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Cancer cells achieve immortality by employing either homology-directed repair (HDR) or the telomerase enzyme to maintain telomeres. ALT (alternative lengthening of telomeres) refers to the subset of cancer cells that employ HDR. Many ALT features are conserved from yeast to human cells, with the yeast equivalent being referred to as survivors. The non-coding RNA TERRA, and its ability to form RNA–DNA hybrids, has been implicated in ALT/survivor maintenance by promoting HDR. It is not understood which telomeres in ALT/survivors engage in HDR, nor is it clear which telomeres upregulate TERRA. Using yeast survivors as a model for ALT, we demonstrate that HDR only occurs at telomeres when they become critically short. Moreover, TERRA levels steadily increase as telomeres shorten and decrease again following HDR-mediated recombination. We observe that survivors undergo cycles of senescence, in a similar manner to non-survivors following telomerase loss, which we refer to as survivor associated senescence (SAS). Similar to ‘normal’ senescence, we report that RNA–DNA hybrids slow the rate of SAS, likely through the elongation of critically short telomeres, however decreasing the rate of telomere shortening may contribute to this effect. In summary, TERRA RNA–DNA hybrids regulate telomere dysfunction-induced senescence before and after survivor formation.

The 2021 has seen the publication of two practice-changing trials on second-line fluoropyrimidine-based doublet chemotherapy for advanced biliary tract cancer (BTC) patients. Herein, we conducted a meta-analysis aimed at assessing the overall survival (OS), disease control rate (DCR), and overall response rate (ORR) in ABC-06 and NIFTY trials. We retrieved all the relevant trials through PubMed/Medline, Cochrane library, and EMBASE; additionally, proceedings of the main international oncological meetings were also searched for relevant abstracts. Outcomes of interest included OS, DCR, and ORR. Hazard Ratios (HRs) and their 95% Confidence Intervals (CIs) for OS, and Odds Ratios (ORs) and 95% CIs for DCR and ORR, were extracted. According to our results, fluoropyrimidine-based doublet chemotherapy significantly decreased the risk of death (HR, 0.63; 95% CI, 0.49���0.8) compared with control treatment. In addition, higher DCR and ORR were observed in BTC patients receiving fluoropyrimidine-based combinations. Although ABC-06 and NIFTY have recently established fluoropyrimidine-based doublet chemotherapy as the standard of care, the role of second-line chemotherapy remains the object of debate in the BTC medical community. Further studies are required to clarify the role of second-line fluoropyrimidine-based chemotherapy in some ���neglected��� populations, including BTC patients with poor ECOG-PS.

Stage I–III triple-negative breast cancer accounts for approximately 15–20% of new diagnoses of early breast cancer. Novel systemic treatment options have recently been assessed as part of the neoadjuvant approach, such as the addition of immune checkpoint inhibitors to cytotoxic chemotherapy. However, several questions remain unanswered, including the identification of predictors of response to immunotherapy in this setting, and further efforts aimed at identifying reliable predictors and clarifying the effective role of PD-L1 status, tumor mutational burden, tumor-infiltrating lymphocytes and other biomarkers are warranted. Herein we will provide an overview of recent clinical studies of neoadjuvant immune checkpoint inhibitors in patients with triple-negative breast cancer, especially focusing on the recently presented and published KEYNOTE-522, IMpassion031 and GeparNUEVO trials.

Background To reduce the overall exposure to dexamethasone (DEX) in patients receiving cisplatin‐based chemotherapy, we evaluated the noninferiority of DEX on day 1, with or without low‐dose DEX on days 2 and 3, combined with an oral fixed‐dose combination of netupitant and palonosetron (NEPA), compared with the guideline‐consistent use of 4‐day DEX. Patients and Methods In this open‐label, multicenter study, chemotherapy‐naïve patients undergoing high‐dose cisplatin (≥70 mg/m2), were given NEPA and DEX (12 mg) on day 1 and randomized (1:1:1 ratio) to receive either (a) no further DEX (DEX1), (b) oral DEX (4 mg daily) on days 2–3 (DEX3), or (c) DEX (4 mg twice daily) on days 2–4 (DEX4). The primary efficacy endpoint was complete response (CR: no emesis and no rescue medication) during the 5‐day overall phase. The noninferiority margin was set at −15% difference (DEX1 or DEX3 minus DEX4). Secondary efficacy endpoints included complete protection (CP: CR and none or mild nausea). Results Two‐hundred twenty‐eight patients, 76 in each arm, were assessable. Noninferiority was met for both DEX‐sparing regimens and the reference arm, with overall phase CR rates of 76.3% in each of the DEX1 and DEX3 arms and 75.0% in the DEX4 arm (95% confidence interval, −12.3% to 15% for each comparison). During the overall phase, CP rates were similar between groups. Conclusion A simplified regimen of NEPA plus single‐dose DEX offers comparable chemotherapy‐induced nausea and vomiting prevention throughout 5 days post‐chemotherapy with the advantage of sparing patients additional doses of DEX in the high–emetic‐risk setting of cisplatin‐based chemotherapy. Implications for Practice Dexamethasone (DEX) has traditionally played an integral role in the management of chemotherapy‐induced emesis. Although generally considered safe, even short‐term DEX use is associated with various side effects, and some evidence suggests that concurrent steroids may reduce the efficacy of immunotherapies. This study demonstrates comparable antiemetic control during the 5 days post‐chemotherapy with a simplified regimen of netupitant/palonosetron plus single‐dose DEX versus the standard 4‐day DEX reference treatment in high‐dose cisplatin. This represents a clinically relevant achievement as it not only simplifies antiemetic prophylaxis but also offers an opportunity to appropriately use in patients where caution with corticosteroid use is advised., This study was designed to test whether two different dexamethasone‐sparing regimens, when administered with NEPA, might provide the opportunity to reduce the total corticosteroid dose while maintaining the same degree of chemotherapy‐induced nausea and vomiting control in patients undergoing cisplatin‐based chemotherapy.

(1) Background: In recent years, immunotherapy has revolutionized the treatment landscape of non-small cell lung cancer (NSCLC), representing a therapeutic breakthrough in this field. Antacid agents such as proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) are commonly prescribed for extended periods in NSCLC patients, and these drugs have the potential to modify the efficacy of immune checkpoint inhibitors (ICIs). (2) Materials and Methods: Herein, we conducted a systematic review and meta-analysis to investigate the impact of PPIs and H2RAs on progression-free survival (PFS) and overall survival (OS) among patients receiving immunotherapy for metastatic NSCLC. Effect measures for OS were Hazard Ratios (HRs) and 95% Confidence Intervals (CIs), which were extracted from available studies. Forest plots were used to assess HRs to describe the relationship between treatment and OS in the specified cohorts of patients. (3) Results: Six studies were included in the analysis, involving 2267 patients. The pooled HRs for OS and PFS were 1.4 (95% CI, 1.25–1.58) and 1.29 (95% CI, 1.17–1.43), respectively, suggesting that PPIs and H2RAs administration was negatively associated with PFS and OS. (4) Conclusion: Concomitant antacid use could modify the activity of ICIs in NSCLC patients.

This paper describes the exploitation of Genetic Algorithms for the selection and optimization of supersonic airfoils. The main objective of the optimization is to ensure the possibility to reach the maximum efficiency at a given lift coefficient. The surrogate model presented in this paper implements the shock-expansion theory, and the optimization problem is constrained with respect to three design variables, since Bézier curves are used for the parameterization of the Diamond-Shaped and the 40-elements Double Circular Arc airfoil geometries. The airfoils were optimized for three different Mach numbers and two different lift coefficients. A thickness-constrained optimization has been run to evaluate the possibility to obtain a specific lift coefficient at a given Mach number and to understand how this parameter influences the optimized airfoil shape performance in terms of efficiency and the range of feasible angles-of-attack. An off-design evaluation is also presented, allowing for a comparison of the optimized geometries in terms of versatility. High fidelity models were validated with RAE 2822 airfoil using STAR CCM+, and they were compared to the surrogated model to ensure higher quality in the results. In conclusion, the Genetics Algorithms optimization coupled with the shock-expansion theory model results to be a fast and valuable solution to select and optimize airfoil solutions. The application of this approach has shown that a 20% reduction in airfoil thickness leads to a 25% efficiency improvement, while widening the range of viable angles of attack.

Cancer cells activate telomere maintenance mechanisms (TMMs) to bypass replicative senescence and achieve immortality by either upregulating telomerase or promoting homology-directed repair (HDR) at chromosome ends to maintain telomere length, the latter being referred to as ALT (Alternative Lengthening of Telomeres). In yeast telomerase mutants, the HDR-based repair of telomeres leads to the generation of ‘survivors’ that escape senescence and divide indefinitely. So far, yeast has proven to provide an accurate model to study the generation and maintenance of telomeres via HDR. Recently, it has been established that up-regulation of the lncRNA, TERRA (telomeric repeat-containing RNA), is a novel hallmark of ALT cells. Moreover, RNA-DNA hybrids are thought to trigger HDR at telomeres in ALT cells to maintain telomere length and function. Here we show that, also in established yeast type II survivors, TERRA levels are increased in an analogous manner to human ALT cells. The elevated TERRA levels are independent of yeast-specific subtelomeric structures, i.e. the presence or absence of Y’ repetitive elements. Furthermore, we show that RNase H1 overexpression, which degrades the RNA moiety in RNA-DNA hybrids, impairs the growth of yeast survivors. We suggest that even in terms of TERRA regulation, yeast survivors serve as an accurate model that recapitulates many key features of human ALT cells.