bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cure-PROs: Next-generation targeted protein degraders.
Authors: Giardina Sarah F. , Valdambrini Elena , Peel Michael , Bacolod Manny D. , Rothenberg Mace L. , Lanman Richard B. , Warren J. David , Barany Francis 
Published: June 2023

e15101 Background: Many proteins, including transcription factors and scaffolding proteins, are not amenable to targeting by traditional small molecule inhibitors due to the lack of a well-defined binding pocket or active site. Proteolysis-Targeting Chimeras (PROTACs) are a new class of hetero-bifunctional molecules that bind both a target protein and an E3 ubiquitin ligase, bringing the two into proximity for appending ubiquitin, and subsequently marking the target protein for proteasomal degradation. Currently, thirteen PROTACs are in clinical trials for oncology indications. However, the clinical utility of PROTACs is challenged by their large size and long development timelines. Also, resistance mutations in the E3 ligase or transporter overexpression inevitably evolve. Thus, a new platform for small-molecule degraders that enables ultra-rapid drug development timelines, efficient cellular uptake, and can be developed to overcome innate and acquired drug resistance is needed. Methods: Coferons, developed in our laboratory, are small molecules that self-assemble upon binding to a target, where they form reversible covalent dimers through bio-orthogonal linker chemistries. We have combined features of the Coferon platform and PROTACs to generate CURE-PROs (Combinatorial Ubiquitination REal-time PROteolysis), consisting of one target protein ligand and one E3 ligase ligand that form reversible heterodimers that lead to targeted protein degradation within cells. By modifying known ligands for BRD4, and the E3 ubiquitin ligases Cereblon, VHL, and MDM2, with linkers able to reversibly join the BRD4 to the ligase ligands, we synthesized libraries of CURE-PRO monomers that can be combined to create thousands of CURE-PRO dimer combinations. We explored whether this platform could yield meaningful BRD4 degradation in vitro and in vivo. Results: Rapid combinatorial cell-based screening identified several BRD4-E3 ligase CURE-PRO combinations that induced greater than 50% BRD4 degradation, with the most promising CURE-PRO pairs achieving more than 95% protein degradation. Consistent with a PROTAC mechanism-of-action, successful CURE-PRO combinations confirmed significant protein degradation which was inhibited by proteasome inhibitors or competition with parent ligands. Significant BRD4 degradation was also observed in mice bearing bilateral human xenograft tumors, confirming CURE-PRO proof-of-mechanism in vivo. Conclusions: The combinatorial nature of our platform has the potential to significantly reduce synthesis time and effort to identify the optimal linker length and E3 ligase for each target protein. The CURE-PRO platform consists of expanding libraries of monomers for both additional oncoprotein targets as well as E3 ligases, which can be redeployed to shorten lead development timelines.
The antinociceptive effects of selective TRPV1 antagonist RCI002 against chemotherapy-induced peripheral neuropathy.
Authors: Kim Minjung , Park Juil , Hasrul Harith , Park Sung Taek , Kim Yong Ho 
Published: June 2023

e15111 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect experienced by cancer patients receiving chemotherapy. Recent reports showed that transient receptor potential (TRP) channels are involved in paclitaxel- or oxaliplatin-induced neuropathic pain. TRP vanilloid 1 (TRPV1) may contribute to the development of mechanical allodynia and thermal hyperalgesia after cisplatin or oxaliplatin treatment. Moreover, paclitaxel-induced behavioral hypersensitivity is prevented and reversed by administration of TRPV1 antagonists. RCI002 is a potent and selective TRPV1 antagonist, blocking capsaicin activation of the target, with a little affect pH or heat activation. We found that RCI002 relieves neuropathic pain by inhibiting TRPV1, an important nociceptor involved in pain signal transduction, and does not cause thermoregulation, a problem with existing TRPV1 antagonists. In this study, Calcium imaging and patch clamp were employed to examine effects of RCI002 on mouse dorsal root ganglion (DRG) neurons and HEK293t cells expressing TRPV1. We also investigated RCI002 associated paclitaxel-induced peripheral neuropathic pain using a rat model. Methods: Dorsal root ganglion (DRG) neurons and TRPV1-transfected human embryonic kidney-derived (HEK) 293 cells were used for calcium imaging or whole-cell patch-clamp recording. CIPN was induced by intraperitoneal administration of paclitaxel 2 mg/kg for 4 consecutive days using adult male Sprague-Dawley rats. RCI002 were administered intraperitoneal and the paw withdrawal thresholds were measured using von Frey filaments. Results: We previously showed that RCI002, a novel TRPV1 antagonist that could be referred to as a new class of TRPV1 modulators that produce a significant analgesic effect formalin-induced behavior and improved mechanical allodynia undergoing spinal nerve ligation(SNL) in rats without hyperthermic effect. In the present study, The selective TRPV1 inhibitor RCI002 impaired capsaicin-induced calcium influx in DRG neurons. hTRPV1 expressed in HEK293 cells mediated a hemin-induced calcium influx which was blocked by RCI002. Behavioral assessment using the von Frey filaments. SD rat that received paclitaxel developed mechanical hypersensitivity to Von Frey filament stimulations of their hindpaws. Paclitaxel-induced hypersensitivity inhibited by TRPV1 antagonist RCI002(RCI002 EC50 = 0.85mg/kg). RCI002 significantly increased the paw withdrawal threshold more than pregabalin in CIPN rats(Pregabalin EC50 = 14.77mg/kg). Conclusions: Our findings suggest that RCI002 may be a promising approach to reduce paclitaxel-induced hyperexcitability and thereby to reduce neuropathy pain.
AX-0085, a novel AXL kinase inhibitor, and effects on osimertinib-resistance in non–small-cell lung cancer.
Authors: Choi Myeong Jun , Rhie Byung-Ho , Woo SangHyeon , Yun Si-Eun , Park Young Jun , Kim Jaesang , Suresh Ramakrishna , Kim Kye-Seong 
Published: June 2023

e15121 Background: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) having high efficacy in treating patients with advanced non-small cell lung cancer (NSCLC) with EGFR activating mutations and EGFR T70M mutations. Although, osimertinib is a frontline anticancer agent for treating NSCLC, many patients inevitably develop osimertinib-resistance tumor recurrence. The activation of AXL was reported to be a major factor driving osimertinib-resistance in NSCLC. Thus, AXL is a promising therapeutic target for the treatment of osimertinib-resistant NSCLC, and we developed a new small-molecule AXL inhibitor, AX-0085. Methods: We established osimertinib-resistant cell lines from EGFR-mutated NSCLC cell lines, HCC827 and H1975, after high dose exposure and stepwise exposure to osimertinib in culture. We investigated the cell viability of AX-0085 and other kinase inhibitors, and the anti-tumor activity of AX-0085 on the proliferation, migration, apoptosis, and epithelial-mesenchymal transition (EMT) in osimertinib-resistant cells. Results: Compared to the parental cells, IC50 of resistant cell to osimertinib was significantly increased and osimertinib-resistant cells showed remarkably increased expression of AXL/pAXL and p-SRC as compared to the parental HCC827 cell. AX-0085 was completely blocked the AXL and SRC activation but EGFR inhibitors (gefitinib and osimertinib) did not inhibit the activation of AXL and SRC in the osimertinib-resistant cell line. AX-0085 (IC50: 4.4nM for AXL kinase in cell-based kinase assay) was one of the most potent AXL inhibitors and showed the strongest cytotoxicity against osimertinib-resistant cells compared to other kinase inhibitors. AX-0085 effectively down-regulated mRNA level of AXL and AXL regulating transcription factors in NSCLC cell lines such as HCC827 and H1975. AX-0085 treatment effectively inhibited the activation of AXL in acquired osimertinib-resistant cells and decreased the mRNA level of AXL and AXL regulating transcription factors. AX-0085 significantly inhibited the cell proliferation, apoptosis, migration, and EMT in acquired osimertinib-resistant cells. Conclusions: Our results showed that AX-0085 selectively inhibits the activation of AXL to overcome acquired resistance to osimertinib, suggesting an effective AXL-based therapy for patients with osimertinib-resistant tumors. Currently, AX-0085 is undergoing non-clinical trials.
Portal hemodynamic effects of different TKIs in patients with advanced hepatocellular carcinoma: A prospective cohort study.
Authors: Li Pingping , Yan Tao , Cheng Jiamin , Zhang Linzhi , Peng Caiyun , Su Guodong , Li Yinyin , Lu Yinying 
Published: June 2023

e15126 Background: Tyrosine kinase inhibitors (TKIs) are considered to have effects on portal collateral circulation with portal hypertension. According to previous small sample clinical reports, short-term administration of sorafenib might have an effect of decreasing portal venous pressure, while lenvatinib aggravated portal hypertension. Long-term effects of TKIs on portal pressure are still unclear. Therefore, We conducted a prospective cohort study to explore the efficacy of different TKIs for portal circulation in patients with advanced hepatocellular carcinoma. Methods: 27 Child-Pugh class A or B patients with advanced HCC were enrolled in this study, 13 patients received lenvatinib, 7 patients sorafenib, and 7 patients regorafenib. Changes of portal hemodynamic parameters were measured by duplex Doppler ultrasonography, including portal venous area (PVA), portal venous flow velocity (PVV) and congestion index (CI) before and after administration of TKIs for an average 40-50 days. Results: In both regorafenib and sorafenib cohorts, PVA decreased after treatment, although the difference was not significant. PVF significantly reduced in sorafenib cohort (24.96±5.60 vs. 15.46±4.50, P= 0.014) and regorafenib cohort (21.43±2.09 vs. 16.01±1.28, P= 0.024), therefore CI significantly increased in sorafenib cohort (0.060±0.042 vs. 0.088±0.040, P= 0.046) and regorafenib cohort (0.068±0.032 vs. 0.090±0.030, P= 0.043). In lenvatinib, both PVA and PVF have no significant change, while CI increased significantly (0.057±0.027 vs. 0.074±0.040, P= 0.030). Conclusions: In this study, TKIs showed different effects on portal hemodynamic change in advanced HCC. Large sample and long time follow-up research will be necessary to verify their clinical and mechanism effects. [Table: see text]
The clinical and genomic characteristics of KRAS G12D mutated cancers.
Authors: Lin Guomin , Yuan Shaohua , Pang Fei 
Published: June 2023

e15151 Background: KRAS mutations are relatively common in solid tumors. It is once considered to be “non-druggable” due to its high affinity to GTP/GDP and lack of other binding sites. Recently, irreversible inhibitors targeting specific KRAS mutations have been developed. We aimed to investigate the correlation of clinical and genomic factors with KRAS G12D mutation in pancreatic cancer (PC), colorectal cancer (CRC) and non-small-cell lung cancer (NSCLC). Methods: We retrospectively reviewed the clinical and genomic data of patients with PC (n = 300), CRC (n = 300), and NSCLC (n = 1800) who provided tumor tissues and matched peripheral blood samples (served as control to eliminate germline variants) for targeted sequencing of 450 cancer-related genes. Experiments were carried out in OrigiMed’s laboratory following the CAP/CLIA standards. Tumor mutation burden (TMB)-high was defined as TMB > 10 muts/Mb. Results: The prevalence of KRAS G12D mutation in PC, CRC and NSCLC was 38.3% (115/300), 15.0% (45/300) and 2.0% (36/1800), respectively. In PC and CRC, G12D was the major type of KRAS mutations, accounting for 44.9% (115/256) and 30.8% (45/146) of all the KRAS mutations, respectively. In contrast, G12C was the most common KRAS mutation in NSCLC (35.9% [79/220]), followed by G12D (16.4% [36/220]). Patients were divided into three groups according to the KRAS mutation status: the G12D (mutated in KRAS G12D), non-G12D (mutated in KRAS, but not G12D), and wild-type (WT; no KRAS mutation) groups. Clinical features including age, sex and disease stage were not associated with the KRAS grouping in PC and CRC. However, the KRAS grouping was significantly correlated with sex in NSCLC (Female vs Male: 1.9% vs 2.1% in G12D, 4.4% vs 13.9% in non-G12D, 93.7% vs 84.1% in WT, P < 0.001). In PC, KRAS G12D and BRAF mutations were mutually exclusive (P < 0.01), while in CRC, KRAS G12D mutation was found to be co-occurring with PIK3CA mutation (P < 0.05). For NSCLC, KRAS G12D mutation was mutually exclusive with EGFR mutation (P < 0.01) and co-occurred with STK11 mutation (P < 0.05). TMB was comparable between the KRAS grouping in PC and CRC. In contrast, TMB was significantly higher in the non-G12D group (median 11.7 [range 0.7-89.8] muts/Mb) compared to the G12D (median 6.9 [range 0-30.9] muts/Mb; P < 0.001) and WT (median 4.6 [range 0-215.2] muts/Mb; P < 0.001) groups in NSCLC. A higher proportion of TMB-high was also observed in the non-G12D group (58.5%) compared to the G12D (22.2%) and WT (22.6%) groups in NSCLC. Conclusions: Patients with KRAS G12D mutation possessed unique clinical and genomic characteristics. It was more prevalent in PC and CRC and was correlated with sex in NSCLC. KRAS G12D mutation co-occurred with STK11 mutation and showed a relatively low TMB value in NSCLC, suggesting that immunotherapy might be ineffective. While KRAS non-G12D mutated NSCLC patients may be favorable to ICI. Our results provide insights into the precision medicine of KRAS G12D-mutated cancers.
Building liquid-liquid perfusion interface (LLPI) –based patient-derived tumoroids (PDTs) model system as clinical research tools for testing cancer therapeutics.
Authors: Giri Pradeep , Ochola Damieanus , Samuel Preethi , Barrot Jared , Dave Bhuvanesh 
Published: June 2023

e15192 Background: Current in vitro cancer model systems are inadequate in their representation and application of an actual tumor. Use of three-dimensional PDTs that consists of stroma and the microenvironment vastly addresses these shortcomings. However, a complete picture of the intratumoral interactions and functions requires optimal supply of oxygen to address problems associated with poor cellular oxygenation. Soft tissue sarcomas are malignant tumors that develop in the tissues that surround and support bones and organs. For non-resectable soft tissue sarcomas, model systems and treatment options are either limited or not available. We are establishing our Matrigel-based PDTs on a Liquid-Liquid Perfusion Interface (LLPI) using a synthetic hemoglobin as a blood substitute to build a comprehensive model system that is an amalgamation of an in vitro-in vivo system. Our objective is to replicate tumor complexity and use our model to serve as an effective and reliable platform to test and investigate therapeutic options. Methods: Soft tissue sarcoma PDT models with LLPI were built and used for testing under the following groups: Drug treatments with Doxorubicin (10nM), HSP90 inhibitor (1)10 nM, (2) 100 nM and (3) 1 mM) and combination (Doxorubicin + HSP90) for 10 days was compared on Sarcoma PDT models with and without oxygenation to test the impact of oxygen on tumor volume. Currently we are pursuing downstream analysis using apoptosis, proliferation and cytokine profiling and dynamic oxygen analysis of the TME. Results: We compared the effect of Doxorubicin with HSP90 inhibitor on a Sarcoma PDT model with and without oxygenation to observe the impact of oxygen on tumor growth. We observed similar rate of cell growth in the untreated samples in both model systems. In the non-oxygenated PDTs Doxorubicin-HSP90 combination was effective in reducing tumor volume. In the oxygenated PDTs the efficacy of the combination therapy (Doxorubicin+HSP90) was no longer observed. Conclusions: The oxygenation status impacts the effect of Doxorubicin, HSP90 combination, a critical influence that would not have been observable without the use of oxygenated PDT model system. The impact of intratumoral variations on oxygenation levels warrants testing other existing and novel therapeutics on oxygenated PDT model systems to investigate the extent of the influence of oxygenation on the tumor biology. [Table: see text]
Prognostic factors of long-term outcomes after primary chemo-radiotherapy in non-metastatic anal squamous cell carcinoma: An international bicentric cohort.
Authors: Iseas Soledad , Prost Diego Martín , Bouchereau Sarah , Golubicki Mariano , Robbio Juan , Oviedo Ana , Coraglio Mariana , Carballido Marcela , Kujaruk Mirta , Mendez Guillermo , Barugel Mario Edmundo , Roca Enrique , Gros Louis , de Parades Vincent , Baba-Hamed Nabil , Adam Julien , Abba Martin C , Raymond Eric 
Published: June 2023

e15501 Background: Anal squamous cell carcinoma (ASCC) is a rare malignancy with a rising incidence associated with Human papillomavirus (HPV) infection. Locally-advanced disease is associated with a 30% rate of treatment failure after standard chemoradiotherapy (CRT). We aimed to elucidate prognostic factors for ASCC after curative CRT. Methods: A retrospective multicenter study of 176 consecutive patients with ASCC having completed CRT treated between 2010 and 2017 at 2 centers. Complete response (CR), disease-free survival (DFS) and overall survival (OS) were analyzed by Kaplan–Meier estimates with log-rank tests. The hierarchical clustering on principal components (HCPC) method was employed in an unsupervised and multivariate approach. Results: CR rate was 68% and was predictive of DFS (p < 0.0001) and OS (p < 0.0001), where non-CR cases were associated shorter DFS (HR = 16.5, 95% CI 8.19-33.21) and OS (HR = 8.42, 95% CI 3.77–18.81) in univariate analysis. Median follow-up was 38 months, with 3-year DFS of 71%. Prognostic factors for DFS were cT1-T2 (p = 0.0001), N0 (p = 0.03), HIV-positive (p = 0.04), HIV-HPV coinfection (p = 0.02), and well-differentiated tumors (p = 0.03). Three-year OS was 81.6%. Female sex (p = 0.05), cT1-T2 (p = 0.019), and well-differentiated tumors (p = 0.003) were associated with better OS. This unsupervised analysis demonstrates clear segregation, identifying that poor prognosis clusters associated with shorter DFS (HR = 1.66, 95% CI = 1.21–2.27, p = 0.0012) were enriched with locally-advanced disease, anal canal location, HPV-HIV coinfection, and non-CR. Conclusions: In conclusion, our results reinforce the prognostic value of T stage, N stage, sex, differentiation status, tumor location, and HIV-HPV coinfection in ASCC after CRT.
20-year incidence trends of anal squamous cell carcinoma.
Authors: Jhaveri Khushali , Modi Karnav , Sarfraz Humaira , Saha Aditi , Buhlmann Melanie , Schell Michael J. , Kim Richard D. 
Published: June 2023

e15503 Background: Anal Squamous Cell Carcinoma (SCCA) accounts for 90% of cases of anal cancer. ~95% of SCCAs are driven by Human Papilloma Virus (HPV). We did a follow-up population-based analysis to assess incidence trends of SCCA over 20 years (2000-2019) in era of HPV vaccination (available since 2006). Methods: Data was extracted from Surveillance, Epidemiology, and End Results (SEER) database for years 2000-2019. Joinpoint regression models were fitted to identify a discrete joints (year) that represented a statistically significant change in direction of the trend of overall SCCA incidence. The average annual percentage change (AAPC) in age-adjusted incidence rate in all subgroups pre- and post-2009 (statistically significant joinpoint year) was measured. (Table 1). Results: 30,294 new cases of SCCA were identified from 2000-2019, with majority in females (61.6%), white population (86.5%), and ages 40-79 years (84.1%). A significant joinpoint for SCCA incidence was observed in 2009, wherein APC of 2.8% (95% CI 2.0-3.6) in 2000-2009 was reduced to 0.5% (95% CI -0.1-1.2) in 2009-2019 (82% relative reduction [RR]). In subgroup analysis, evaluating the trends after identifying a discrete joint (2009), we found that APC for White population reduced from 3.1% (P < 0.0001) to 1.1% (P = 0.022) (65% RR), and for Black population, APC of 3.2% (P = 0.0015) seem to flatten out at 0.3% (P = 0.768) in post-2009 years (91% RR). Ages 20-39 had a -4.2% (P = 0.028) APC pre-2009 that showed increase to 1.3% (P = 0.214) post-2009, however, small sample size noted. In ages 40-59, APC of 4.7% (P < 0.0001) seem to flatten out at -0.5% (P = 0.393) (111% RR). Ages 60-79 had a similar APC (2.4% [P = 0.0011] and 2.5% [P = 0.0001], respectively). In males, APC of 2.8% (P = 0.002) flattened out to 0.5% (P = 0.249) and females reduced from 3.2% (P < 0.001) to 1.2% (P = 0.009). Conclusions: In this study, we found a trend of decrease in the rate of growth of SCCA incidence pre- and post-2009, overall and among various subgroups. Furthermore, our results suggest that widespread education and scaling up access to HPV vaccination can decrease and potentially reverse the SCCA incidence. [Table: see text]
The long journey of patients with anal carcinoma in a Mexican cohort.
Authors: Martinez Moyano Javier Alejandro , Reyna de la Garza Roberto Adrián , Torres-Cisneros Eduardo Rey , Hernandez Barajas David , Ruiz Sanchez Daneli , Burguete-Torres Alan , Alcorta Garza Adelina , González Guerrero Juan Francisco , Vidal-Gutiérrez Oscar 
Published: June 2023

e15504 Background: Yearly 1000 new cases of anal cancer will be diagnosed in the USA, in Mexico this information is limited. Increasing incidence is the reflection of improvements in knowledge of risk factors and diagnostic studies. Female sex, HPV infection, genital warts, number of sexual partners, receptive anal intercourse, smoking and HIV infection are well established risk factors. Methods: We performed a retrospective analysis of patients with pathology-confirmed anal carcinoma treated at an Oncology Reference Center in North-East Mexico from 2010 to 2020. Using the digital database of our center we searched the time passed since debut of symptoms to first medical contact, date of biopsy and first oncology consultation. Results: 81 patients were found in the database from January 2010 to December 2020. Forty-one patients were included in the final analysis, 11 patients where reassessed as rectal cancer and 29 patients only attended one consultation and did not continue follow up. Mean age at diagnosis was 61.4 +/- 13.8 years and 58.5% were women. 69% of patients had an education degree lower than highschool. HIV status was known only in 9.8% as they were living with HIV before the diagnosis of anal cancer was made, contrasting from 63.4% of cases who had unknown status at cancer diagnosis. The time from symptom onset until the patient attended a healthcare provider was a mean of 7.6 months (5 – 1000 days) and 11.4 months (9-1435 days) to receive a diagnosis. Patients had an average delay of 80 days from biopsy result to be evaluated by an oncologist. 44% of patients were initially misdiagnosed as hemorrhoids. None of the female patients had history of recent Pap smear test. 65% of patients had nodal involvement at presentation. Conclusions: There is notable delay between the onset of symptoms and diagnosis of anal cancer. This information is crucial for the general population and all healthcare providers not only oncology related workers. The stigma as well as the cultural barriers associated with this disease may negatively impact the prognosis and quality of life by delaying promptly treatment. Although it is a rare disease, conducting educational campaigns with the intention of improving clinical suspicion and an early recognition may shorten the long journey of patients bearing with anal carcinoma.