canSAR: update to the cancer translational research and drug discovery knowledgebase.

canSAR (https://cansar.ai) is the largest public cancer drug discovery and translational research knowledgebase. Now hosted in its new home at MD Anderson Cancer Center, canSAR integrates billions of experimental measurements from across molecular profiling, pharmacology, chemistry, structural and systems biology. Moreover, canSAR applies a unique suite of machine learning algorithms designed to inform drug discovery. Here, we describe the latest updates to the knowledgebase, including a focus on significant novel data. These include canSAR's ligandability assessment of AlphaFold; mapping of fragment-based screening data; and new chemical bioactivity data for novel targets. We also describe enhancements to the data and interface.

Targeting the NAT10/NPM1 axis abrogates PD-L1 expression and improves the response to immune checkpoint blockade therapy.

BACKGROUND: PD-1/PD-L1 play a crucial role as immune checkpoint inhibitors in various types of cancer. Although our previous study revealed that NPM1 was a novel transcriptional regulator of PD-L1 and stimulated the transcription of PD-L1, the underlying regulatory mechanism remains incompletely characterized. METHODS: Various human cancer cell lines were used to validate the role of NPM1 in regulating the transcription of PD-L1. The acetyltransferase NAT10 was identified as a facilitator of NPM1 acetylation by coimmunoprecipitation and mass spectrometry. The potential application of combined NAT10 inhibitor and anti-CTLA4 treatment was evaluated by an animal model. RESULTS: We demonstrated that NPM1 enhanced the transcription of PD-L1 in various types of cancer, and the acetylation of NPM1 played a vital role in this process. In particular, NAT10 facilitated the acetylation of NPM1, leading to enhanced transcription and increased expression of PD-L1. Moreover, our findings demonstrated that Remodelin, a compound that inhibits NAT10, effectively reduced NPM1 acetylation, leading to a subsequent decrease in PD-L1 expression. In vivo experiments indicated that Remodelin combined with anti-CTLA-4 therapy had a superior therapeutic effect compared with either treatment alone. Ultimately, we verified that the expression of NAT10 exhibited a positive correlation with the expression of PD-L1 in various types of tumors, serving as an indicator of unfavorable prognosis. CONCLUSION: This study suggests that the NAT10/NPM1 axis is a promising therapeutic target in malignant tumors.

Discovery and biological evaluation of novel dual PTP1B and ACP1 inhibitors for the treatment of insulin resistance.

In this study, a virtual screening pipeline comprising ligand-based and structure-based approaches was established and applied for the identification of dual PTP1B and ACP1 inhibitors. As a result, a series of benzoic acid derivatives was discovered, and compound H3 and S6 demonstrated PTP1B and ACP1 inhibitory activity, with IC50 values of 3.5 and 8.2 µM for PTP1B, and 2.5 and 5.2 µM for ACP1, respectively. Molecular dynamics simulations illustrated that H3 interacted with critical residues in the active site, such as Cys215 and Arg221 for PTP1B, and Cys17 and Arg18 for ACP1. Enzymatic kinetic research indicated that identified inhibitors competitively inhibited PTP1B and ACP1. Additionally, cellular assays demonstrated that H3 and S6 effectively increased glucose uptake in insulin-resistant HepG2 cells while displaying very limited cytotoxicity at their effective concentrations. In summary, H3 and S6 represent novel dual-target inhibitors for PTP1B and ACP1, warranting further investigation as potential agents for the treatment of diabetes.

2-Aryladenine Derivatives as a Potent Scaffold for Adenosine Receptor Antagonists: The 6-Morpholino Derivatives.

A set of 2-aryl-9-H or methyl-6-morpholinopurine derivatives were synthesized and assayed through radioligand binding tests at human A1, A2A, A2B, and A3 adenosine receptor subtypes. Eleven purines showed potent antagonism at A1, A3, dual A1/A2A, A1/A2B, or A1/A3 adenosine receptors. Additionally, three compounds showed high affinity without selectivity for any specific adenosine receptor. The structure-activity relationships were made for this group of new compounds. The 9-methylpurine derivatives were generally less potent but more selective, and the 9H-purine derivatives were more potent but less selective. These compounds can be an important source of new biochemical tools and/or pharmacological drugs.

China special issue on gastrointestinal tumors-Radiological features of pathological complete response in mismatch repair deficient colorectal cancer after neoadjuvant PD-1 blockade: A post hoc analysis of the PICC phase II trial.

Neoadjuvant programmed cell death protein 1 (PD-1) blockade exhibits promising efficacy in patients with mismatch repair deficient (dMMR) colorectal cancer (CRC). However, discrepancies between radiological and histological findings have been reported in the PICC phase II trial (NCT03926338). Therefore, we strived to discern radiological features associated with pathological complete response (pCR) based on computed tomography (CT) images. Data were obtained from the PICC trial that included 36 tumors from 34 locally advanced dMMR CRC patients, who received neoadjuvant PD-1 blockade for 3 months. Among the 36 tumors, 28 (77.8%) tumors achieved pCR. There were no statistically significant differences in tumor longitudinal diameter, the percentage change in tumor longitudinal diameter from baseline, primary tumor sidedness, clinical stage, extramural venous invasion status, intratumoral calcification, peritumoral fat infiltration, intestinal fistula and tumor necrosis between the pCR and non-pCR tumors. Otherwise, tumors with pCR had smaller posttreatment tumor maximum thickness (median: 10 mm vs 13 mm, P = .004) and higher percentage decrease in tumor maximum thickness from baseline (52.9% vs 21.6%, P = .005) compared to non-pCR tumors. Additionally, a higher proportion of the absence of vascular sign (P = .003, odds ratio [OR] = 25.870 [95% CI, 1.357-493.110]), nodular sign (P < .001, OR = 189.000 [95% CI, 10.464-3413.803]) and extramural enhancement sign (P = .003, OR = 21.667 [2.848-164.830]) was observed in tumors with pCR. In conclusion, these CT-defined radiological features may have the potential to serve as valuable tools for clinicians in identifying patients who have achieved pCR after neoadjuvant PD-1 blockade, particularly in individuals who are willing to adopt a watch-and-wait strategy.

CT-based deep learning model for the prediction of DNA mismatch repair deficient colorectal cancer: a diagnostic study.

BACKGROUND: Stratification of DNA mismatch repair (MMR) status in patients with colorectal cancer (CRC) enables individual clinical treatment decision making. The present study aimed to develop and validate a deep learning (DL) model based on the pre-treatment CT images for predicting MMR status in CRC. METHODS: 1812 eligible participants (training cohort: n = 1124; internal validation cohort: n = 482; external validation cohort: n = 206) with CRC were enrolled from two institutions. All pretherapeutic CT images from three dimensions were trained by the ResNet101, then integrated by Gaussian process regression (GPR) to develop a full-automatic DL model for MMR status prediction. The predictive performance of the DL model was evaluated using the area under the receiver operating characteristic curve (AUC) and then tested in the internal and external validation cohorts. Additionally, the participants from institution 1 were sub-grouped by various clinical factors for subgroup analysis, then the predictive performance of the DL model for identifying MMR status between participants in different groups were compared. RESULTS: The full-automatic DL model was established in the training cohort to stratify the MMR status, which presented promising discriminative ability with the AUCs of 0.986 (95% CI 0.971-1.000) in the internal validation cohort and 0.915 (95% CI 0.870-0.960) in the external validation cohort. In addition, the subgroup analysis based on the thickness of CT images, clinical T and N stages, gender, the longest diameter, and the location of tumors revealed that the DL model showed similar satisfying prediction performance. CONCLUSIONS: The DL model may potentially serve as a noninvasive tool to facilitate the pre-treatment individualized prediction of MMR status in patients with CRC, which could promote the personalized clinical-making decision.

Neoadjuvant Modified FOLFOXIRI With Selective Radiotherapy in Locally Advanced Rectal Cancer: Long-term Outcomes of Phase II Study and Propensity-Score-Matched Comparison With Chemoradiotherapy.

BACKGROUND: Neoadjuvant modified FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) chemotherapy with selective radiotherapy did not compromise pathologic complete response and tumor downstaging in locally advanced rectal cancer. OBJECTIVE: The study aimed to analyze disease-free survival and local recurrence of neoadjuvant chemotherapy with modified FOLFOXIRI (mFOLFOXIRI). DESIGN: This was a prospective single-arm phase II study. A propensity score-adjusted method was implemented to compare outcomes against historical controls of chemoradiotherapy. SETTINGS: The study was conducted at single institutions. PATIENTS: One hundred 6 patients with stage II and III rectal cancers were included. INTERVENTION: All patients received neoadjuvant mFOLFOXIRI chemotherapy before total mesorectal excision. Patients with mesorectal fascia-positive or ycT4a/b after reevaluation with MRI received radiation before surgery. Otherwise, immediate total mesorectal excision would be performed. MAIN OUTCOME AND MEASURES: The primary end point was tumor downstaging (ypStage 0-I) rate, which was reported previously. Disease-free survival and local recurrence rate were the main outcomes for the current study. RESULTS: After a median follow-up of 43.3 months, the 2-year disease-free survival rate was 85.6% and the 3-year disease-free survival rate was 78.9%. The local recurrence rate was 7.8% after surgery. After propensity score matching, 73 patients were available for comparison in each group. The pathologic complete response rate was 23.3% and 13.7% ( p = 0.14), the proportion of ypStage 0-I was 45.2% vs 39.7% ( p = 0.5), the 3-year disease-free survival was 87.6% vs 75.8% (HR = 0.46; 95% CI, 0.22-0.95, p = 0.037). The local recurrence rate in the mFOLFOXIRI group was 5.5% and in the chemoradiotherapy group was 4.1% ( p = 0.70). Patients receiving mFOLFOXIRI had a lower incidence of anastomotic fistula compared with the chemoradiotherapy group (5.5% vs 17.8%, p = 0.02). LIMITATIONS: This was a single-arm, nonrandomized phase II study. CONCLUSIONS: Neoadjuvant mFOLFOXIRI with selective radiotherapy was feasible and safe, and it improved 3-year disease-free survival compared with propensity score-matched historical controls who received chemoradiotherapy. See Video Abstract at http://links.lww.com/DCR/B989 .Trial registration: NCT02217020. FOLFOXIRI MODIFICADO NEOADYUVANTE CON RADIOTERAPIA SELECTIVA EN CNCER DE RECTO LOCALMENTE AVANZADO RESULTADOS A LARGO PLAZO DEL ESTUDIO DE FASE II Y COMPARACIN EMPAREJADA POR PUNTUACIN DE PROPENSIN CON QUIMIORRADIOTERAPIA: ANTECEDENTES:La quimioterapia neoadyuvante con FOLFOXIRI modificado (ácido folínico, 5-fluoruracilo, oxaliplatino e irinotecan) con radioterapia selectiva no comprometió la respuesta patológica completa ni la reducción del estadio del tumor en el cáncer de recto localmente avanzado.OBJETIVO:El estudio tuvo como objetivo analizar la sobrevida libre de enfermedad y la recurrencia local de la quimioterapia neoadyuvante con FOLFOXIRI modificado (mFOLFOXIRI).DISEÑO:Este fue un estudio prospectivo de fase II de un solo brazo. Se implementó un método ajustado por puntaje de propensión para comparar los resultados con los controles históricos de quimiorradioterapia.ESCENARIO:El estudio se realizó en instituciones individuales.PACIENTES:Se incluyeron 106 pacientes con cáncer de recto en estadio II y III.INTERVENCIÓN:Todos los pacientes recibieron quimioterapia neoadyuvante con mFOLFOXIRI antes de la escisión total del mesorrecto. Los pacientes con fascia mesorrectal positiva o ycT4a/b después de la reevaluación con MRI recibirían radiación antes de la cirugía. En caso contrario, se realizaría una escisión mesorrectal total inmediata.PRINCIPALES RESULTADOS Y MEDIDAS:El criterio principal de valoración fue la tasa de disminución del estadio del tumor (ypEstadio 0-I), que se informó anteriormente. La sobrevida libre de enfermedad y la tasa de recurrencia local son los principales resultados del estudio actual.RESULTADOS:Después de una mediana de seguimiento de 43,3 meses, las tasas de sobrevida libre de enfermedad a 2 y 3 años fueron del 85,6 % y 78,9 %, respectivamente. La tasa de recidiva local fue del 7,8% tras la cirugía. Después del emparejamiento por puntaje de propensión, 73 pacientes estaban disponibles para la comparación en cada grupo. La tasa de respuesta patológica completa fue de 23,3 % y de 13,7 % (p = 0,14), la proporción de ypEstadio 0-I fue del 45,2 % frente al 39,7 % (p = 0,5), la SLE a los 3 años fue del 87,6 % frente al 75,8 % (HR = 0,46, IC del 95 % 0,22-0,95, p = 0,037) y la tasa de recurrencia local fue del 5,5 % y del 4,1 % (p = 0,70) en el grupo de mFOLFOXIRI frente al grupo de quimiorradioterapia, respectivamente. Los pacientes que recibieron mFOLFOXIRI tuvieron una menor incidencia de fístula anastomótica en comparación con el grupo de quimiorradioterapia (5,5 % frente a 17,8 %, p = 0,02).LIMITACIONES:Este fue un estudio de fase II no aleatorizado de un solo brazo.CONCLUSIONES:El mFOLFOXIRI neoadyuvante con radioterapia selectiva fue factible y seguro, y mejoró la SSE a los 3 años en comparación con los controles históricos emparejados por puntaje de propensión que recibieron quimiorradioterapia. Consulte Video Resumen en http://links.lww.com/DCR/B989 . (Traducción-Dr. Felipe Bellolio ).

Capecitabine maintenance therapy in metastatic colorectal cancer patients with no evidence of disease: CAMCO trial.

Background: In patients with metastatic colorectal cancer (mCRC) exhibiting no evidence of disease (NED), this study assessed the efficacy and safety of capecitabine maintenance therapy. Methods: The single-arm, phase II CAMCO trial enrolled mCRC-NED patients after first-line treatment, administering oral capecitabine maintenance for 1 year. Results: A total of 93 patients were enrolled. The primary end point, 3-year disease-free survival, yielded a rate of 51.6% (95% CI: 41.3-62.0%). Secondary end points included a 3-year overall survival rate of 83.9% (95% CI: 76.3-91.5%). Grade 3 adverse events (AE) were observed in seven patients (7.5%). Predominantly grade 1 and 2, the most common AE was hand-foot syndrome. Conclusion: In mCRC-NED patients, capecitabine maintenance demonstrated a manageable 3-year disease-free survival rate of 51.6%, accompanied by manageable AEs. Clinical Trial Registration: NCT01880658 (ClinicalTrials.gov).

A prognostic nomogram for intrahepatic progression-free survival in patients with colorectal liver metastases after ultrasound-guided percutaneous microwave ablation.

PURPOSE: The present study identified predictors of intrahepatic progression-free survival (ihPFS) after ultrasound (US)-guided percutaneous microwave ablation (MWA) for colorectal liver metastases (CRLMs) and developed a nomogram to predict ihPFS. METHODS: From January 2013 to December 2018, a total of 314 patients (224 men and 90 women; mean age, 57.1 ± 11.8 years; range, 23-86 years) with 645 CRLMs (mean diameter, 16.6 ± 6.5 mm; range, 6.0-45.0 mm) treated with US-guided percutaneous MWA were included and analyzed. The average number of CRLMs per patient treated was 2 (range, 1-8). A nomogram to predict ihPFS was developed based on a multivariable Cox model. Validation of the nomogram was performed using the concordance index (C-index), calibration curves, and decision curve analyses. RESULTS: The 1-, 2-, and 3-year cumulative ihPFS rates were 59.0%, 38.9%, and 30.8%, respectively. Maximal CRLM size, number of CRLMs, ablative margin, primary tumor lymph node status, and chemotherapy were five independent prognostic factors for ihPFS. The C-index of the nomogram was 0.702 (CI: 0.681-0.723). A risk classification system that perfectly classified the patients into three risk groups was constructed. The median ihPFS of patients in the low-, intermediate-, and high-risk groups was 36.3 months (95% CI: 21.4-51.1), 13.4 months (95% CI: 12.1-14.6), and 3.8 months (95% CI: 2.3-5.3), respectively. CONCLUSION: The nomogram and risk classification system will facilitate the personalized assessment of ihPFS for patients receiving US-guided percutaneous MWA for CRLMs.

Chemical Composition and Antifungal, Anti-Inflammatory, Antiviral, and Larvicidal Activities of the Essential Oils of Zanthoxylum acanthopodium DC. from China and Myanmar.

Zanthoxylum acanthopodium DC. is a widely used traditional medicinal plant to treat fever, flu, stomachache, traumatic injury, and mosquito bite in tropical and subtropical Asia. This study aimed to investigate the antifungal, anti-inflammatory, antiviral, and larvicidal activities of its fruit essential oil. The essential oil sample from China (EOZC) was mainly composed of limonene (29.78%) and ß-myrcene (26.65%), while the sample from Myanmar (EOZM) was dominated by Terpinen-4-ol (43.35%). Both essential oils showed antifungal activity, with 90% minimum inhibitory concentration (MIC90) values ranging from 26.3 to 499 µg/mL. By obviously inhibiting nitric oxide (NO) in RAW 264.7 cells, EOZC (IC50, 16 µg/mL) showed comparable anti-inflammatory activity to the positive control L-NMMA (IC50, 12.2 µg/mL). EOZM showed significant antiviral activity against the dengue virus with an IC50 value of 13 µg/mL. Additionally, both EOZC and EOZM demonstrated dose-dependent larvicidal activity against Aedes albopictus, with LC50 and LC90 values ranging from 45.8 to 144.0 µg/mL. Our results contribute a theoretical foundation for the further application of Zanthoxylum acanthopodium DC. as an antifungal and anti-inflammatory ingredient in the pharmaceutical industry and further indicate that it has the potential to be developed as a new source of natural and eco-friendly medicine for the prevention and treatment of dengue virus.

Cost-Effectiveness of Pembrolizumab plus Axitinib Versus Sunitinib as First-Line Therapy in Advanced Renal Cell Carcinoma in the U.S.

BACKGROUND: The data from the phase III clinical trial KEYNOTE-426 indicated that pembrolizumab plus axitinib compared with sunitinib could generate clinical benefits in patients with previously untreated advanced renal cell carcinoma (RCC). Given the incremental clinical benefits, we examined the potential cost-effectiveness of pembrolizumab plus axitinib versus sunitinib in the first-line setting for patients with advanced RCC from the U.S. payers' perspective. MATERIALS AND METHODS: Cost and health outcomes were estimated at a willingness-to-pay (WTP) threshold of $100,000 to $150,000 per quality-adjusted life-year (QALY). One-way and probabilistic sensitivity analyses were performed by varying potentially modifiable parameters, and additional subgroup analyses were performed as well. RESULTS: Upon our analyses, the total treatment costs in the pembrolizumab plus axitinib and sunitinib groups were $522,796 and $348,424 and the QALYs gained 2.90 and 1.72, respectively. In the base-case analysis, compared with receiving sunitinib, patients with advanced RCC receiving pembrolizumab plus axitinib gained 1.18 more QALYs at an incremental cost-effectiveness ratio of $148,676/QALY. The results of subgroup analyses demonstrated that pembrolizumab plus axitinib was most cost-effective for patients who had one organ with metastasis. CONCLUSION: First-line treatment with pembrolizumab plus axitinib, compared with sunitinib, is a cost-effective strategy when the value of WTP is from $100,000 to $150,000 per QALY in patients with advanced RCC. For patients with one-organ metastasis and those in International Metastatic Renal Cell Carcinoma Database Consortium poor risk group, first-line treatment with pembrolizumab plus axitinib is more cost-effective than others. IMPLICATIONS FOR PRACTICE: This was the first study to examine the cost-effectiveness of pembrolizumab plus axitinib versus sunitinib in advanced renal cell carcinoma (RCC). This study found that first-line treatment with pembrolizumab plus axitinib is a cost-effective strategy when the value of willingness-to-pay is from $100,000 to $150,000 per quality-adjusted life-year in patients with advanced RCC from the U.S. payers' perspective.

Modified FOLFOXIRI With or Without Cetuximab as Conversion Therapy in Patients with RAS/BRAF Wild-Type Unresectable Liver Metastases Colorectal Cancer: The FOCULM Multicenter Phase II Trial.

PURPOSE: This trial evaluated the addition of cetuximab to a modified FOLFOXIRI (mFOLFOXIRI: 5-fluorouracil/folinic acid, oxaliplatin, irinotecan) as conversion therapy in a two-group, nonrandomized, multicenter, phase II trial in patients with initially technically unresectable colorectal liver-limited metastases (CLM) and BRAF/RAS wild-type. PATIENTS AND METHODS: Patients were enrolled to receive cetuximab (500 mg/m2 ) plus mFOLFOXIRI (oxaliplatin 85 mg/m2 , irinotecan 165 mg/m2 , folinic acid 400 mg/m2 , 5-fluorouracil 2,800 mg/m2 46-hour infusion, every 2 weeks) (the cetuximab group) or the same regimen of mFOLFOXIRI alone (the control group), in a 2:1 ratio allocation. The primary endpoint was the rate of no evidence of disease (NED) achieved. Secondary endpoints included resection rate, objective response rate (ORR), survival, and safety. RESULTS: Between February 2014 and July 2019, 117 patients were registered for screening at six centers in China, and 101 of these were enrolled (67 cetuximab group, 34 control group). The rate of NED achieved was 70.1% in the cetuximab group and 41.2% in the control group (difference 29.0%; 95% confidence interval [CI], 9.1%-48.8%; p = .005). Patients in the cetuximab group had improved ORR (95.5% vs. 76.5%; difference 19.1%; 95% CI, 17.4%-36.4%; p = .010) compared with those in control group. Progression-free survival and overall survival showed the trend to favor the cetuximab group. The incidence of grade 3 and 4 adverse events was similar in the two groups. CONCLUSION: Addition of cetuximab to mFOLFOXIRI improved the rate of NED achieved. This combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable CLM. IMPLICATIONS FOR PRACTICE: This trial evaluated the addition of cetuximab to a modified FOLFOXIRI as conversion therapy in a phase II trial in patients with initially technically unresectable colorectal liver-limited metastases and BRAF/RAS wild-type. The rate of no evidence of disease achieved was 70.1% in the cetuximab plus modified FOLFOXIRI group and 41.2% in the modified FOLFOXIRI group. Objective response rates, overall survival, and progression-free survival were improved in the cetuximab group when compared with the modified FOLFOXIRI group. Addition of cetuximab to modified FOLFOXIRI increased the rate of no evidence of disease achieved, and this combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable colorectal liver-limited metastasis.

Cost-Effectiveness Analysis of Durvalumab Plus Chemotherapy in the First-Line Treatment of Extensive-Stage Small Cell Lung Cancer.

BACKGROUND: In the CASPIAN trial, durvalumab + chemotherapy demonstrated significant improvements in overall survival compared with chemotherapy alone in patients with extensive-stage small cell lung cancer (SCLC). We aimed to assess the cost-effectiveness of durvalumab in patients with extensive-stage SCLC from the US healthcare system perspective. PATIENTS AND METHODS: A comprehensive Markov model was adapted to evaluate cost and effectiveness of durvalumab combination versus platinum/etoposide alone in the first-line therapy of extensive-stage SCLC based on data from the CASPIAN study. The main endpoints included total costs, life years (LYs), quality-adjusted life-years (QALYs), and incremental cost-e-ectiveness ratios (ICERs). Model robustness was assessed with sensitivity analysis, and additional subgroup analyses were also performed. RESULTS: Durvalumab + chemotherapy therapy resulted in an additional 0.27 LYs and 0.20 QALYs, resulting in an ICER of $464,711.90 per QALY versus the chemotherapy treatment. The cost of durvalumab has the greatest influence on this model. Subgroup analyses showed that the ICER remained higher than $150,000/QALY (the willingness-to-pay threshold in the United States) across all patient subgroups. CONCLUSIONS: Durvalumab in combination with platinum/etoposide is not a cost-effective option in the first-line treatment of patients with extensive-stage SCLC.

Comparison of outcomes between neoadjuvant imatinib and upfront surgery in patients with localized rectal GIST: An inverse probability of treatment weighting analysis.

BACKGROUND AND OBJECTIVES: This study aimed to compare outcomes between neoadjuvant imatinib and upfront surgery in patients with localized rectal gastrointestinal stromal tumors (GIST) patients. METHODS: Eighty-five patients with localized rectal GIST were divided into two groups: upfront surgery ± adjuvant imatinib (Group A, n = 33) and the neoadjuvant imatinib + surgery + adjuvant imatinib (Group B, n = 52). Baseline characteristics between groups were controlled for with inverse probability of treatment weighting (IPTW) adjusted analysis. RESULTS: The response rate to neoadjuvant imatinib was 65.9%. After the IPTW-adjusted analysis, patients who underwent neoadjuvant therapy had better distant recurrence-free survival (DRFS) and disease-specific survival (DSS) compared with those who underwent upfront surgery (5-year DRFS 97.8 vs. 71.9%, hazard ratio [HR], 0.15; 95% CI, 0.03-0.87; p = 0.03; 5-year DSS 100 vs. 77.1%; HR, 0.11; 95% CI, 0.01-0.92; p = 0.04). While no significant association was found between overall survival (OS) and treatment groups (p = 0.07), 5-year OS was higher for the neoadjuvant group than upfront surgery group (97.8% vs. 71.9%; HR, 0.2; 95% CI, 0.03-1.15). CONCLUSIONS: In patients with localized rectal GIST, neoadjuvant imatinib not only shrunk the tumor size but also decreased the risk of metastasis and tumor-related deaths when compared to upfront surgery and adjuvant imatinib alone.

Adapting the DeepSARM approach for dual-target ligand design.

The structure-activity relationship (SAR) matrix (SARM) methodology and data structure was originally developed to extract structurally related compound series from data sets of any composition, organize these series in matrices reminiscent of R-group tables, and visualize SAR patterns. The SARM approach combines the identification of structural relationships between series of active compounds with analog design, which is facilitated by systematically exploring combinations of core structures and substituents that have not been synthesized. The SARM methodology was extended through the introduction of DeepSARM, which added deep learning and generative modeling to target-based analog design by taking compound information from related targets into account to further increase structural novelty. Herein, we present the foundations of the SARM methodology and discuss how DeepSARM modeling can be adapted for the design of compounds with dual-target activity. Generating dual-target compounds represents an equally attractive and challenging task for polypharmacology-oriented drug discovery. The DeepSARM-based approach is illustrated using a computational proof-of-concept application focusing on the design of candidate inhibitors for two prominent anti-cancer targets.

Systematic assessment of structure-promiscuity relationships between different types of kinase inhibitors.

Given the increasing quest for selective kinase inhibitors, we have systematically investigated structural and structure-promiscuity relationships between promiscuous kinase inhibitors and other types with increasing potential for selective kinase inhibition. Therefore, inhibitors with different modes of action were extracted from X-ray structures of kinase complexes. For more than 18,000 promiscuous kinase inhibitors and 1253 type I1/2, II, and allosteric inhibitors with structurally confirmed mechanisms, analogue space was systematically charted. These inhibitors were active against a total of 426 human kinases. While nearly 80% of the promiscuous inhibitors formed related analogues series, only ~30% of other types of inhibitors were involved in such structural relationships and many of these inhibitors also had multi-kinase activity. Thus, most of the investigated type I1/2, II, and allosteric inhibitors with reported single-kinase activity were distinguished from promiscuous inhibitors, thus indicating potential for kinase selectivity. Structural relationships between promiscuous inhibitors and the subset of other inhibitors were organized in a matrix format including kinase activity profiles, revealing structure-promiscuity relationships for follow-up investigations.

First-line pembrolizumab plus chemotherapy for extensive-stage small-cell lung cancer: a United States-based cost-effectiveness analysis.

BACKGROUND: The clinical trial of Keynote-604 showed that pembrolizumab plus chemotherapy could generate clinical benefits for extensive-stage small-cell lung cancer (ES-SCLC). We aim to assess the efficacy and cost of pembrolizumab combined with chemotherapy in the first-line treatment setting of ES-SCLC from the United States (US) payers' perspective. METHODS: A synthetical Markov model was used to evaluate cost and effectiveness of pembrolizumab plus platinum-etoposide(EP) versus EP in first-line therapy for ES-SCLC from the data of Keynote-604. Lifetime costs life-years(LYs), quality adjusted LYs(QALYs) and incremental cost-effectiveness ratios(ICERs) were estimated. One-way and probabilistic sensitivity analyses were performed. Furthermore, we performed subgroup analysis. RESULTS: Pembrolizumab plus EP resulted in additional 0.18 QALYs(0.32 LYs) and corresponding incremental costs $113,625, resulting an ICER of $647,509 per QALY versus EP. The price of pembrolizumab had a significant impact on ICER. Probabilistic sensitivity analysis indicated that pembrolizumab combined chemotherapy may become a cost-effective option with a probability of 0%. Besides, subgroup analysis suggested that all subgroups were not cost-effective. CONCLUSION: From the perspective of the US payer, pembrolizumab plus EP is not a cost-effective option for first-line treatment patients with ES-SCLC at a WTP threshold of $150,000 per QALY.

Development of a strategy for a quick process for separation of volatile compounds in counter-current chromatography: purification of cinnamaldehyde from Cinnamomum cassia by high performance counter-current chromatography.

It is a challenge for many researchers to separate volatile compounds. In this study, we introduce a rapid and efficient method of separating target compound from the twigs of Cinnamomum cassia by high performance counter-current chromatography. Under the bioassay guidance, the total extract exhibited a potential activity against NO production in RAW 264.7 macrophages and the total extract was further separated by high performance counter-current chromatography. Cinnamaldehyde (1) was enriched by counter-current chromatography (CCC) with reversed-phase mode using n-hexane-ethyl acetate-methanol-water (1:1:1:1,v/v/v/v) as the solvent system. Further identification was achieved by high performance liquid chromatography (HPLC).

Systematic Exploration of Activity Cliffs Containing Privileged Substructures.

The privileged substructure (PS) and activity cliff (AC) concepts are popular in pharmaceutical research. PSs have been empirically identified as preferred building blocks for target-class-directed generation of active compounds. Although some PSs are controversially viewed, they continue to receive much attention in drug discovery. ACs are formed by structurally similar active compounds with large potency differences and thus capture structure-activity relationship (SAR) discontinuity and reveal SAR determinants. So far, the PS and AC concepts have not been investigated in context. We have systematically explored ACs formed by compounds containing different PSs (PS-ACs). Such ACs were frequently identified in different series of compounds. PS-ACs were thoroughly characterized and compared to ACs formed by other compounds. The analysis revealed differences in AC formation between PSs. For example, individual PSs with an unusually high proportion of AC-forming compounds were identified. Furthermore, PS-AC network analysis identified clusters of ACs containing the same PS in different compound structure contexts with activity against different targets. From such PS-AC clusters, target-specific SAR information for PSs in different structural environments can be extracted.

Cost-Effectiveness Analysis of First-Line FOLFIRI Combined With Cetuximab or Bevacizumab in Patients With RAS Wild-Type Left-Sided Metastatic Colorectal Cancer.

BACKGROUND: The FIRE-3 phase III clinical trial demonstrated the marked advantage of prolonging the median overall survival of patients with final RAS wild-type (WT) left-sided metastatic colorectal cancer (mCRC) by 38.3 months after treatment with irinotecan, fluorouracil, and leucovorin (FOLFIRI) plus cetuximab and by 28.0 months after treatment with FOLFIRI plus bevacizumab. However, the substantial cost increase and economic impact of using cetuximab imposes a considerable burden on patients and society. METHODS: A Markov model based on the data collected in the FIRE-3 trial was developed to investigate the cost-effectiveness of treating patients with FOLFIRI plus either cetuximab or bevacizumab from the perspective of the Chinese health-care system. Costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated over a lifetime horizon. One-way and probabilistic sensitivity analyses were performed by varying potentially modifiable parameters. RESULTS: In our analysis, the total treatment costs in the bevacizumab and cetuximab groups were $92 549.31 and $94 987.31, respectively, and the QALYs gained were 1.58 and 2.05. In the base-case analysis, compared with bevacizumab, left-sided RAS WT patients receiving cetuximab gained 0.47 more QALYs at an ICER of $5187.23/QALY ($3166.23/LY). The 1-way sensitivity analysis showed that the most influential parameter was the cost of cetuximab. Probabilistic sensitivity analysis indicated that the cost-effective probability of cetuximab group was 92.8% under the willingness-to-pay threshold of $24 081. CONCLUSIONS: Treatment with FOLFIRI plus cetuximab in Chinese patients with left-sided RAS WT mCRC may improve health outcomes and use financial resources more efficiently than FOLFIRI plus bevacizumab.