bluuebunny/crossref_metadata_2025 huggingface dataset:
INTEGRATE IIb: A randomized phase III open label study of regorafenib + nivolumab versus standard chemotherapy in refractory advanced gastroesophageal cancer (AGOC).
Authors: Pavlakis Nick , Shitara Kohei , Sjoquist Katrin Marie , Martin Andrew James , Jaworski Anthony , Yip Sonia , Oh Do-Youn , Moehler Markus H. , Bekaii-Saab Tanios S. , Simes John , Goldstein David
Published: January 2022

TPS366

Background: Advanced Gastro-oesophageal Carcinoma (AGOC) has a poor prognosis, and there is no established standard treatment following failure of first- and second-line chemotherapy. Regorafenib (BAY 73-4506) is an investigational oral multi-targeted tyrosine kinase inhibitor (TKI) which targets angiogenic (VEGF, TIE-2), stromal (PDGF-β), and oncogenic (RAF, RET and KIT) receptor tyrosine kinases, and has shown activity in this setting. Single agent regorafenib prolonged progression free survival (PFS) versus placebo across all regions/subgroups in the INTEGRATE randomised phase 2 trial. Current options in refractory AOGC involves sequencing through chemotherapy with the latest active agent approved being trifluridine/tipiracil, TAS-102. Promising activity in refractory AOGC has been seen with the combination of regorafenib & nivolumab. INTEGRATE IIb–will compare the effectiveness of the combination of regorafenib & nivolumab in pre-treated patients with AGOC to current standard chemotherapy. Methods: Randomised phase III, open label study with 2:1 randomisation (RegoNivo : standard chemotherapy) and stratification by: Geographic region (Asia vs. Rest of World); Prior VEGF inhibitors (Yes vs No); Prior immunotherapy (Yes vs No). RegoNivo arm will receive 90mg (3x30mg) of regorafenib days 1-21 of each 28-day treatment cycle with intravenous nivolumab 240 mg day 1 of each 14 day cycle until disease progression or prohibitive adverse events as per protocol. The control arm will receive the investigator’s choice of the following chemotherapy; a taxane (paclitaxel or docetaxel), irinotecan or oral trifluridine/tipiracil (TAS102). Primary endpoint: OS. Secondary endpoints: PFS, response rate, quality of life, toxicity, exploratory correlative biomarkers. Clinical trial information: NCT04879368.
SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations—Biliary tract cancer cohort.
Authors: Bekaii-Saab Tanios S. , Ramos Jorge , Tan Qianwen , Nakamura Yoshiaki
Published: January 2022

TPS489

Background: Tucatinib (TUC), a highly selective HER2-directed TKI approved in multiple regions for HER2+ metastatic breast cancer, is being investigated as a novel therapy for patients (pts) with metastatic colorectal cancer, gastric cancer, and other GI tumors. Preclinical and clinical data have shown HER2-targeted agents may improve clinical outcomes. In xenograft models of HER2+ and HER2-mutated tumors, dual targeting of HER2 with TUC + trastuzumab (Tras) showed superior activity to either agent alone (Kulukian 2020). Interim results from the MOUNTAINEER study have shown promising activity for TUC + Tras in HER2+ colorectal cancer. In 23 response-evaluable pts, an objective response rate (ORR) of 52% was observed with a median progression-free survival (PFS) of 8.1 months (mo) (Strickler 2019). The prognosis for pts with biliary tract cancers (BTCs) remain poor, and treatment options are limited. Given that approximately 12%-15% of BTC pts are HER2+, and 1%-8% have HER2 mutations, TUC + Tras warrants further evaluation in this patient population. The SGNTUC-019 basket study (NCT04579380) is evaluating TUC + Tras in pts with previously treated, locally advanced, unresectable or metastatic solid tumors including BTC that display HER2 overexpression/amplification or activating mutations. We describe the design of the BTC cohort. Methods: SGNTUC-019 is a multi-cohort, open-label, international Phase 2 study. Pts must be ≥18 years old; have an ECOG PS of ≤1; have adequate hepatic, hematological, renal, and cardiac functions; and have no previous exposure to HER2-directed therapy. BTC pts must have progressed on or after ≥1 previous line of treatment. The HER2+ BTC cohort will enroll 12 response-evaluable pts. If >2 responses are observed, the cohort will be expanded to 30 pts. HER2-mutated BTC patients may also be enrolled in a 30 pts cohort for other HER2-mutated solid tumors. The primary objective is antitumor activity with confirmed ORR as the primary endpoint. Secondary efficacy endpoints include disease control rate, duration of response, PFS, and OS. For eligibility, HER2 alterations can be demonstrated by HER2 overexpression/amplification in tumor tissue by prior IHC/ISH, or by HER2 amplification/mutation in a prior or on-study NGS assay of ctDNA or prior tissue NGS assay. Pts will receive TUC 300 mg orally twice a day and Tras 8 mg/kg intravenously on Cycle 1 Day 1 then 6 mg/kg every 21 days from Cycle 2 Day 1. Disease assessments per RECIST 1.1 are every 6 weeks for the first 24 weeks, then every 12 weeks. Quality of life will be evaluated every 2 cycles using EQ-5D-5L. Sites are currently enrolling within the US, EU and Asia-Pacific. Clinical trial information: NCT04579380.
Bridge-to-transplant stereotactic body radiation therapy in patients with hepatocellular carcinoma and advanced cirrhosis.
Authors: Hissourou Mohammad , Farsad Khashayar , Enestvedt C. Kristian , Fung Alice , Schlansky Barry , Naugler Willscott E , Nabavizadeh Nima
Published: January 2022

TPS496

Background: Liver cancer is the third most common cause of cancer related death worldwide, and hepatocellular carcinoma (HCC) accounts for 90% of all primary liver cancers, with pre-existing cirrhosis being a very strong risk factor for HCC development. Liver transplantation (LTx) is the best treatment for patients with HCC and advanced cirrhosis as both conditions can be very effectively treated at once. As LTx wait-lists can be many months, liver-directed therapies (LDT), including stereotactic body radiation therapy (SBRT) to one or few lesions are essential as oncologic temporizing measures to bridge patients to LTx and prevent progression outside of LTx criteria. However, due to the fear of further hepatic decompensation, many patients with advanced cirrhosis are excluded from receiving LDT. Rather, recent studies suggest that SBRT be of safe and practical use in this fragile patient population with advanced cirrhosis and HCC, and thereby reduce the rate of transplantation drop-out. This pilot prospective study will assess the feasibility, safety and efficacy of bridge-to-transplantation SBRT for patients with advanced cirrhosis and HCC. Methods: Patients with non-metastatic and unresectable HCC and Child-Pugh (CP)-B8 or worse cirrhosis who are within Milan criteria (one tumor ≤ 5 cm in diameter or no more than 3 tumors each ≤ 3 cm in diameter) and have been listed or recommended to be listed for liver transplantation will be eligible for participation. Eligible participants will undergo SBRT consisting of 40 Gy to be given in 5 fractions every other day to the only or largest lesion, provided that criteria for normal organ constraints are met. In cases where normal organ constraints are not met, the dose will be iteratively de-escalated to two dose levels (35 Gy in 5 fractions, then 30 Gy in 5 fractions). If normal organ constraints are unable to be met at 30 Gy in 5 fractions, the participant will be considered ineligible for SBRT and considered a screen failure. The primary endpoint is the proportion of participants who are transplanted or with localized disease control that meets Milan criteria within a year of SBRT. Secondary endpoints will include localized control rate (mRECIST), incidence of intra- or extra-hepatic progressive disease (mRECIST), overall survival, incidence of liver toxicity per CTCAE v5.0, incidence of non-classical radiation-induced liver disease (defined as CTCAE grade 4 AST/ALT elevation or an increase in CP score of ≥ 2 within 3 months of SBRT) and quality of life scores per QLQ-C30 and FACT-Hep questionnaires. The study is open, aiming to enroll 15 patients with 8 patients enrolled at time of submission. Clinical trial information: NCT03812289.
Comparing the outcome of doublet therapy (gemcitabine and cisplatin) with triplet therapy (gemcitabine, cisplatin and nab paclitaxel) in locally advanced or metastatic gall bladder carcinoma patients: An open-label randomized control trial.
Authors: Khatri Chandrani , Das Pratap K. , Patowary Jayanta
Published: January 2022

TPS497

Background: There are various studies evaluating the role of dual agent chemotherapy like gemcitabine and cisplatin in locally advanced or metastatic gall bladder cancer (1). This has been the standard of treatment up till now. Also there has been a single arm phase II trial of gemcitabine, cisplatin and nab-paclitaxel (triplet therapy) by Shroff et al (2) reporting an impressive data with RR (response rate) of 45 %, median PFS (progression free survival) of 11.8 months (5% CI; 6.0-15.6) and median OS (overall survival) was 19.2 months. This data was promising when compared to historical data of dual agents like gemcitabine and cisplatin. So it would be informative to conduct an RCT comparing doublet chemotherapy in locally advanced or metastatic GBC with triplet regimen chemotherapy. Methods: It is an open label randomized control study conducted in Indraprastha Apollo hospital New Delhi, India in newly diagnosed locally advanced or metastatic gall bladder cancer patients proven histologically and on imaging. The sample size calculated using the appropriate formula is, 27 in each arm that is total of 54 patients, but 60 patients will be enrolled in the study keeping in view 10% drop out rate. For simple randomization, we will use online computer generated random number table and then patients will be assigned in two groups, arms A and B. Arm A receiving two drugs gemcitabine 1,000mg/m2 i.v and cisplatin 25mg/m2 i.v on Day 1 and Day 8 of 21-day cycle and arm B receiving three drugs gemcitabine, 1,000 mg/m2, cisplatin, 25 mg/m2, and nab-paclitaxel, 125 mg/m2, on days 1 and 8 of 21-day cycle. Primary end point was response rates based on radiological response as per RECIST or PRECIST. Secondary end points were to determine median progression free survival and median overall survival and to evaluate the toxicities according to NCI-CTC v 4.0.Then response [on basis of RECIST or PRECIST criteria] will be seen after 3 and 6 cycles of chemotherapy are completed and at follow up of every 6 months for 2 years period for assessment of primary and secondary end points of the study. Statistical analysis for correlation between clinical and laboratory features and treatment outcomes will be done using the SPSS software. Till now we have enrolled 1 patient in each arm. CTRI/2021/09/036362. References: Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362:1273-81. Shroff RT, Javle MM, Xiao L, et al. Gemcitabine,Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers: A Phase 2 Clinical Trial JAMA Oncol 2019. Clinical trial information: CTRI/2021/09/036362.
A phase 1b/2, open-label study of tivozanib in combination with durvalumab in subjects with advanced hepatocellular carcinoma (Deductive).
Authors: Dayyani Farshid , Lee Arielle Shebay , Li Daneng , Rowe Julie Haewon , Beg Muhammad Shaalan , Kasturi Vijay , Iyer Renuka V.
Published: January 2022

TPS499

Background: Tivozanib (T, a potent and selective VEGFR 1, 2 & 3 TKI) and durvalumab (D, a PD-L1 antibody) have both demonstrated single agent activity in HCC and have been combined safely with other therapies. T blocks all three VEGF receptors, and when combined with a PD-L1 inhibitor may improve patient outcomes. The combination of atezolizumab and bevacizumab (which blocks VEGF-A ligand binding to VEGFR2) has improved the standard of care in advanced hepatocellular cancer with a median PFS of 6.8 months and 1-year overall survival of 67.2%. All the currently used agents in the second-line setting, have been evaluated in pts with HCC only after exposure to sorafenib. Treatment option for the patients with HCC that progress on atezolizumab and bevacizumab, are therefore limited. Methods: Deductive (NCT03970616) is a phase 2, multicenter, open-label study to assess the safety and efficacy of tivozanib in combination with durvalumab in patients with advanced HCC. Cohort A (n=20) includes patients with untreated advanced HCC. Cohort B (n=20) includes patients with advanced HCC who have progressed on/after treatment with prior bevacizumab and atezolizumab. Eligibility criteria include age >18 years, histologically or cytologically confirmed HCC, measurable or evaluable disease, Child-Pugh Class A, and ECOG PS of 0 or 1. Subjects will receive tivozanib 0.89 mg orally once daily for 21 consecutive days followed by 7 days off, and durvalumab 1500 mg intravenously every 4 weeks, and will be treated until progression or unacceptable toxicity. Study assessments include CT scan or MRI of the chest, abdomen, and pelvis every 8 weeks following Cycle 1 Day 1 until the end of treatment, and every 12 weeks during the first year and every 6 months thereafter until disease progression or start of another anti-cancer therapy. The primary objective is to establish the safety and tolerability of tivozanib in combination with durvalumab in subjects who are untreated (cohort A) or have been pre-treated with both bevacizumab and atezolizumab (cohort B). Secondary endpoints include estimation of objective response rate (ORR), median PFS and OS. Exploratory endpoints are to assess the durvalumab pharmacokinetics in the presence of tivozanib. Deductive is currently enrolling at 12 sites in the United States. Clinical trial information: NCT03970616.
HELIX-ICC: An-open label phase II trial of induction systemic mFOLFIRINOX followed by concurrent hepatic arterial infusion of floxuridine and systemic mFOLFIRI for unresectable intrahepatic cholangiocarcinoma.
Authors: Walker Brett S , Kardosh Adel , Eil Robert , Wong Melissa , Fung Alice , Brody Jonathan , Anand Sudarshan , Corless Christopher L. , Hansen Lissi , Rosenkranz Susan , Park Byung , Chen Emerson Yu-sheng , Jackson Anna , Vo Johnson , Fahlman Anne , Rocha Flavio G. , Lopez Charles D. , Goodyear Shaun , Mayo Skye C.
Published: January 2022

TPS500

Background: The majority of patients with intrahepatic cholangiocarcinoma (ICC) present with advanced liver dominant disease rendering them unresectable. The current standard of care supports palliative treatment of unresectable ICC with gemcitabine plus cisplatin. Alternatively, continuous liver-directed therapy using a surgically implanted hepatic arterial infusion (HAI) pump allows for maximal treatment of liver tumors with limited systemic side-effects and can facilitate conversion to a resectable status. No prospective clinical trial has utilized FOLFIRINOX in combination with HAI floxuridine-dexamethasone for ICC. Methods: HELIX-ICC is a first-line, single-center, single-arm, phase II clinical trial enrolling patients with liver-dominant unresectable or multifocal ICC. Only patients with microsatellite stable cancer and no prior liver radiotherapy will be included. Patients are administered dose-modified FOLFIRINOX systemically for 4 cycles over 8 weeks. Those with evidence of disease control on restaging imaging and laparoscopy will proceed to HAI pump placement. Treatment continues with two 28-day cycles of combined HAI floxuridine (1.08 mg/kg) with dexamethasone for 14 days and systemic dose-modified FOLFIRI starting on day 15. The primary objectives are to evaluate the safety and efficacy (disease control rate [DCR] at 6 months) of this novel treatment approach that utilizes our institutional dose-reduced HAI floxuridine protocol in combination with modified systemic regimens to facilitate control of liver disease and maximize patient quality of life (QoL). HELIX-ICC includes many exploratory analyses through longitudinal collection of blood samples, liver biopsies (including an end of trial research biopsy), and QoL metrics (Table). The study is open to n = 30 with an initial safety run-in of 6 patients, of which 4 have enrolled at the time of submission. This study is designed to allow for drop out of 9 patients, with total accrual of 21 patients to protocol completion achieving 80.2% power at 0.05 significance to detect a 25% increase in DCR at 6 months. Clinical trial information: NCT04251715. [Table: see text]
Randomized phase II study of nalicap (nal-IRI/capecitabine) compared to NAPOLI (nal-IRI/5-FU/LV) in gemcitabine-pretreated advanced pancreatic cancer: Trial-in-progress.
Authors: Oh Do-Youn , Kim Jin Won , Lee Myung Ah , Kim Ilhwan , Lee Choong-kun , Seol Young Mi , Yoo Changhoon , Oh Sang Cheul , Bae Woo Kyun , Chon Hongjae , Choi In Sil , Yoon Jeesun , Park Joon Oh
Published: January 2022

TPS621

Background: Liposomal irinotecan (nal-IRI) in combination with fluorouracil (5-FU) and folinic acid (LV), called the NAPOLI regimen, improves survival in advanced pancreatic cancer patients who failed gemcitabine-based chemotherapy (Wang-Gillam A et al. 2016). Capecitabine is an oral anti-cancer agent as the prodrug of 5-FU. Capecitabine has proven its efficacy in gastrointestinal cancers like stomach cancer, colon cancer, or pancreatic cancer. Replacing continuous 5-FU infusions with oral capecitabine with equivalent efficacy has been tested and is now widely used. However, in pancreatic cancer, replacing continuous infusion of 5-FU with an oral drug has not yet been tested. Therefore, this trial is being conducted with the aim of improving patient convenience while maintaining efficacy, when the continuous infusion of 5-FU/LV in NAPOLI (nal-IRI/5-FU/LV) regimen are replaced with oral capecitabine. This study is a two-arm, open-label, multicenter, randomized phase 2 trial to assess whether capecitabine plus nal-IRI combination treatment (NaliCap) is non-inferior to NAPOLI regimen in gemcitabine-pretreated patients with advanced pancreatic cancer. Methods: Eligible patients have histologically confirmed pancreatic adenocarcinoma who have failed to gemcitabine-based chemotherapy. This trial is composed of two parts: safety lead-in-part and randomization part. NaliCap regimen consists of administration of capecitabine twice daily for day 1-14 and intravenous administration of nal-IRI for day 1 every 3weeks. To figure out recommended phase 2 dose of the NaliCap combination regimen, the safety lead-in-part is being conducted as a 3+3 design. In the randomization part, patients will be assigned to NAPOLI or NaliCap in a 1:1 ratio. The planned enrollment is 184 patients in the randomization part. Patients allocated to the NaliCap group will receive recommended phase 2 dose of NaliCap determined through the safety lead-in-part. Patients allocated with the NAPOLI group will receive nal-IRI 70mg/m2 intravenously day 1, LV 400mg/m2 IV day 1, and continuous 5-FU 2400mg/m2 infusion over 48hours every 2weeks. Response assessments are performed every 6 weeks using the RECIST criteria version 1.1 (every 2 cycles in the NaliCap group and every 3 cycles in the NAPOLI group). The primary endpoint is progression-free survival, with a non-inferior margin of the hazard ratio of 1.4. Key secondary endpoints are overall response rate, disease control rate, overall survival, safety, and quality of life. This study is prospectively registered at ClinicalTrials.gov, NCT04371224. Clinical trial information: NCT04371224.
An open, single-center, exploratory clinical trial to evaluate the safety and efficacy of RNA CAR-mesothelin T cells in patients with advanced refractory pancreatic cancer.
Authors: Yang Hui , Guo Liting , Zhou Chenfei , Liu Xiaojun , Zhao Yangbing , Zhang Jun , Shi Yan
Published: January 2022

TPS628

Background: Pancreatic cancer is an aggressive gastrointestinal cancer characterized by late diagnosis initially, prone to distant metastasis and poor prognosis. The current treatment of pancreatic cancer is very limited, resulting in its 5-year survival rate of less than 10%. It is necessary to seek new treatment methods and treatments. Chimeric antigen receptor T (CART) cell therapy has made a breakthrough in hematological malignancies. Therefore, the goal of this clinical trial is to study the safety, efficacy and pharmacokinetics of mRNA-engineered anti-Mesothelin Chimeric Antigen Receptor T-Cell (anti-MESO CAR-T cells) therapy in patients with mesothelin expression-positive, advanced pancreatic tumors that have failed at least first-line or second-line therapy. Methods: The study will adopt the "3+3" dose escalation design exploring two doses of 1×109 and 3×109. The administration is planned to infuse 3 times a week for 2 consecutive weeks. The subjects will receive a total dose of 1x109 RNA transduced anti-MESO CAR-T cells in the first week, following lymphodepleting chemotherapy with cyclophosphamide 300 mg/m2/day and fludarabine 30 mg/m2/day given over 3 days by intravenous infusion. If there is no obvious dose-limiting toxicity (DLT) after the first week of infusion, three times consecutive infusions of 1x109 anti-MESO CAR-T cells each time is planned in the second week. Each subject needs to be observed for at least 2 weeks (14 days) after completing the last infusion. Lymphodepleting chemotherapy will not be repeated prior to additional infusions of anti-MESO CAR-T cells. Clinical trial information: 04981691.
A phase I study to evaluate the safety and tolerability of SX-682 in combination with PD-1 inhibitor as maintenance therapy for unresectable pancreatic adenocarcinoma.
Authors: Dunne Richard Francis , Ullman Nicholas A. , Belt Brian A. , Ruffolo Luis I. , Burchard Paul , Hezel Aram F , Zittel Jason , Wang Wenjia , Ramsdale Erika E. , Kaul Vivek , Zebala John , Linehan David
Published: January 2022

TPS631

Background: Survival outcomes for advanced pancreatic ductal adenocarcinoma (PDAC) remain dismal despite improvements in systemic therapy regimens developed over the past decade. In addition, current first-line therapies result in cumulative cytopenias and neuropathy, highlighting the need for more effective, less toxic maintenance treatment strategies. There are currently no standard approved maintenance treatments for patients with PDAC not associated with BRCA or DNA-repair mutations. Pre-clinical data suggest a potential synergistic effect of combining blockade of CXC chemokine receptors (CXCR) with immunotherapy or chemotherapy in pancreatic cancer1,2. We are currently conducting a Phase I study (NCT04477343) evaluating SX-682, an oral CXCR1/2 inhibitor, and Nivolumab as maintenance treatment for advanced PDAC. Methods: This is an open-label, dose escalation Phase I clinical trial evaluating the combination of SX-682 and Nivolumab. Patients must have histologically confirmed unresectable PDAC and have completed at least 16 weeks of first-line chemotherapy with disease stability or treatment response at time of enrollment. Radiographically measurable disease must be present per iRECIST criteria. Patients receive a 3-week run-in phase of twice-daily dosing of SX-682, followed by combination of twice-daily dosed SX-682 and every 2-week Nivolumab (240 mg IV). Dose finding of SX-682 is performed using Bayesian optimal interval (BOIN) design to determine the maximum tolerated dose (MTD) when combined with Nivolumab. Pre-treatment and one on treatment (Day 28-35) biopsies are required for enrollment to evaluate change in tumor microenvironment immune cell composition by single cell-RNA sequencing, flow cytometry, RNA RT-qPCR, and IHC. The primary endpoint is to determine MTD; the key secondary endpoint is progression-free survival (PFS), defined as the time from enrollment to progression via iRECIST criteria or death. Nine of a planned 20 patients have been enrolled. Dose-level 1 (SX-682 50 mg BID) completed enrollment without dose-limiting toxicity (DLT). Dose-level 2, which commenced in June 2021, (SX-682 100 mg BID) is without DLTs, but has not completed enrollment at time of abstract submission.

Nywening TM, Belt BA, Cullinan DR, et al. Targeting both tumour-associated CXCR2(+) neutrophils and CCR2(+) macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma. 1) Gut. 2018;67(6):1112-1123.

Steele CW, Karim SA, Leach JDG, et al. CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma. 2) Cancer Cell. 2016;29(6):832-845. Clinical trial information: NCT04477343.
Biomarker-oriented study of pembrolizumab in combination with chemotherapy in chemotherapy-naïve advanced pancreatic cancer: A phase 2 trial-in-progress.
Authors: Yoon Jeesun , Kim Jin Won , Kim Ji-Won , Kim Tae-Yong , Nam Ah-Rong , Bang Ju-Hee , Kim Jae-Min , Oh Kyoung Seok , Oh Do-Youn
Published: January 2022

TPS639

Background: Pancreatic cancer (PC) is well-known as a strongly immunosuppressive tumor. The tumor microenvironment of PC play a fundamental part in maintaining a non-immunogenic and immuno-suppressive environment through the production of inhibitory cytokines and complex interaction between tumor cells, regulatory T cells, and myeloid-derived suppressor cells (Li KY et al. 2020). However, through integrated genomics and immunophenotyping, the immune-rich type had a relatively good prognosis in advanced PC (Wartenberg M et al. 2018). Based on this, various attempts have been made to apply immune checkpoint inhibitor (ICI) to PC. Disappointingly, ICI monotherapy is ineffective in most advanced PCs, and a strategy of combining ICI with ICI, chemotherapy or targeted therapy has been recently tried. However, the mechanism of immune modulation induced by ICI in combination with chemotherapy in PC is still not well-known, so biomarker studies are needed to understand the role of immunotherapy in advanced PC. Also based on this, it is expected to develop an effective ICI treatment strategy in PC. This study is a non-randomized, parallel assignment phase 2 trial aimed to explore dynamic modulation of the immune system caused by co-administration of pembrolizumab and cytotoxic chemotherapy in patients with advanced PC. Methods: Eligible patients have recurred or metastatic pancreatic cancer. Patients who have received chemotherapy for advanced PC are excluded, except for previous adjuvant chemotherapy. Patients who have received ICI are excluded. There are 2 chemotherapy cohorts (FOLFIRINOX, n=41; Gemcitabine/Nab-paclitaxel, n=36). Patients enrolled in the FOLFIRINOX cohort will receive pembrolizumab 200mg intravenously once every 3 weeks, plus FOLFIRINOX chemotherapy every 2 weeks. In Gemcitabine/Nab-paclitaxel cohort, patients will receive gemcitabine 1000mg/m2 plus nab-paclitaxel 125mg/m2 day 1, 8, 15 of a 4-week cycle, plus pembrolizumab 200mg intravenously once every 3 weeks. The primary endpoint is objective response rate, with key secondary endpoints including progression-free survival, duration of response, disease control rate, overall survival, safety, and patient-reported outcome. For evaluating metabolic response, 18F-FDG PET-CT scan will be conducted before treatment and at the first response evaluation. Tumor tissue biopsies are performed three times in total: screening, the first response evaluation, and disease progression. Blood samples are being collected every cycles for translational biomarker studies. Clinical trial information: NCT04447092.
Generic anisotropic Lifshitz scalar field theory: New massive minimal subtraction
Authors: Leite Marcelo M.
Published: January 2022

We formulate the simplest minimal subtraction version for massive

scalar fields with O(N) symmetry for generic anisotropic Lifshitz spacetimes. We introduce the simplest geometric concepts to define it as a special manifold. Then we restrict ourselves to flat Euclidean spaces. An appropriate partial-p operation is applied in the bare two-point vertex function diagrams, which separates the original diagram into a sum of two different integrals which are the coefficients of the corresponding polynomials in the mass and external momentum. Within the proposed method, the coefficient of the mass terms can be discarded and we obtain a minimal subtraction method almost identical to the same scheme in the massless theory in every external momentum/mass subspace. We restrict our demonstration of the method up to three-loop order in the two-point vertex part. We verify its consistency through a diagrammatic computation of static critical exponents, which validates the universality hypothesis.
A model for DHX15 mediated disassembly of A-complex spliceosomes
Authors: Maul-Newby Hannah M. , Amorello Angela N. , Sharma Turvi , Kim John H. , Modena Matthew S. , Prichard Beth E. , Jurica Melissa S.
Published: January 2022

A critical step of pre-mRNA splicing is the recruitment of U2 snRNP to the branch point sequence of an intron. U2 snRNP conformation changes extensively during branch helix formation, and several RNA-dependent ATPases are implicated in the process. However, the molecular mechanisms involved remain to be fully dissected. We took advantage of the differential nucleotide triphosphates requirements for DExD/H-box enzymes to probe their contributions to in vitro spliceosome assembly. Both ATP and GTP hydrolysis support the formation of A-complex, indicating the activity of a DEAH-enzyme because DEAD-enzymes are selective for ATP. We immunodepleted DHX15 to assess its involvement, and although splicing efficiency decreases with reduced DHX15, A-complex accumulation incongruently increases. DHX15 depletion also results in the persistence of the atypical ATP-independent interaction between U2 snRNP and a minimal substrate that is otherwise destabilized in the presence of either ATP or GTP. These results lead us to hypothesize that DHX15 plays a quality control function in U2 snRNP's engagement with an intron. In efforts to identify the RNA target of DHX15, we determined that an extended polypyrimidine tract is not necessary for disruption of the atypical interaction between U2 snRNP and the minimal substrate. We also examined U2 snRNA by RNase H digestion and identified nucleotides in the branch binding region that become accessible with both ATP and GTP hydrolysis, again implicating a DEAH-enzyme. Together, our results demonstrate that multiple ATP-dependent rearrangements are likely involved in U2 snRNP addition to the spliceosome and that DHX15 may have an expanded role in maintaining splicing fidelity.
Συγκριτική μελέτη αερισμού με διαφυγή και χωρίς διαφυγή στην έκβαση της παρατεταμένης νεογνικής ασφυξίας
Authors: Δουβανάς Αλέξανδρος
Published: January 2022

Εισαγωγή: Η σοβαρή και παρατεταμένη ασφυξία μπορεί να έχει ως αποτέλεσμα είτε τον ενδομήτριο εμβρυϊκό θάνατο όσο και τον θάνατο στον τοκετό ή την πολυοργανική ανεπάρκεια στα επιζώντα νεογνά. Η διασφάλιση αποτελεσματικού αερισμού είναι ο πρωταρχικός στόχος της αναζωογόνησης σε νεογνά με ασφυξία. Σκοπός αυτής της μελέτης ήταν η διερεύνηση της έκβασης της παρατεταμένης νεογνικής ασφυξίας μετά από ανάνηψη που πραγματοποιείται με αερισμό με Ενδοτραχειακό Σωλήνα με διαφυγή ή χωρίς διαφυγή. Υλικό και Μέθοδος: Πρόκειται για μια προοπτική, τυχαιοποιημένη ελεγχόμενη εργαστηριακή μελέτη. Χρησιμοποιήθηκαν 30 νεογνά χοιρίδια (Landrace/Large-White), ηλικίας 1-4 ημερών και βάρους 1.754±218 gr. Τα ζώα τυχαιοποιήθηκαν σε 3 διαφορετικές ομάδες ανάλογα με τον ενδοτραχειακό σωλήνα (ΕΤΤ) που είχαν διασωληνωθεί . Η Ομάδα C (ελάχιστη διαφυγή, ΕΤΤ no 4.0, n=10), Ομάδα A (μεγάλη διαφυγή, EΤΤ no 3.0, n=10) και η Ομάδα Β (μέτρια διαφυγή, ΕΤΤ no 3.5, n=10). Υποβλήθηκαν σε ασφυξία και αφέθηκαν χωρίς θεραπεία έως ότου ο καρδιακός ρυθμός ήταν μικρότερος από 60 bpm ή η μέση αρτηριακή πίεση ήταν κάτω από 15 mmHg. Σε όλα τα ζώα με ανάκτηση αυτόματης κυκλοφορίας (ROSC) παρακολουθούταν για 4 ώρες οι αιμοδυναμικές τους παράμετροι, ο αρτηριακός κορεσμός οξυγόνου και τα επίπεδα γαλακτικού οξέος.Αποτελέσματα: Βρέθηκε ότι το 70% των ζώων που επέζησαν οξυγονώνονταν με ΕΤΤ με διαφυγή (νούμερο 3,5 και 3). Παρατηρήθηκε στατιστικά σημαντική διαφορά στην PO2 (p=0,032) στο Group B (126.4±53,4 mmHg) σε σχέση με το Group A (72.28±29.18mmHg) και το Group C (94.28±20.46mmHg) και επίσης στη Πίεση του Δεξιού Κόλπου (p<0.001) ανάμεσα στο Group C (4,5mmHg) σε σχέση με τα Groups A (2mmHg) και B (2mmHg) στη φάση ROSC. Τα επίπεδα Γαλακτικού Οξέος ήταν στατιστικά σημαντικά χαμηλότερα (p=0.035) στο Group C (mean=0.92± 0.07mmol/L) σε σχέση με το Group A (mean=1.13±0.1mmol/L) και το Group B (mean= 1.08 ± 0.07mmol /L; p = 0.034) 4h μετά την φάση ROSC. Συμπέρασμα: Η μελέτη μας δείχνει ότι η διασωλήνωση με ΕΤΣ με διαφυγή βελτίωσε σημαντικά τη ROSC στα 30 δευτερόλεπτα και την επιβίωση σε μοντέλο χοίρου ανάνηψης νεογνών. Τα Landrace/Large λευκά χοιρίδια έχουν πολύ καλή προσαρμογή για τον πειραματισμό σε νεογνική υποξία
Comparisons of the effects of solute interactions on partition coefficient, kD, in selected binary immiscible solvents: a case of oxalic acid and succinic acid
Authors: V. O. Onyeocha , A. I. Onuchukwu , R. E. Enemo
Published: January 2022

Background: The molecular distributions of solutes in binary immiscible solvents as used in partition coefficient technique serve as measures of the solute separation, concentration and beneficiation from contaminants.

Methods: The effects of solute interactions on partition coefficient, kD, in selected binary immiscible solvents were investigated at 300C and atmospheric pressure. The activities from the interactions with changes of concentrations within the solvents were analysed. These were done using simple titration method. The solutes were distributed in the binary solvents and the concentrations from the two layers formed were determined by titration method. The interactions of oxalic acid and succinic acid in carbon tetrachloride-water, diethyl ether-water, and n-hexane-water were studied for the partition coefficient values in the respective systems, to determine the nature and degree of the interfering reactions that are affecting the distributions, and to ascertain the best binary solvents from the three systems.

Results: Oxalic acid has the partition coefficient of 0.0738 in carbon tetrachloride-water with the dimerization constant of -15.7092 and ionization constant of 0.0303. Oxalic acid has the distribution coefficient of 0.0173, dimerization constant of 144.0167 and the ionization constant of 0.0035 in diethyl ether-water. Oxalic acid has the partition coefficient of 0.0279, dimerization constant of 20.2798 and ionization constant of 0.0019 in n-hexane-water. Succinic acid has the partition coefficient of -0.05617, dimerization constant of -18.5655 and ionization constant of 0.0284 in carbon tetrachloride-water. In diethyl ether-water, succinic acid has the partition coefficient of 0.0427, dimerization constant of -18.1611 and ionization constant of 0.0332. In n-hexane-water, succinic acid has the partition coefficient of -0.04274, dimerization constant of 71.9491 and ionization constant of 0.0265.

Conclusion: From these results, carbon tetrachloride-water is recommended for the purification and extraction of oxalic acid from contaminants. Carbon tetrachloride-water is also the best binary immiscible solvent for succinic acid.
Analysis of the Results of a Complex of Monitoring Studies on Socio-Economic Mechanisms for the Implementation of E-Learning and Distance Learning Technologies
Authors: Dorogavcev A. , Ganeev A.
Published: January 2022

The article discusses the features of the transition of Russian education to distance learning. The most common problems that have arisen in connection with the new training format have been identified. The need to assess the compliance and readiness of educational organizations, teachers, students and their families to introduce a distance learning regime is indicated. In connection with this need, the importance of conducting a set of monitoring studies related to various socio-economic mechanisms for the implementation of e-learning and distance learning technologies, including models of financial, economic and resource support for distance learning at the level of the constituent entities of the Russian Federation, educational organizations, teachers, students and their families in the context of the transition to the specified format of classes. The results of the analysis of a complex of monitoring studies on the socio-economic mechanisms of the implementation of e-learning and distance learning technologies of various target groups are considered. Studies of strategies / models / organizational forms of ensuring the implementation of e-learning were carried out, an assessment of the financial, economic, methodological and resource support of distance learning at the level of regions, educational organizations and families was carried out, possible ways of forming an ecosystem of the digital economy in the general education system at the regional level were determined, studying the current conditions for ensuring the implementation of e-learning and the use of distance learning technologies in the context of the region, educational organization and family, assessed the level of the teacher's skills in working in the context of the implementation of e-learning and the use of distance learning technologies in the educational organization, as well as assessing the degree of parental satisfaction with the quality of educational process in the context of the implementation of e-learning. The advantages and disadvantages of the transition of educational organizations to distance learning are noted.
Formation of Foreign Language Communicative Competence in Teaching a Foreign Language in Higher Education
Authors: Maklakova E.
Published: January 2022

The article examines the concepts of competence and competence on the example of foreign language proficiency on the example of higher education; the types of competence are analyzed, attention is paid to the communicative competence of students necessary for effective professional communication with representatives of foreign countries and cultures.
Model and Pedagogical Conditions for Preparing a Future Teacher for the Implementation of Psychological and Pedagogical Support for Intellectually Gifted Schoolchildren
Authors: Nikitina E. , Sharonova O.
Published: January 2022

In this article, the authors consider the structural components of a future teacher's readiness to provide psychological and pedagogical support for intellectually gifted schoolchildren. The authors present the model as a certain system of organization, management and implementation of practical activities for the preparation of future teachers for the implementation of psychological and pedagogical support of gifted schoolchildren.
On the Design of a Model of Vocational Guidance Work with High School Students
Authors: Bakurova N.
Published: January 2022

This article analyzes the conditions for creating a model of career guidance at a civil aviation university. It describes the creation and description of the interactive model of professional orientation of civil aviation university students in interaction with educational institutions of secondary general education. The advantage of online career guidance services over traditional methods is shown.
Dziewiętnastowieczna polszczyzna cieszyńska – w prasie, szkole, kościele
Authors: Raclavská Jana
Published: January 2022

Wiek XIX był dla germanizowanych mieszkańców Śląska Cieszyńskiego, znajdującego się pod panowaniem dynastii Habsburgów od pierwszej połowy XVI wieku, niezwykle bogaty w wydarzenia polityczne i kulturalne. Skutki Wiosny Ludów oraz uświadomienie wspólnoty Cieszynian z narodem polskim i jego tradycjami prowadziły do zacieśniania kontaktów z językiem i kulturą polską. Stan ten przejawił się w upowszechnieniu polszczyzny ogólnej wśród mieszkańców Śląska Cieszyńskiego, szczególnie jej odmiany pisanej. Analizowane dokumenty polskie z XIX wieku zawierają elementy innojęzyczne, przede wszystkim zaś czeskie i niemieckie. Z drugiej strony obecność pierwiastków staro- i średniopolskich we wszystkich planach językowych świadczy o peryferyjności, ale i zachowawczości polszczyzny cieszyńskiej badanego okresu.
Tradycyjne wartości polskie – źródłem siły i nadziei kobiet walczących o suwerenność Polski w latach 1945–1956
Authors: Kryńska Elwira
Published: January 2022

W latach 1945–1956, gdy nastąpiła nasilona indoktrynacja polityczna, doszło do utraty „pojęcia człowieka jako osoby o przyrodzonych, nienaruszalnych prawach osobowych, stworzono dla niego […] polityczne, prawne i kulturowe formy represji”. Przestrzeń życiowa była wyznaczona przez władze partyjno-państwowe narzucające „moralność socjalistyczną” i „stalinowski dyskurs o istocie ludzkiej”. Tych, którzy nie poddali się totalitarnej militaryzacji rzeczywistości, uznano za wrogów „ludowej ojczyzny”. Sowietyzacja kraju spowodowała opór patriotyczny i działalność konspiracyjną. Przeciwników „nowego ustroju” osądzano w majestacie „ludowego prawa” zgodnie z „formalnym kodeksem sądowym”. Wśród tej olbrzymiej rzeszy skazanych przez Wojskowe Sądy Rejonowe były kilkunastoletnie dziewczęta i bardzo młode kobiety oskarżone o udział w konspiracyjnych organizacjach niepodległościowych. Zdecydowały się one wspierać podziemny ruch oporu mimo stosowanych przez komunistyczny reżim cynicznych aktów zastraszania, tortur, wyroków śmierci i długoletniego więzienia. Źródłem ich siły były polskie tradycje patriotyczne oparte na idei rycerza bez trwogi i skazy, obrońcy ojczyzny, wierne hasłu: „Bóg, honor, Ojczyzna”.
Tożsamość językowa Gruzinów a język rosyjski
Authors: Przybyłowska Gvantsa
Published: January 2022

Droga do zachowania języka gruzińskiego jako języka państwowego w sytuacjach zagrożenia była trudna. Te procesy nie trwały po 20–50 lat, ale o wiele dłużej. W różnych okresach historycznych Gruzja była okupowana, dzielona przez „inne”, „obce” narody, które kulturowo nie miały wiele wspólnego z Gruzją. Kultura gruzińska mocno ucierpiała, w tym język gruziński. W Gruzji znajomość języka rosyjskiego, jak pokazują wyniki, nadal jest na wysokim poziomie. Ci, którzy urodzili się w ZSRR lub krótko po rozpadzie Związku Radzieckiego, musieli się uczyć języka rosyjskiego. Znajomość czy nieznajomość języka może być tylko kwestią znajomości obcych języków w danym państwie, a nie musi koniecznie być związana z prorosyjską polityką państwa. W propagandzie nauczania języka rosyjskiego dużą rolę mogą odgrywać dobre stosunki z Rosją (np. niektóre kraje postradzieckie), ale nie zawsze tak musi być (np. w przypadku Gruzji). Wysoki odsetek osób znających język rosyjski może być spowodowany położeniem geograficznym (kraj sąsiadujący z Rosją), historią (Imperium Rosyjskie, ZSRR), interesami (wysoki procent rosyjskich inwestycji, np. w Armenii), edukacją („najlepsze” uniwersytety są w Rosji, więc warto się uczyć rosyjskiego), kulturą (Słowianie) itd.
The effect of dietary fat supplements on the activity of palmitic and stearic acid desaturases based on the results of a study of the fatty acid composition of neutral lipids in blood serum and liver of rats receiving a fat-free diet
Authors: Levitsky A. , Gozhenko A. , Velichko V. , Selivanskaya I.
Published: January 2022

Background. Desaturase enzymes are involved in the formation of monoenoic acids from saturated fatty acids. One such enzyme is stearyl-CoA-desaturase (SCD1), which converts stearic acid to oleic acid. The aim of this work was to determine the effect of edible fats with different fatty acid compositions on SCD1 activity.

Methods. High linoleic sunflower oil (HLSO), high oleic sunflower oil (HOSO) and palm oil (PO) were used. The rats were fed for 30 days with a semi-synthetic diet that did not contain any fats (FFD) and fat diets containing 5 % of each of the above oils. In animals, lipids were extracted from serum and liver and divided into 3 fractions: neutral lipids (NL), phospholipids (PL), and free fatty acids (FFA).

The fatty acid composition of each fraction was determined by gas chromatography. The SCD18 activity was determined by the C18:1 n-9/C18:0  ‒ ratio, and the SCD16 activity was determined by the C16:1 n-7/C16:0  ratio.

Results. A higher activity of SCD16 and SCD18 was found in the NL fraction, and the activity of SCD18 significantly exceeds that of SCD16. A decrease in the content of C16:0, C16:1 and C18:0 in the NL fraction of the liver and blood serum was shown. The activity of SCD16 in blood serum and liver decreases in rats fed fat diets­, while the activity of SCD18 does not decrease, and even increases with the consumption of HOSO.­

Conclusions. To determine the SCD1 activity, it is advisable to use the C18:1/C18:0 ratio in terms of the level of fatty acids in the NL fraction. Fatty diet inhibits SCD16 activity, and consumption of HOSO increases SCD18 activity.
Acercamiento Cualitativo a la Emancipación Residencial en Periodos de Crisis.
Authors: Echaves-García Antonio , Echaves-García Carlos
Published: January 2022

La emancipación residencial es un fenómeno que despierta un gran interés académico, político y social. Más allá del claro efecto que la crisis económica, iniciada en 2008, tuvo en este proceso en España, retrasando la salida del hogar familiar/de origen por parte de los jóvenes, la realidad a la que se enfrenta este colectivo en la actualidad sigue siendo problemática. Siguen existiendo contextos adversos que dificultan el tránsito a la independencia residencial, y así lo han constatado numerosas investigaciones sociológicas, la mayoría de carácter cuantitativo. En el presente artículo, y desde una aproximación cualitativa, se analiza el fenómeno de la emancipación residencial en España recurriendo a reuniones de grupo (para emancipados y no emancipados) realizadas en 2014. Llevadas a cabo en distintas ciudades, se recogen así percepciones, valoraciones e interpretaciones que hacen los jóvenes de la realidad en la que se encuentran inmersos y se constatan los factores que actúan de freno, principalmente el mercado de trabajo y la vivienda.
Territorios Segregados. Experiencias de Dignificación frente a la Exclusión Socioterritorial.
Authors: Rodríguez-Rejas María-José
Published: January 2022

El artículo aborda las respuestas de un barrio, Polígono Sur (Sevilla), que se enfrenta a la estigmatización socioterritorial. Se analiza el peso de los impactos sociales e ideológico-culturales de la exclusión en su (in)visibilización. Metodológicamente se recurrió a las herramientas de la geografía del poder y se trabajó con entrevistas narrativas de 24 vecinas y vecinos sobre trayectorias y diagnóstico del tejido social en tres proyectos significativos orientados al mejoramiento barrial, con resultados reconocidos: el CEIP Andalucía, la Residencia Universitaria Flora Tristán, y el grupo de adultas mayores “Instrucción General Básica para la Vida”. La narrativa del relato, desde la perspectiva de Bertaux y Caicedo, permitió articular memoria, experiencia y utopía, como proyección de futuros en potencia. Los resultados revelan la incidencia de la ideología del “no merecimiento” de los pobres (undeserving poor) en la narrativa hegemónica, que invisibiliza a los desfavorecidos y sus experiencias dignificadoras, así como su potencial de transformación.
La influencia de Instagram en la creación y reproducción del ideal de belleza femenino
Authors: Martín Teresa , Chaves Vázquez Beatriz
Published: January 2022

Las redes sociales hacen gala de una gran presencia en la sociedad contemporánea, afectando incluso cómo percibimos los cánones de belleza. Este trabajo estudia la posible influencia del fenómeno de los influencer en la reproducción del ideal de belleza femenino, analizando los contenidos publicados en Instagram por algunas de estas figuras públicas e indagando en el tipo de uso que hacen las personas anónimas de esta red social. Para ello, se ha recurrido a una metodología mixta compuesta por un análisis de contenido cualitativo de las publicaciones y una encuesta en línea (n= 509). La presente investigación ha permitido comprobar, entre otros aspectos, cuál es el patrón de belleza que impera en Instagram y las posibles evoluciones sobre el canon de belleza “tradicional”, dictaminando si existen implicaciones de género en dichos estereotipos.
Consumer Search, Price Promotions, and Counter-Cyclic Pricing
Authors: Haviv Avery
Published: January 2022

Price promotions and countercyclical pricing are driven by consumer search. This explanation is tested using a dynamic, structural, and seasonal inventory model.