dynamic bonding with oxidized chondroitin sulfate. Significant inhibitory effects against Staphylococcus aureus and Escherichia coli (95 % of inhibition rate) are achieved through the synergistic contributions of the polysaccharide and PRP. Additionally, the resulting hydrogel promotes the migration of NIH-3T3 fibroblasts and collagen deposition by approximately 1.7 and 1.8 times, respectively, thereby accelerating the healing process of infected wounds. This work may bring new perspectives for potent applications of PRP-based hydrogel dressings for antibiotic-free management of infected wounds.

Research on the intervention effect of Five-Element Music combined with Eight-Section Brocade on depression among medical students in higher vocational colleges.

Background: Depression is the main risk factor leading to suicidal ideation among college students. This study focused on observing and assessing how the combination of Five-Element Music and Eight-Section Brocade affected depression levels among medical students attending higher vocational colleges. Methods: From a total of 1,030 medical students studying in higher vocational colleges, we selected 160 students who showed depressive symptoms and met the specific criteria for the study. We used the SDS scale to identify these students and made them the participants of our experiment. Participants were randomly divided into four groups: the music intervention group (listening to traditional Chinese Five-Element Music for 15 min daily), the Eight-Section Brocade intervention group (practicing the Eight-Section Brocade exercises once daily, approximately 15 min), the combined intervention group (first practicing the Eight-Section Brocade exercises once, then listening to music for 15 min), and the control group (no intervention). Each group consisted of 40 participants. The three intervention groups (excluding the control group) underwent continuous intervention for 4 weeks. The SDS, SAS, and PSQI scales were used for evaluation before and after the intervention. Results: Except for the control group, the SDS, SAS, and PSQI scores of the other three groups were lower after the intervention than before the intervention (p < 0.01). After the treatment, the scores on SDS, SAS, and PSQI tests did not vary much between the students who listened to music and those who practiced Eight-Section Brocade (the difference was not statistically significant, p > 0.05). However, the students who did both music and Eight-Section Brocade showed significantly lower scores than those who did only one activity (both p < 0.01). Conclusion: Five-Element Music and Eight-Section Brocade can improve depression, anxiety, and sleep status among medical students in higher vocational colleges. The combined intervention of the two is more effective than a single method, and it is worth promoting and applying in higher vocational colleges. Clinical Trial Registration: https://www.chictr.org.cn/showproj.html?proj=210705.

Identification of necroptosis-related gene expression and the immune response in polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common reproductive and endocrine disorder; however, the understanding of the pathogenesis of PCOS remains unclear. Necroptosis is a newly discovered mechanism of cell death, and it is closely related to reproductive endocrine-related diseases. This study aimed to investigate the hub necroptosis-related genes in PCOS patients and its correlation with immune cell infiltration by bioinformatics methods. METHOD: The gene expression chip result matrix and the annotation matrix files of the GSE34526, GSE8157, and GSE5090 datasets were downloaded from the GEO database. We analyzed the expression and correlation of the necroptosis-related genes in all samples, constructed a diagnostic model based on all necroptosis-related genes and genes with significant differences, performed unsupervised clustering of samples and gene enrichment analysis, and evaluated the correlations between the hub gene and immune cell infiltration levels by the R packages GSVA and CIBERSORT. Finally, PPI networks were constructed using the Cytoscape software GeneMANIA plug-in, and the miRNA, transcription factors, RBP, and drugs were predicted. CONCLUSION: Necroptosis-related genes have important relationships in the development of PCOS and are potentially associated with immune infiltration in PCOS patients.

Molecular mechanism and potential role of mitophagy in acute pancreatitis.

Acute pancreatitis (AP) is a multifaceted inflammatory disorder stemming from the aberrant activation of trypsin within the pancreas. Despite the contribution of various factors to the pathogenesis of AP, such as trypsin activation, dysregulated increases in cytosolic Ca2+ levels, inflammatory cascade activation, and mitochondrial dysfunction, the precise molecular mechanisms underlying the disease are still not fully understood. Mitophagy, a cellular process that preserves mitochondrial homeostasis under stress, has emerged as a pivotal player in the context of AP. Research suggests that augmenting mitophagy can mitigate pancreatic injury by clearing away malfunctioning mitochondria. Elucidating the role of mitophagy in AP may pave the way for novel therapeutic strategies. This review article aims to synthesize the current research findings on mitophagy in AP and underscore its significance in the clinical management of the disorder.

Blocking the PD-1 signal transduction by occupying the phosphorylated ITSM recognition site of SHP-2.

Targeting the PD-1/PD-L1 axis with small-molecular inhibitors is a promising approach for immunotherapy. Here, we identify a natural pentacyclic triterpenoid, Pygenic Acid A (PA), as a PD-1 signaling inhibitor. PA exerts anti-tumor activity in hPD-1 knock-in C57BL/6 mice and enhances effector functions of T cells to promote immune responses by disrupting the PD-1 signaling transduction. Furthermore, we identify SHP-2 as the direct molecular target of PA for inhibiting the PD-1 signaling transduction. Subsequently, mechanistic studies suggest that PA binds to a new druggable site in the phosphorylated PD-1 ITSM recognition site of SHP-2, inhibiting the recruitment of SHP-2 by PD-1. Taken together, our findings demonstrate that PA has a potential application in cancer immunotherapy and occupying the phosphorylated ITSM recognition site of SHP-2 may serve as an alternative strategy to develop PD-1 signaling inhibitors. In addition, our success in target recognition provides a paradigm of target identification and confirmation for natural products.

Posttreatment experiences of reproductive concerns among young breast cancer survivors: A descriptive phenomenological study.

PURPOSE: The long-term fertility impact of cancer treatments is a significant concern for young breast cancer survivors. These reproductive concerns often become a persistent source of stress, negatively affecting their quality of life. This study aims to explore the reproductive concerns experienced by young breast cancer survivors post-treatment and the factors influencing their perceptions. METHODS: This phenomenological study utilized semi-structured interviews to collect data. Eighteen participants were recruited from a tertiary hospital in Mainland China. The interviews were transcribed verbatim and analysed using Colaizzi's method. RESULTS: Data analysis revealed five themes and fourteen subthemes: (1) multiple emotional burdens interwoven with concerns about fertility; (2) concerns about risks associated with reproduction; (3) dilemma of childrearing; (4) the significance of reproduction; (5) support needs from family, peers, and professionals. CONCLUSIONS: Young breast cancer survivors in China face significant challenges related to reproductive issues. Reproductive health is a crucial aspect of breast cancer survivorship care. Healthcare providers must be attentive to the reproductive concerns of survivors, recognize the importance of multidimensional support for positive adaptation, and offer tailored and ongoing interventions to manage reproductive health in young breast cancer survivors.

Design, synthesis and structure-activity relationship of malonic acid non-nucleoside derivatives as potent CD73 inhibitors.

High levels of extracellular adenosine in tumor microenvironment (TME) has extensive immunosuppressive effect. CD73 catalyzes the conversion of AMP into adenosine and regulates its production. Inhibiting CD73 can reduce the level of adenosine and reverse adenosine-mediated immune suppression. Therefore, CD73 has emerged as a valuable target for cancer immunotherapy. Here, a new series of malonic acid non-nucleoside derivatives were designed, synthesized and evaluated as CD73 inhibitors. Among them, compounds 18 and 19 exhibited significant inhibition activities against hCD73 with IC50 values of 0.28 µM and 0.10 µM, respectively, suggesting the feasibility of replacing the benzotriazole moiety in the lead compound. This study explored the novelty and structural diversity of CD73 inhibitors.

Involvement of the Metallothionein gene OsMT2b in Drought and Cadmium Ions Stress in Rice.

Abiotic stress is one of the major factors restricting the production of rice (Oryza sativa L.). Developing rice varieties with dual abiotic stress tolerance is essential to ensure sustained rice production, which is necessary to illustrate the regulation mechanisms underlying dual stress tolerance. At present, only a few genes that regulate dual abiotic stress tolerance have been reported. In this study, we determined that the expression of OsMT2b was induced by both drought and Cd2+ stress. After stress treatment, OsMT2b-overexpression lines exhibited enhanced drought tolerance and better physiological performance in terms of relative water content and electrolyte leakage compared with wild-type (WT). Further analysis indicated that ROS levels were lower in OsMT2b-overexpression lines than in WT following stress treatment, suggesting that OsMT2b-overexpression lines had a stronger ability to scavenge ROS under stress. Reverse transcription-quantitative PCR (RT-qPCR) results demonstrated that under drought stress, OsMT2b influenced the expression of genes involved in ROS scavenging to enhance drought tolerance in rice. In addition, OsMT2b-overexpression plants displayed increased tolerance to Cd2+ stress, and physiological assessment results were consistent with the observed phenotypic improvements. Thus, enhancing ROS scavenging ability through OsMT2b overexpression is a novel strategy to boost rice tolerance to both drought and Cd2+ stress, offering a promising approach for developing rice germplasm with enhanced resistance to the abiotic stressors.

Deubiquitinating enzyme USP28 inhibitor AZ1 alone and in combination with cisplatin for the treatment of non-small cell lung cancer.

Lung cancer is one of the most common malignant tumors. Despite decades of research, the treatment of lung cancer remains challenging. Non-small cell lung cancer (NSCLC) is the primary type of lung cancer and is a significant focus of research in lung cancer treatment. The deubiquitinase ubiquitin-specific protease 28 (USP28) plays a role in the progression of various tumors and serves as a potential therapeutic target. This study aims to determine the role of USP28 in the progression of NSCLC. We examined the impact of the USP28 inhibitor AZ1 on the cell cycle, apoptosis, DNA damage response, and cellular immunogenicity in non-small cell lung cancer. We observed that AZ1 and siUSP28 induce DNA damage, leading to the activation of Noxa-mediated mitochondrial apoptosis. The dsDNA and mtDNA released from DNA damage and mitochondrial apoptosis activate tumor cell immunogenicity through the cGAS-STING signaling pathway. Simultaneously, targeting USP28 promotes the degradation of c-MYC, resulting in cell cycle arrest and inhibition of DNA repair. This further promotes DNA damage-induced cell apoptosis mediated by the Noxa protein, thereby enhancing tumor cell immunogenicity mediated by dsDNA and mtDNA. Moreover, we found that the combination of AZ1 and cisplatin (DDP) can enhance therapeutic efficacy, thereby providing a new strategy to overcome cisplatin resistance in NSCLC. These findings suggest that targeting USP28 and combining it with cisplatin are feasible strategies for treating NSCLC.

Design, synthesis, and biological evaluation of diphenyl ether substituted quinazolin-4-amine derivatives as potent EGFRL858R/T790M/C797S inhibitors.

Epidermal growth factor receptor (EGFR) is a validated target for non-small-cell lung cancer (NSCLC). However, the treatment for EGFR-C797S mutation induced by third-generation EGFR inhibitors remains a concern. Therefore, the development of the fourth-generation EGFR inhibitors to overcome the EGFR-C797S mutation has great potential for clinical treatment. In this article, we designed and synthesized a series of diphenyl ether substituted quinazolin-4-amine derivatives that simultaneously occupy the ATP binding pocket and the allosteric site of EGFR. Among the newly synthesized compounds, 9d displayed excellent kinase activity against EGFRL858R/T790M/C797S with an IC50 value of 0.005 µM, and exhibited anti-proliferation activity in BaF3-EGFRL858R/T790M/C797S cells with the IC50 value of 0.865 µM. Furthermore, 9d could suppress phosphorylation of EGFR and induce cell apoptosis and cycle arrest at G2 phase in a dose-dependent manner in BaF3-EGFRL858R/T790M/C797S cells. More importantly, 9d displayed significant antitumor effects in BaF3-EGFRL858R/T790M/C797S xenograft mouse model (30 mg/kg, TGI = 71.14 %). All the results indicated compound 9d might be a novel fourth-generation EGFR inhibitor for further development in overcoming the EGFR-C797S resistance mutation.

Efficacy of acupuncture on drinkers with chronic prostatitis / chronic pelvic pain syndrome: secondary analysis of a randomized clinical trial.

OBJECTIVE: To evaluate the efficacy of acupuncture in drinkers with chronic prostatitis / chronic pelvic pain syndrome (CP/CPPS). METHODS: We conducted a secondary analysis of a randomized controlled trial across multiple centers, involving 224 drinkers. Patients received either acupuncture or sham acupuncture treatment. The primary outcome was the proportion of responders, defined as participants who had a reduction of 6 points or more from baseline in the National Institute of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) total score at weeks 8 and 32. Secondary outcomes measures included the Global Response Assessment (GRA), International Prostate Symptom Score (IPSS) and International Index of Erectile Function 5 (IIEF-5). RESULTS: One hundred and twelve drinkers were included in each group (n = 224 in total). The proportion of responders in terms of NIH-CPSI was 58.9% versus 40.3% in the acupuncture group (AG) and sham acupuncture group (SAG), respectively, with a statistically significant difference of 18.6% (p = 0.002) at week 8. Higher proportions of responders with respect to NIH-CPSI (p < 0.001 at week 32) and GRA (p < 0.001 at week 8 and p = 0.01 at week 32) were observed in the AG compared with the SAG. No between-group differences were found in the changes in IPSS at any assessment time point. Changes in IIEF-5 score were significantly higher in the AG than in the SAG at weeks 20 and 32, while the difference was not statistically significant at week 8. CONCLUSION: Acupuncture appeared to alleviate the symptoms of pain among drinkers with CP/CPPS and improve their quality of life, but had no demonstrable effect on urinary tract symptoms or erectile function among these patients. TRIAL REGISTRATION NUMBER: NCT03213938 (ClinicalTrials.gov).

The role of cuproptosis-related genes in pan-cancer and the development of cuproptosis-related risk model in colon adenocarcinoma.

Cancer is widely regarded as a leading cause of death in humans, with colon adenocarcinoma (COAD) ranking among the most prevalent types. Cuproptosis is a novel form of cell death mediated by protein lipoylation. Cuproptosis-related genes (CRGs) participate in tumourigenesis and development. Their role in pan-cancer and COAD require further investigation. This study comprehensively evaluated the relationship among CRGs, pan-cancer, and COAD. Our research revealed the differential expression of CRGs and the cuproptosis potential index (CPI) between normal and tumour tissues, and further explored the correlation of CRGs or CPI with prognosis, immune infiltration, tumor mutant burden(TMB), microsatellite instability (MSI), and drug sensitivity in pan-cancer. Gene set enrichment analysis (GSEA) revealed that oxidative phosphorylation and fatty acid metabolism pathways were significantly enriched in the high CPI group of most tumours. FDX1 and CDKN2A were chosen for further exploration, and we found an independent association between FDX1 and CDKN2A and prognosis, immune infiltration, TMB, and MSI in pan-cancer. Furthermore, a prognostic risk model based on the association between CRGs and COAD was built, and the correlations between the risk score and prognosis, immune-related characteristics, and drug sensitivity were analysed. COAD was then divided into three subtypes using cluster analysis, and the differences among the subtypes in prognosis, CPI, immune-related characteristics, and drug sensitivity were determined. Due to the level of LIPT1 was notably positive related with the risk score, the cytological identification was carried out to identify the association of LIPT1 with proliferation and migration of colon cancer cells. In summary, CRGs can be used as potential prognostic biomarkers to predict immune infiltration levels in patients with pan-cancer. In addition, the risk model could more accurately predict the prognosis and immune infiltration levels of COAD and better guide the direction of clinical medication. Thus, FDX1, CDKN2A, and LIPT1 may serve as prospective new targets for cancer therapy.

The mechanism of lovastatin in suppressing the proliferation of esophageal squamous cell carcinoma based on proteomics.

BACKGROUND: Lovastatin, a type of statin usually considered as a lipid-lowering drug that lowers blood cholesterol and low-density lipoprotein cholesterol levels, has been rediscovered to have anticancer activity. Fewer studies exist regarding the effect of lovastatin on esophageal squamous cell carcinoma (ESCC). METHODS: Here, we report that lovastatin shows anticancer effect on ESCC By affecting the mitochondrial autophagy pathway. Moreover, based on proteomics and computer molecular simulations found that RAB38 and RAB27A may be a target of lovastatin. RESULTS: We observed that autophagy of mitochondria is inhibited by lovastatin, affecting esophageal squamous cell proliferation. There is a possible link between the expression of RAB38, RAB27A and immune cell invasion in esophageal cancer. CONCLUSIONS: These results demonstrate the huge potential of lovastatin as an RAB38, RAB27A inhibitor in esophageal cancer chemotherapy and chemoprevention.

Strategies for successful dose optimization in oncology drug development: a practical guide.

Dose optimization is a critical challenge in drug development. Historically, dose determination in oncology has followed a divergent path from other non-oncology therapeutic areas due to the unique characteristics and requirements in Oncology. However, with the emergence of new drug modalities and mechanisms of drugs in oncology, such as immune therapies, radiopharmaceuticals, targeted therapies, cytostatic agents, and others, the dose-response relationship for efficacy and toxicity could be vastly varied compared to the cytotoxic chemotherapies. The doses below the MTD may demonstrate similar efficacy to the MTD with an improved tolerability profile, resembling what is commonly observed in non-oncology treatments. Hence, alternate strategies for dose optimization are required for new modalities in oncology drug development. This paper delves into the historical evolution of dose finding methods from non-oncology to oncology, highlighting examples and summarizing the underlying drivers of change. Subsequently, a practical framework and guidance are provided to illustrate how dose optimization can be incorporated into various stages of the development program. We provide the following general recommendations: 1) The objective for phase I is to identify a dose range rather than a single MTD dose for subsequent development to better characterize the safety and tolerability profile within the dose range. 2) At least two doses separable by PK are recommended for dose optimization in phase II. 3) Ideally, dose optimization should be performed before launching the confirmatory study. Nevertheless, innovative designs such as seamless II/III design can be implemented for dose selection and may accelerate the drug development program.

Using amide proton transfer-weighted magnetic resonance imaging (MRI) in peritumor tissue to predict parametrial infiltration of cervical cancer: a case-control study.

Background: Parametrial infiltration (PMI) is an important indicator for staging and treatment of cervical cancer (CC). The potential of amide proton transfer-weighted (APTw) parameters of peritumor tissue in predicting PMI is still uncertain. This study aims to explore whether the APTw parameters of peritumor tissue can improve diagnostic value of diffusion-weighted imaging (DWI) in magnetic resonance imaging (MRI). Methods: Eighty-one patients with pathologic analysis-confirmed CC were enrolled in this retrospective study. All patients underwent APTw MRI and DWI. The APTw values of tumor (APTw-t), APTw values in peritumor tissues (APTw-p) and apparent diffusion coefficient (ADC) values were independently reviewed by two radiologists to map the regions of interest and measure the corresponding values. Receiver operating characteristic curves were generated to evaluate the diagnostic performance of these quantitative parameters. Results: The study patients were divided into the PMI group (n=22) and non-PMI group (n=59). The APTw-t and APTw-p values (%) of PMI group were higher than those of the non-PMI group [3.71 (interquartile range, IQR, 3.60-3.98) and 2.75 (IQR, 2.68-2.77) vs. 3.33 (IQR, 3.24-3.60) and 1.98 (IQR, 1.82-2.36); P<0.001]. The ADC values of PMI group were lower than those of non-PMI group [0.88 (IQR, 0.83-0.94) ×10-3 vs. 0.95 (IQR, 0.88-1.04)×10-3 mm2/sec; P<0.001]. The area under the curve (AUC) of APTw-t, APTw-p and ADC value for PMI diagnosis were 0.810, 0.831 and 0.806 respectively. In addition, the AUC value (0.918) of APTw-p + ADC was optimal, with a sensitivity and specificity of 91.20% and 87.20% respectively. Conclusions: APTw in peritumor tissues, combined with ADC value can be used to efficiently distinguish PMI of CC.