Inhibition of HIF-1 alpha by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma

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Objective response by mRECIST as a predictor and potential surrogate end point of overall survival in advanced HCC

Background & Aims: The Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was developed to overcome the limitations of standard RECIST criteria in response assessment of hepatocellular carcinoma (HCC). We aimed to investigate whether objective response by mRECIST accurately predicted overall survival (OS) in patients with advanced HCC treated with systemic targeted therapies and also to preliminarily assess this endpoint as a potential surrogate of OS.Methods: Individual patient data from the BRISK-PS randomized phase III trial comparing brivanib vs. placebo (the first to prospectively incorporate mRECIST) were used to analyze objective response as a predictor of OS in a time-dependent covariate analysis. Patients with available imaging scans during follow-up were included (n = 334; 85% of those randomized). Moreover, a correlation of the survival probability in deciles vs. the observed objective response was performed to evaluate its suitability as a surrogate end-point.Results: Objective response was observed in 11.5% and 1.9% of patients treated with brivanib and placebo respectively, and was associated with a better survival (median OS 15.0 vs. 9.4 months, p < 0.001). In addition, objective response had an independent prognostic value (HR = 0.48; 95% confidence interval [CI], 0.26-0.91, p = 0.025) along with known prognostic factors. Finally, objective response showed promising results as a surrogate of OS in this trial (R = -0.92; 95% CI, -1 to -0.73, p < 0.001). It was an early indicator of the treatment effect (median time to objective response was 1.4 months).Conclusions: Objective response by mRECIST in advanced HCC predicts OS and thus can be considered as a candidate surrogate end-point. Further studies are needed to support this finding.Lay summary: There is a need to identify surrogate end-points for overall survival in advanced hepatocellular carcinoma. We studied patients from the phase III BRISK trial, comparing brivanib treatment with placebo after sorafenib progression. We demonstrate that objective response is an independent predictor of survival and qualifies as a potential surrogate end-point for overall survival in this patient population.Clinical trial number: NCT00825955

Selective impact of CDK4/6 suppression on patient-derived models of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) harbors an exceedingly poor prognosis, and is generally considered a therapy-recalcitrant disease due to poor response to conventional chemotherapy coupled with non-actionable genetic drivers (e.g. KRAS mutations). However, PDA frequently loses p16ink4a, thereby leading to deregulation of CDK4/6. Surprisingly, in established cell models and xenografts, CDK4/6 inhibition has a modest effect on proliferation and resistance develops rapidly. To determine if such weak response was an intrinsic feature of PDA, we developed primary tumor explants that maintain the tumor environment and recapitulate feuture of primary PDA. The CDK4/6 inhibitor PD-0332991 was highly efficient at suppressing proliferation in 14 of the 15 explants. In the single resistant explant, we identified the rare loss of the RB tumor suppressor as the basis for resistance. Patient-derived xenografts (PDXs) were developed in parallel, and unlike the xenografts emerging from established cell lines, the PDXs maintained the histoarchitecture of the primary tumor. These PDXs were highly sensitive to CDK4/6 inhibition, yielding a complete suppression of PDA proliferation. Together, these data indicate that primary PDA is sensitive to CDK4/6 inhibition, that specific biomarkers can delineate intrinsic resistance, and that established cell line models may not represent an adequate means for evaluating therapeutic sensitivities

Diyarbakır Ulu Cami Batı Maksuresinde araştırma kazıları

Diyarbakır Great Mosque is a community building located in the district of Cami-i Kebir in the northwest of the traditional city area surrounded by walls. The building on Gazi Street opposite Hasan Pasha Han is inside the road, and the eastern entrance overlooks a square which very likely corresponds to the old forum of the city of Amida. Surrounded by the streets to the North and West, the South overlooks the traditional Sipahi Bazaar. Around the full court near the square of the building, in the south there are: Hanafis section, Shafis section, northern vestibule, Mesudiye Madrasa and its southern portico, a traditional house, and a lavatory. To the east, there is a library, which used to be apparently a timing room (muvakkithane) and an entrance to the East (Eastern Maksurah). To the west, in the Western portico (Western Maksurah), that also includes the Western entrance, there is a Qur'anic school. The octagonal and pointed pyramidal coned fountain, built during the Ottoman period, and the prayer hall and pool, which were raised with several steps, form the other units in the spacious courtyard. In the north of the courtyard, we can find the portico of Mesudiye Madrasa. There is also a solar clock in front of the northern vestibule. The aims of this study are: ● introducing the excavations in the Diyarbakır Great Mosque Western Maksurah and explaining the reasons of these excavations; ● presenting the results of these excavations; ● giving information on the excavation findings; ●explaining the importance of research excavations in restoration works. The evaluations made for the preservation of the excavation findings, which were deemed necessary during the restoration works in the great Mosque, will also be explained in this study.Diyarbakır Ulu Camii, surlarla çevrili antik kentin kuzeybatısında, Cami-i Kebir mahallesinde yer almaktadır. Caminin kapladığı alan, Amida şehrinin antik forumu olarak kabul edilmiştir. Doğuda, Hasan Paşa Hanı'nın karşısındaki kentsel meydan boyunca yer almaktadır. Yapı topluluğunun güneyi Sipahi Çarşısı’na bakmaktadır. Cami kuzey ve doğudan duvarla çevrilidir. Hâlihazırda avlu çevresinde güneyde Hanefiler Bölümü, batı ve doğuda iki maksure, kuzeyde Mesudiye Medresesi ile Şafiler Bölümü yer almaktadır. Caminin doğu, batı ve kuzeyden olmak üzere üç girişi vardır. Merkezde, meydanda, konik sekizgen ve piramidal sivri uçlu şadırvanın yanı sıra namazgâh ve havuz bulunmaktadır. Avluda ayrıca bir güneş saati bulunmaktadır. Birçok antik devşirme malzeme hala görülebilmektedir. Batı Maksura’da yapılan kazılar, Ulu Cami'nin restorasyonu ve tarihinin anlaşılması için önemli bilgiler sağlamıştır. Bu iki konu için elde edilen sonuçlar burada sunulmaktadır. Ulu Cami'deki restorasyon çalışmaları sırasında gerekli görülen kazı buluntularının korunması için yapılan değerlendirmeler de bu çalışmada anlatılacaktır

Reverse transcription-quantitative polymerase chain reaction: description of a RIN-based algorithm for accurate data normalization

<p>Abstract</p> <p>Background</p> <p>Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is the gold standard technique for mRNA quantification, but appropriate normalization is required to obtain reliable data. Normalization to accurately quantitated RNA has been proposed as the most reliable method for in vivo biopsies. However, this approach does not correct differences in RNA integrity.</p> <p>Results</p> <p>In this study, we evaluated the effect of RNA degradation on the quantification of the relative expression of nine genes (<it>18S</it>, <it>ACTB</it>, <it>ATUB</it>, <it>B2M</it>, <it>GAPDH</it>, <it>HPRT</it>, <it>POLR2L</it>, <it>PSMB6</it> and <it>RPLP0</it>) that cover a wide expression spectrum. Our results show that RNA degradation could introduce up to 100% error in gene expression measurements when RT-qPCR data were normalized to total RNA. To achieve greater resolution of small differences in transcript levels in degraded samples, we improved this normalization method by developing a corrective algorithm that compensates for the loss of RNA integrity. This approach allowed us to achieve higher accuracy, since the average error for quantitative measurements was reduced to 8%. Finally, we applied our normalization strategy to the quantification of <it>EGFR</it>, <it>HER2 </it>and <it>HER3 </it>in 104 rectal cancer biopsies. Taken together, our data show that normalization of gene expression measurements by taking into account also RNA degradation allows much more reliable sample comparison.</p> <p>Conclusion</p> <p>We developed a new normalization method of RT-qPCR data that compensates for loss of RNA integrity and therefore allows accurate gene expression quantification in human biopsies.</p

Augmenter of liver regeneration

‘Augmenter of liver regeneration’ (ALR) (also known as hepatic stimulatory substance or hepatopoietin) was originally found to promote growth of hepatocytes in the regenerating or injured liver. ALR is expressed ubiquitously in all organs, and exclusively in hepatocytes in the liver. ALR, a survival factor for hepatocytes, exhibits significant homology with ERV1 (essential for respiration and viability) protein that is essential for the survival of the yeast, Saccharomyces cerevisiae. ALR comprises 198 to 205 amino acids (approximately 22 kDa), but is post-translationally modified to three high molecular weight species (approximately 38 to 42 kDa) found in hepatocytes. ALR is present in mitochondria, cytosol, endoplasmic reticulum, and nucleus. Mitochondrial ALR may be involved in oxidative phosphorylation, but also functions as sulfhydryl oxidase and cytochrome c reductase, and causes Fe/S maturation of proteins. ALR, secreted by hepatocytes, stimulates synthesis of TNF-α, IL-6, and nitric oxide in Kupffer cells via a G-protein coupled receptor. While the 22 kDa rat recombinant ALR does not stimulate DNA synthesis in hepatocytes, the short form (15 kDa) of human recombinant ALR was reported to be equipotent as or even stronger than TGF-α or HGF as a mitogen for hepatocytes. Altered serum ALR levels in certain pathological conditions suggest that it may be a diagnostic marker for liver injury/disease. Although ALR appears to have multiple functions, the knowledge of its role in various organs, including the liver, is extremely inadequate, and it is not known whether different ALR species have distinct functions. Future research should provide better understanding of the expression and functions of this enigmatic molecule

Efficacy, safety, and pharmacokinetics of the anti-programmed cell death receptor-1 (PD-1) monoclonal antibody, tislelizumab (BGB-A317) in a phase 2, open-label, multicenter study to investigate in patients with unresectable hepatocellular carcinoma - Trial in progress.

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Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Phase 3 Randomized Clinical Trial

Importance: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and additional first-line treatments are needed. The programmed cell death protein 1 inhibitor tislelizumab demonstrated efficacy and a tolerable safety profile as second-line HCC treatment. // Objective: To investigate efficacy and safety of tislelizumab vs sorafenib tosylate for first-line treatment of unresectable HCC. // Design, Setting, and Participants: The open-label, global, multiregional phase 3 RATIONALE-301 randomized clinical trial enrolled systemic therapy–naive adults with histologically confirmed HCC, Barcelona Clinic Liver Cancer stage B or C disease, disease progression following (or patient was not amenable to) locoregional therapy, Eastern Cooperative Oncology Group performance status of 1 or less, and Child-Pugh class A, between December 27, 2017, and October 2, 2019. Data cutoff was July 11, 2022. // Intervention: Patients were randomized 1:1 to receive tislelizumab, 200 mg intravenously every 3 weeks, or sorafenib tosylate, 400 mg orally twice daily. // Main Outcomes and Measures: The primary end point was overall survival (OS); secondary end points included objective response rate, progression-free survival, duration of response, and safety. // Results: A total of 674 patients were included in the analysis (570 men [84.6%]; median age, 61 years [range, 23-86 years]). As of July 11, 2022, minimum study follow-up was 33 months. The primary end point of OS noninferiority of tislelizumab vs sorafenib was met in the intention-to-treat population (n = 674); median overall survival was 15.9 (95% CI, 13.2-19.7) months vs 14.1 (95% CI, 12.6-17.4) months, respectively (hazard ratio [HR], 0.85 [95.003% CI, 0.71-1.02]), and superiority of tislelizumab vs sorafenib was not met. The objective response rate was 14.3% (n = 49) for tislelizumab vs 5.4% (n = 18) for sorafenib, and median duration of response was 36.1 (95% CI, 16.8 to not evaluable) months vs 11.0 (95% CI, 6.2-14.7) months, respectively. Median progression-free survival was 2.1 (95% CI, 2.1-3.5) months vs 3.4 (95% CI, 2.2-4.1) months with tislelizumab vs sorafenib (HR, 1.11 [95% CI, 0.92-1.33]). The incidence of treatment-emergent adverse events (AEs) was 96.2% (325 of 338 patients) for tislelizumab and 100% (n = 324) for sorafenib. Grade 3 or greater treatment-related AEs were reported in 75 patients (22.2%) receiving tislelizumab and 173 (53.4%) receiving sorafenib. There was a lower incidence of treatment-related AEs leading to drug discontinuation (21 [6.2%] vs 33 [10.2%]) and drug modification (68 [20.1%] vs 187 [57.7%]) with tislelizumab vs sorafenib. // Conclusions and Relevance: In RATIONALE-301, tislelizumab demonstrated OS benefit that was noninferior vs sorafenib, with a higher objective response rate and more durable responses, while median progression-free survival was longer with sorafenib. Tislelizumab demonstrated a favorable safety profile vs sorafenib. // Trial Registration: ClinicalTrials.gov Identifier: NCT0341277