Biosynthesis of Halogenated Tryptophans for Protein Engineering using Genetic Code Expansion.

Genetic Code Expansion technology offers significant potential in incorporating noncanonical amino acids into proteins at precise locations, allowing for the modulation of protein structures and functions. However, this technology is often limited by the need for costly and challenging-to-synthesize external noncanonical amino acid sources. In this study, we address this limitation by developing autonomous cells capable of biosynthesizing halogenated tryptophan derivatives and introducing them into proteins using Genetic Code Expansion technology. By utilizing inexpensive halide salts and different halogenases, we successfully achieve the selective biosynthesis of 6-chloro-tryptophan, 7-chloro-tryptophan, 6-bromo-tryptophan, and 7-bromo-tryptophan. These derivatives are introduced at specific positions with corresponding bioorthogonal aminoacyl-tRNA synthetase/tRNA pairs in response to the amber codon. Following optimization, we demonstrate the robust expression of proteins containing halogenated tryptophan residues in cells with the ability to biosynthesize these tryptophan derivatives. This study establishes a versatile platform for engineering proteins with various halogenated tryptophans.

Research on Gas-Assisted Extrusion of Elastic Material Round-Tube for Flexible Robot Body.

The flexible robot is widely used in a variety of fields such as medical treatment, rescue and disaster relief, industry, and agriculture. Using elastic materials to prepare flexible robot body structures is the core of the study of flexible robots. Due to the small selection of materials, single preparation method, and long fabrication time, in this study, a new method of gas-assisted extrusion (GAE) of elastic material round-tube for flexible robot body was proposed, and the numerical simulation of GAE was carried out with nonsilicone elastic material round-tube under different viscosities. The results showed that with the change of viscosity, the velocity, pressure drop, and shear rate of melt in all directions change accordingly. When the viscosity is too small or too large, it is easy to bring negative effects on the GAE process of elastic materials. TPE and TPU were completely plasticized in the GAE, and the surface of the extruded elastic products was smooth and straight, with full gloss. Therefore, in the preparation of the flexible robot body, nonsilicone elastic materials and GAE forming methods can be considered.

SMARCA5 reprograms AKR1B1-mediated fructose metabolism to control leukemogenesis.

A significant variation in chromatin accessibility is an epigenetic feature of leukemia. The cause of this variation in leukemia, however, remains elusive. Here, we identify SMARCA5, a core ATPase of the imitation switch (ISWI) chromatin remodeling complex, as being responsible for aberrant chromatin accessibility in leukemia cells. We find that SMARCA5 is required to maintain aberrant chromatin accessibility for leukemogenesis and then promotes transcriptional activation of AKR1B1, an aldo/keto reductase, by recruiting transcription co-activator DDX5 and transcription factor SP1. Higher levels of AKR1B1 are associated with a poor prognosis in leukemia patients and promote leukemogenesis by reprogramming fructose metabolism. Moreover, pharmacological inhibition of AKR1B1 has been shown to have significant therapeutic effects in leukemia mice and leukemia patient cells. Thus, our findings link the aberrant chromatin state mediated by SMARCA5 to AKR1B1-mediated endogenous fructose metabolism reprogramming and shed light on the essential role of AKR1B1 in leukemogenesis, which may provide therapeutic strategies for leukemia.

The adjuvant treatment role of ω-3 fatty acids by regulating gut microbiota positively in the acne vulgaris.

Objectives:We aimed to explore the potential role of omega-3 (ω-3) fatty acids on acne vulgaris by modulating gut microbiota.Materials and Methods:We randomly divided the untreated acne patients into two groups with or without ω-3 fatty acids intervention for 12 weeks. The Sprague Dawley (SD) rats with acne model were given isotretinoin, ω-3 fatty acids or their combination respectively. Then the colonic contents samples of the drug intervention SD rats were transferred to the pseudo sterile rats with acne model. The severity of the disease was assessed by the Global Acne Grading System (GAGS) score of the patients, and the swelling rate of auricle and the pathological section of the rat with acne model. The 16S rDNA gene sequencing was performed to detect the alteration of the gut microbiota.Results:ω-3 fatty acids could increase the diversity of the gut microbiota and regulate the flora structure positively both in the patients and rats, increase the abundance of butyric acid producing bacteria and GAGS score in the patients, and alleviate the inflammation and comedones of rats.Conclusion:Supplementation of ω-3 fatty acids could alleviate the inflammation of acne vulgaris by increasing the abundance of butyric acid producing bacteria.

Differences in the incidence and mortality of digestive cancer between Global Cancer Observatory 2020 and Global Burden of Disease 2019.

The burden of digestive cancers is increasing worldwide. The Global Cancer Observatory (GLOBOCAN) 2020 and the Global Burden of Disease (GBD) 2019 are two primary cancer databases, which have a significant impact on policy formulation and resource allocation. We aim to compare the incidence and mortality of digestive cancers between them. Digestive cancer (esophageal, stomach, colorectal, liver, gallbladder and pancreatic cancer) incidence was obtained from the Cancer Today and GBD 2019 result tool. The top five countries with the most or minor difference between GLOBOCAN 2020 and GBD 2019 in age-standardized incidence rates (ASIRs) of digestive cancers were identified. A systematic search on the incidence of specific digestive cancer in selected countries from PubMed and Embase was conducted, and 20 of 281 publications were included. The most significant differences in digestive cancers incidence were commonly found in Asian countries (70%), particularly Indonesia, Vietnam and Myanmar, located in Southeast Asia. The ASIRs for most digestive cancers, except liver cancer, in GLOBOCAN 2020 were higher than those in GBD 2019. Gallbladder cancer had the highest average ratio, followed by liver cancer. The most commonly used standard population was Segi's standard population, followed by the World Health Organization standard population. The data sources nor the processing methods of GLOBOCAN 2020 and GBD 2019 were not similar. Low- and middle-income countries without population-based cancer registries were more likely to have selection bias in data collection and amplify regional variations of etiological factors. Better judgments on the quality of cancer data can be made.

A Point-of-Care Testing Device Utilizing Graphene-Enhanced Fiber Optic SPR Sensor for Real-Time Detection of Infectious Pathogens.

Timely detection of highly infectious pathogens is essential for preventing and controlling public health risks. However, most traditional testing instruments require multiple tedious steps and ultimately testing in hospitals and third-party laboratories. The sample transfer process significantly prolongs the time to obtain test results. To tackle this aspect, a portable fiber optic surface plasmon resonance (FO-SPR) device was developed for the real-time detection of infectious pathogens. The portable device innovatively integrated a compact FO-SPR sensing component, a signal acquisition and processing system, and an embedded power supply unit. A gold-plated fiber is used as the FO-SPR sensing probe. Compared with traditional SPR sensing systems, the device is smaller size, lighter weight, and higher convenience. To enhance the detection capacity of pathogens, a monolayer graphene was coated on the sensing region of the FO-SPR sensing probe. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was used to evaluate the performance of the portable device. The device can accurately detect the SARS-CoV-2 spike S1 protein in phosphate-buffered saline (PBS) and artificial saliva within just 20 min, and the device successfully detected cultured SARS-CoV-2 virus. Furthermore, the FO-SPR probe has long-term stability, remaining stable for up to 8 days. It could distinguish between the SARS-CoV-2 spike protein and the MERS-CoV spike protein. Hence, this FO-SPR device provides reliable, rapid, and portable access to test results. It provides a promising point-of-care testing (POCT) tool for on-site screening of infectious pathogens.

Clinical features and prognosis of patients with metastatic ocular and orbital melanoma: A bi-institutional study.

PURPOSE: Metastatic ocular and orbital melanomas are extremely rare. The clinical characteristics and standard treatments for these patients are not fully established. MATERIALS AND METHODS: We retrospectively analyzed patients with metastatic ocular and orbital melanoma from Fudan University Shanghai Cancer Center and Eye & ENT Hospital of Fudan University between January 2012 and May 2022. RESULTS: Overall, 51 patients with metastatic ocular and orbital melanoma were included. The most common primary sites were uvea (73%), followed by conjunctiva (22%), lacrimal sac (4%), and orbit (2%). Patients with uveal melanoma (UM) had a significantly younger age (48 vs. 68 years, p < 0.001), higher incidence of liver metastases (89% vs. 9%, p<0.001), a lower incidence of lymph nodes metastases (16% vs. 46%, p = 0.043) and a lower incidence of BRAF mutation (0% vs. 55%, p<0.001) compared with patients with conjunctival melanoma (CM). The overall response rate of the first-line treatment was 18%. Three of the four patients with BRAF-mutated CM responded to dabrafenib and trametinib treatment. The median progression-free survival (PFS) and overall survival (OS) of first-line treatment were 5.1 and 11.9 months, respectively. Among patients with liver metastases, liver-directed treatment was correlated with better patient PFS (p < 0.001) and OS (p < 0.001) after adjusting for number of metastatic sites and primary sites. CONCLUSION: CM and UM have different characteristics. Patient with CM had a high incidence of BRAF mutation, and the treatment of BRAF and MEK inhibitors conferred clinical benefit. Liver directed therapies had a potential benefit in disease control in patients with liver metastases.

Early changes in soluble intracellular adhesion molecule-1 as prognostic biomarkers to immune checkpoint inhibitor.

Serologic biomarker to predict clinical outcome is needed for immune checkpoint inhibitors (ICIs). We evaluated soluble intercellular adhesion molecules-1 (sICAM-1) as a predictor of response to ICIs treatment. Ninety-five patients with cancer treated with ICI were studied. The serum sICAM-1 levels of baseline, post two cycle therapy and end of therapy (EOT) were measured by enzyme-linked immunoassay. We randomly assigned the patients into the primary cohort (n = 47) and validation cohort (n = 48). Serum sICAM-1 post two cycle (277.7 ± 181.6 ng/mL) and EOT (403.9 ± 218.9 ng/mL) were significantly elevated compared to baseline (244.8 ± 153.8 ng/mL, p = 0.008 and p = 0.004, respectively). Early changes of sICAM-1 (ΔsICAM-1), deemed as sICAM-1 after two cycles minus baseline, were assessed. Following ICI treatments, responders had significantly lower ΔsICAM-1 compared with nonresponders in the primary cohort (p = 0.040) and the validation cohort (p = 0.026). High ΔsICAM-1 was strongly associated with inferior progression-free survival (PFS; (primary cohort: p = 0.001 and validation cohort: p = 0.002) and overall survival (OS; (primary cohort: p < 0.001 and validation cohort: p = 0.007). The ΔsICAM-1 remained independently associated with worse PFS and OS in the primary cohort and the validation cohort. Subgroup analysis indicated patients whose sICAM-1 significantly elevated had shorter PFS and OS in both anti-PD-1 and anti-PD-L1 treatment groups. Early change of serum sICAM-1 could be used to monitor and predict clinical benefit of ICI therapy in patients with solid cancer.

Early Changes of Serum Interleukin 14α Levels Predicts the Response to Anti-PD-1 Therapy in Cancer.

Background: Programmed cell death-1 (PD-1) blockade has been shown to confer clinical benefit in cancer patients. Here, we assessed the level of serum interleukin 14α (IL14α) in patients receiving anti-PD-1 treatment. Methods: This prospective study recruited 30 patients with advanced solid cancer who received pembrolizumab treatment in Northern Jiangsu People's Hospital between April 2016 and June 2018. The western blot analysis was used to assess the expression level of serum IL14α in patients at baseline and after 2 cycles of treatment. Interleukin 14α was performed using the unpaired 2-tailed Student test. The progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method and compared by the log-rank test. Results: The early change of IL14α after 2 cycles of anti-PD-1 therapy was calculated as delta IL14α % change = (IL14α level after 2 cycles - IL14α level before treatment)/IL14α level before treatment × 100%. Receiver operating characteristic (ROC) was analyzed to get a cutoff point of delta IL14α % change as 2.46% (sensitivity = 85.71%, specificity = 62.5%; area under the ROC curve [AUC] = 0.7277, P = .034). Using this cutoff to subgroup the patients, an improved objective response rate was observed in patients with a delta IL14α change higher than 2.46% (P = .0072). A delta IL14α change over 2.46% was associated with a superior PFS (P = .0039). Conclusions: Early changes of serum IL14α levels may be a promising biomarker to predict outcomes in patients with solid cancer following anti-PD-1 treatment.

CircAGO2 promotes colorectal cancer progression by inhibiting heat shock protein family B (small) member 8 via miR-1-3p/retinoblastoma binding protein 4 axis.

This paper was to uncover the mechanism of circular RNA Argonaute 2 (circAGO2) in colorectal cancer (CRC) progression. The expression of circAGO2 was detected in CRC cells and tissues, and the relationship between clinicopathological features of CRC and circAGO2 level was evaluated. The growth and invasion of CRC cells and subcutaneous xenograft of nude mice were measured to evaluate the effect of circAGO2 on CRC development. Bioinformatics databases were applied to analyze levels of retinoblastoma binding protein 4 (RBBP4) and heat shock protein family B 8 (HSPB8) in cancer tissues. The relevance of circAGO2 and RBBP4 expression and the relationship between RBBP4 and HSPB8 during histone acetylation were assessed. The targeting relationship between miR-1-3p and circAGO2 or RBBP4 was predicted and confirmed. The effects of miR-1-3p and RBBP4 on biological functions of CRC cells were also verified. CircAGO2 was upregulated in CRC. CircAGO2 promoted the growth and invasion of CRC cells. CircAGO2 competitively bound to miR-1-3p and regulated RBBP4 expression, thus inhibiting HSPB8 transcription by promoting histone deacetylation. Silencing circAGO2 enhanced miR-1-3p expression and reduced RBBP4 expression, while suppression of miR-1-3p downgraded levels of miR-1-3p, up-regulated RBBP4, and facilitated cell proliferation and invasion in the presence of silencing circAGO2. RBBP4 silencing decreased RBBP4 expression and reduced proliferation and invasion of cells where circAGO2 and miR-1-3p were silenced. CircAGO2 overexpression decoyed miR-1-3p to increase RBBP4 expression, which inhibited HSPB8 transcription via histone deacetylation in HSPB8 promoter region, promoting proliferation and invasion of CRC cells.

Inhibition of USP1 reverses the chemotherapy resistance through destabilization of MAX in the relapsed/refractory B-cell lymphoma.

The patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) have poor prognosis, and a novel and effective therapeutic strategy for these patients is urgently needed. Although ubiquitin-specific protease 1 (USP1) plays a key role in cancer, the carcinogenic effect of USP1 in B-cell lymphoma remains elusive. Here we found that USP1 is highly expressed in DLBCL patients, and high expression of USP1 predicts poor prognosis. Knocking down USP1 or a specific inhibitor of USP1, pimozide, induced cell growth inhibition, cell cycle arrest and autophagy in DLBCL cells. Targeting USP1 by shRNA or pimozide significantly reduced tumor burden of a mouse model established with engraftment of rituximab/chemotherapy resistant DLBCL cells. Pimozide significantly retarded the growth of lymphoma in a DLBCL patient-derived xenograft (PDX) model. USP1 directly interacted with MAX, a MYC binding protein, and maintained the stability of MAX through deubiquitination, which promoted the transcription of MYC target genes. Moreover, pimozide showed a synergetic effect with etoposide, a chemotherapy drug, in cell and mouse models of rituximab/chemotherapy resistant DLBCL. Our study highlights the critical role of USP1 in the rituximab/chemotherapy resistance of DLBCL through deubiquitylating MAX, and provides a novel therapeutic strategy for rituximab/chemotherapy resistant DLBCL.

Plasmonic fiber-optic sensing system for in situ monitoring the capacitance and temperature of supercapacitors.

Compared with ex situ measurement, the in situ measurement is more suitable for inspecting complex electrochemical reactions and improving the intelligent energy storage management. However, most of the in situ investigation instruments are bulky and expensive. Here we demonstrate a miniaturized, portable, and low-cost fiber-optic sensing system for in situ monitoring the capacitance and temperature. It can help evaluate the self-discharge rate in supercapacitors (SCs). The fiber-optic sensing system with two probes are implanted inside the SCs to monitor the capacitance and temperature, respectively. The dual fiber-optic probes can work independently and avoid cross-interference through structure design. The fiber-optic localized surface plasmon resonance (LSPR) probe near the electrode surface can detect the capacitance in real-time by monitoring ion aggregation on the opposite electrode. The fiber-optic surface plasmon resonance (SPR) probe encapsulated in the thermosensitive liquid can independently detect the temperature change. The measurement uncertainties of the two sensing probes are 5.6 mF and 0.08 ℃, respectively. The proposed tiny and flexible fiber-optic sensing system provides a promising method for in situ monitoring the critical parameters. It is also a powerful tool for investigating electrochemical reactions in various energy storage devices.

Pegylated Liposomal Doxorubicin Combined with Ifosfamide for Treating Advanced or Metastatic Soft-tissue Sarcoma: A Prospective, Single-arm Phase II Study.

PURPOSE: This prospective single-arm phase II clinical trial aimed to evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) combined with ifosfamide (IFO) as the first-line treatment for patients with advanced or metastatic soft-tissue sarcoma (STS). PATIENTS AND METHODS: Patients received PLD (30 mg/m2; day 1) in combination with IFO (1.8 g/m2; days 1-5) every 21 days until disease progression, unacceptable toxicities, patient death, or for up to six cycles. The primary endpoint was progression-free survival (PFS; NCT03268772). RESULTS: Overall, 69 patients with chemotherapy-naïve advanced or metastatic STS were enrolled between May 2015 and November 2019. At a median follow-up of 47.2 months, the median PFS and overall survival (OS) were found to be 7.3 [95% confidence interval (CI): 5.7-8.9] and 20.6 (95% CI: 16.3-25.0) months, respectively. The response and disease control rates were 26.1% and 81.2%, respectively. Adverse events were manageable, and no grade 3-4 cardiotoxicities were observed. There was no significant change in left ventricular ejection fraction values between baseline and after treatment (P = 0.669). Exploratory biomarker analysis suggested NF1 single-nucleotide variant was associated with poor OS (P < 0.0001) and PFS (P = 0.044). In addition, 2 patients with BRCA2 loss progressed in the initial 2 months and died within 10 months. Improved OS was observed in homologous recombination deficiency (HRD)-negative patients compared with their HRD-positive counterparts (P = 0.0056). CONCLUSIONS: Combination therapy comprising PLD and IFO is an effective and well-tolerated first-line treatment for patients with advanced or metastatic STS.

Clinical Characteristics and Prognostic Factors in Primary Breast Diffuse Large B-Cell Lymphoma.

Background: Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare subtype of non-Hodgkin lymphoma (NHL) with limited data on the clinical features and prognostic factors. Patients and Methods: A consecutive cohort of patients with PB-DLBCL was retrospectively analyzed in our hospital from February 1997 through July 2018. The primary endpoint is overall survival (OS) contributing to any cause. Results: A total of 76 patients were diagnosed with PB-DLBCL. The median age at diagnosis was 51 years (range: 25-80 years), with female prevalence (98.7%). Forty (52.6%) patients had right-sided breast involvement but no bilateral breast involvement at diagnosis. Overall, disease stages IE and IIE were seen in 55 (72.4%) and 21 (27.6%) patients, respectively. According to the stage-modified International Prognostic Index (IPI), 37 (48.7%) patients were classified in the very good risk group (IPI 0). Of the 72 patients available, the non-germinal center B-cell (non-GCB) subtype of DLBCL was observed in 66 (91.6%) patients. All patients received anthracycline-based chemotherapy, 56 (73.7%) with rituximab, 31 (40.8%) also with additional radiation therapy, and 14 (18.4%) patients received a prophylactic intrathecal injection. Seven (9.2%) patients had refractory disease. With a median follow-up of 6.8 years (range 0.4-25.0 years), 10 (13.2%) patients had a relapse in the central nervous system (CNS) site. The 5-year and 10-year OS of all the patients was 97.2% (95% CI: 99.3-89.5) and 84.8% (95% CI: 70.0-93.5), respectively. The median OS was not reached. The median progression-free survival (PFS) was 10.3 years for patients with PB-DLBCL. The 5-year PFS of all the patients was 76.3% (95% CI: 64.6-84.6). Univariate analysis revealed several prognostic factors, including stage-modified IPI, breast surgery, refractory disease, and CNS relapse. Multivariate analyses produced two independent prognostic factors for patients with PB-DLBCL, including stage-modified IPI score (2-3 versus 0) (hazard ratio: 19.114, 95% CI 1.841 to 198.451, p=0.013) and CNS relapse (hazard ratio: 5.522, 95% CI 1.059 to 28.788, p=0.043). Conclusion: In our cohort, PB-DLBCL clinical features are similar to prior literature reports. Stage-modified IPI score and CNS relapse were associated with overall survival.

HNOXPred: a web tool for the prediction of gas-sensing H-NOX proteins from amino acid sequence.

SUMMARY: HNOXPred is a webserver for the prediction of gas-sensing heme-nitric oxide/oxygen (H-NOX) proteins from amino acid sequence. H-NOX proteins are gas-sensing hemoproteins found in diverse organisms ranging from bacteria to eukaryotes. Recently, gas-sensing complex multi-functional proteins containing only the conserved amino acids at the heme centers of H-NOX proteins, have been identified through a motif-based approach. Based on experimental data and H-NOX candidates reported in the literature, HNOXPred is created to automate and facilitate the identification of similar H-NOX centers across systems. The server features HNOXSCORES scaled from 0 to 1 that consider in its calculation, the physicochemical properties of amino acids constituting the heme center in H-NOX in addition to the conserved amino acids within the center. From user input amino acid sequence, the server returns positive hits and their calculated HNOXSCORES ordered from high to low confidence which are accompanied by interpretation guides and recommendations. The utility of this server is demonstrated using the human proteome as an example. AVAILABILITY AND IMPLEMENTATION: The HNOXPred server is available at https://www.hnoxpred.com. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Prognostic significance of baseline neutrophil-lymphocyte ratio in patients with non-small-cell lung cancer: a pooled analysis of open phase III clinical trial data.

Aim: This study aimed to assess survival and hematological prognostic indicators of patients with non-small-cell lung cancer (NSCLC). Material & methods: Through the Project Data Sphere portal, two phase III clinical trial datasets were downloaded to analyze survival outcomes and related risk factors. Results: The median progression-free survival and overall survival of 756 patients with stage III-IV NSCLC were 6.2 and 14.2 months, respectively. In multivariate Cox analysis, high baseline neutrophil-lymphocyte ratio (NLR; ≥3.8) was associated with worse progression-free survival (hazard ratio: 1.37; p = 0.0004) and overall survival (hazard ratio: 1.65; p < 0.0001). In addition, it exerted an unfavorable impact on survival across multiple subgroups. Conclusions: NLR, a powerful inflammatory and immunologic indicator, is an independent prognostic indicator in patients with advanced NSCLC.

A Traditional Chinese Herb Citri Reticulatae Pericarpium Induced Melanonychia.

The common causes for melanonychia include melanoma, repetitive trauma, underlying systemic diseases, onychomycosis, pseudomonas infection and drugs. Drug-induced melanonychia usually affects numerous nails and appears as light brown to black pigmentation on the deck or nail bed with longitudinal, transverse or diffuse distribution. In previous cases, a number of chemotherapeutic agents such as azathioprine, bleomycin sulfate, cyclophosphamide, hydroxyurea and methotrexate were usually linked to melanonychia. Citri reticulatae pericarpium (CRP) is a traditional Chinese herb which is widely used in many foods and health care products in China. Up till now, there were no adverse reactions of CRP reported throughout the literature. Herein, we firstly reported a case of melanonychia in a 67-year-old man caused by CRP for external use.

A prognostic nomogram constructed for relapsed or refractory diffuse large B-cell lymphoma patients.

AIM: The clinical course of diffuse large B-cell lymphoma (DLBCL) is variable and there is a lack of prognostic markers and models for relapsed or refractory (r/r) DLBCL. Hence, we conducted this study to identify independent factors that can predict the survival rate of r/r DLBCL patients. METHODS: A total of 416 r/r DLBCL patients who were pretreated with first-line anthracycline-based chemotherapy at the National Cancer Center in China between 2006 and 2016 were divided into the primary (n = 291) and validation (n = 125) cohorts. The effect of preclinical and clinical indicators on DLBCL survival rates of the two cohorts were evaluated by univariate and multivariate analyses. Factors showing good correlation with patient survival rates were used to construct a prognostic nomogram. RESULTS: Multivariate analysis of the primary cohort revealed five independent prognostic factors: lactate dehydrogenase level at diagnosis, response to front line treatment, progression/recurrence pattern, location, and invasion on progression/recurrence, which were then used to construct a nomogram. The nomogram was shown to have a C-index of 0.76 and AUC values of 0.81 and 0.80 for the primary and validation cohorts, respectively, suggesting good prognostic power. We further stratified the r/r DLBCL patients into four risk groups according to the newly developed nomogram. CONCLUSION: The prognostic nomogram constructed using the five identified clinical indicators can potentially be applied in the clinical setting to guide treatment decision.

Rh-endostatin combined with chemotherapy in patients with advanced or recurrent mucosal melanoma: retrospective analysis of real-world data.

BACKGROUND: Mucosal melanoma is rare and has distinct clinical and genetic features. Even with advances in targeted and immune therapies, the survival of patients with advanced or recurrent mucosal melanomas remains poor. The standard treatment remains controversial and we conducted this real-world study aimed to explore continuous intravenous recombinant human endostatin (Rh-endostatin) infusion plus chemotherapy in this population in the first-line setting. METHODS: Overall, 43 patients with advanced or recurrent mucosal melanoma treated at Fudan University Shanghai Cancer Center between April 2017 and August 2020 were retrospectively included. Patients received dacarbazine plus cisplatin or temozolomide plus cisplatin per the investigators' preference. Rh-endostatin (105 mg/m2) was administered with continuous infusion for 168 h (Civ 168 h). RESULTS: Of the 43 patients, 72.1% had metastatic disease, and the most common primary site was the gastrointestinal tract (51.2%). The most commonly observed mutations were NRAS (23.1%), BRAF (7.7%) and CKIT mutations (5.1%). An objective response was observed in 12 (30.0%) of the 40 evaluable patients, and disease control was achieved in 31 (77.5%) patients. With a median follow-up of 17.6 months, the median progression-free survival (PFS) and overall survival (OS) were 4.9 and 15.3 months, respectively. Additionally, high lymphocyte-to-monocyte ratio (LMR) (p = 0.023, HR 0.29, 95% CI: 0.10-0.84) and BRAF/KIT/RAS mutation (p = 0.028, HR 0.24, 95% CI: 0.07-0.86) were independently correlated with prolonged OS. Toxicity was manageable overall. CONCLUSION: Continuous Rh-endostatin infusion plus chemotherapy was effective and safe for the treatment of advanced or recurrent mucosal melanoma. High LMR was correlated with favorable PFS and OS in this patient population.

Common Immune-Related Adverse Events of Immune Checkpoint Inhibitors in the Gastrointestinal System: A Study Based on the US Food and Drug Administration Adverse Event Reporting System.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, immune-related adverse events (irAEs) in the gastrointestinal (GI) system commonly occur. In this study, data were obtained from the US Food and Drug Administration adverse event reporting system between July 2014 and December 2020. Colitis, hepatobiliary disorders, and pancreatitis were identified as irAEs in our study. Reporting odds ratio (ROR) with information components (IC) was adopted for disproportionate analysis. A total of 70,330 adverse events were reported during the selected period, 4,075 records of which were associated with ICIs. GI toxicities have been reportedly increased with ICI, with ROR025 of 17.2, 6.7, and 2.3 for colitis, hepatobiliary disorders, and pancreatitis, respectively. The risks of colitis, hepatobiliary disorders, and pancreatitis were higher with anti-CTLA-4 treatment than that with anti-PD-1 (ROR025 2.6, 1.3, and 1.1, respectively) or anti-PD-L1 treatment (ROR025 4.8, 1.3, and 1.3, respectively). Logistic analysis indicated that hepatobiliary disorders and pancreatitis more frequently occurred in female patients (adjusted odds ratio, 1.16 and 1.52; both p < 0.05). Consistently, polytherapy was a strong risk factor for colitis (adjusted odds ratio 2.52, p < 0.001), hepatobiliary disorders (adjusted odds ratio 2.50, p < 0.001), and pancreatitis (adjusted odds ratio 2.29, p < 0.001) according to multivariate logistic analysis. This pharmacovigilance analysis demonstrated an increased risk of all three GI irAEs associated with ICI therapies. The comparative analysis offered supportive insights on selecting GI irAEs for patients treated with ICIs.