Analyses of Neural Circuits Governing Behavioral Plasticity in the Nematode Caenorhabditis elegans.

Behavioral plasticity is subjected to various sensory stimuli, experiences, and physiological states, representing the temporal and spatial patterns of neural circuit dynamics. Elucidation of how genes and neural circuits in our brain actuate behavioral plasticity requires functional imaging during behavioral assays to manifest temporal and spatial neural regulation in behaviors. The exploration of the nervous systems of Caenorhabditis elegans has catalyzed substantial scientific advancements in elucidating the mechanistic link between circuit dynamics and behavioral plasticity. The analyses of the nervous system of C. elegans have technologically flourished owing to the development of optogenetic instruments and fluorescent protein-based imaging compatible with its optically transparent body and the understanding of its completely revealed neural connectome and gene expression profiles at single-neuron resolution (The C. elegans Neuronal Gene Expression Map & Network, CeNGEN project). Using examples of the two temperature learning behaviors in C. elegans, this chapter delves into a selection of pivotal imaging tools, including genetically encoded calcium indicators, biosensors for second messenger imaging, and their usage in freely moving worms that have propelled our grasp of sensory representation in C. elegans neural circuits. To further connect the circuit dynamics to behavioral plasticity, this chapter will focus on technological advancements enabling simultaneous imaging and tracking system together with methodologies to quantify multiple behavioral elements of freely behaving C. elegans in a dynamic environment.

Analyses of Genetic Regulation of the Nervous System in the Nematode Caenorhabditis elegans.

This chapter aims to provide a comprehensive overview of the methodologies available to dissect genetic regulation of the nervous systems in the nematode Caenorhabditis elegans. These techniques encompass genetic screens and genetic tools to unravel the spatial-temporal contribution of genes on neural structure and function. Unbiased genetic screens on random mutations induced by ethyl methanesulfonate (EMS) or target gene silencing by genome-wide RNA interference (RNAi) help progress our understanding of the genetic control of neural development and functions. Complement to unbiased genetic approaches, gene- and protein-targeted manipulation by Cre/LoxP recombination system and auxin-inducible degron (AID) protein degradation system, respectively, helps identify tissues/cells and the time window critical for gene and protein function during the proper execution of a particular behavior. Considering the remarkable conservation of genetic pathways between C. elegans and mammalian systems, elucidating the genetic underpinnings of neural functions and learning behaviors in C. elegans may furnish invaluable insights into analogous processes in more complex organisms. As shown in the following chapter, leveraging these diverse methodologies enable researchers to elucidate the intricate network governing neural function and structure, laying the foundation for innovating strategies to ameliorate cognitive alterations.

The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial.

The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3) associated with lack of clinical benefit [defined post-hoc as PFS < 6 months]. Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.

AKT1 interacts with DHX9 to Mitigate R Loop-Induced Replication Stress in Ovarian Cancer.

PARP inhibitor (PARPi)-resistant BRCA-mutant (BRCAm) high-grade serous ovarian cancer (HGSOC) represents a new clinical challenge with unmet therapeutic needs. Here, we performed a quantitative high-throughput drug combination screen that identified the combination of an ATR inhibitor (ATRi) and an AKT inhibitor (AKTi) as an effective treatment strategy for both PARPi-sensitive and PARPi-resistant BRCAm HGSOC. The ATRi and AKTi combination induced DNA damage and R loop-mediated replication stress (RS). Mechanistically, the kinase domain of AKT1 directly interacted with DHX9 and facilitated recruitment of DHX9 to R loops. AKTi increased ATRi-induced R loop-mediated RS by mitigating recruitment of DHX9 to R loops. Moreover, DHX9 was upregulated in tumors from patients with PARPi-resistant BRCAm HGSOC, and high coexpression of DHX9 and AKT1 correlated with worse survival. Together, this study reveals an interaction between AKT1 and DHX9 that facilitates R loop resolution and identifies combining ATRi and AKTi as a rational treatment strategy for BRCAm HGSOC irrespective of PARPi resistance status. SIGNIFICANCE: Inhibition of the AKT and ATR pathways cooperatively induces R loop-associated replication stress in high-grade serous ovarian cancer, providing rationale to support the clinical development of AKT and ATR inhibitor combinations. See related commentary by Ramanarayanan and Oberdoerffer, p. 793.

Quantitative Assessment of Lipiodol-Related Artifact Reduction for Dual-Energy Computed Tomography After Transcatheter Arterial Chemoembolization: A Phantom Study Evaluating the Use of Metal Artifact Reduction Algorithms.

OBJECTIVE: This study used metal artifact reduction (MAR) software to examine the computed tomography (CT) number of dual-energy CT (DECT) of hepatocellular carcinoma after transcatheter arterial chemoembolization. METHODS: Hollow columnar acrylic phantoms were filled with lipiodol and inserts of 2 sizes (large and small) were used to simulate liver tumors on a Revolution GSI CT scanner. The CT numbers of a single test object were collected twice: once with and once without the MAR algorithm. Lipiodol beam-hardening artifacts were quantified by measuring CT numbers in a region of interest around the tumor-simulating insert. RESULTS: The virtual monochromatic CT numbers of large and small tumors were closely related to energy. For small tumors, CT numbers increased with energy. For large tumors, CT numbers increased with energy at 1 cm from the margin but decreased with an increase in energy at 5 cm. Regardless of the size, distance, or location of the tumor, the CT numbers fluctuated more at low energy levels. CONCLUSIONS: At 1 cm from the margin, the CT numbers with MAR were significantly different from those without MAR. Low-energy CT numbers with MAR were near reference values. Metal artifact reduction exhibited superior performance for small tumors. Tumor margin images are affected by artifacts caused by Lipiodol. However, with MAR, CT numbers can be effectively calibrated, thus enabling clinicians to more accurately evaluate hepatocellular carcinoma development and identify residual tumors and recurrent or metastatic lesions.

Prediction of extranodal extension in head and neck squamous cell carcinoma by CT images using an evolutionary learning model.

BACKGROUND: Extranodal extension (ENE) in head and neck squamous cell carcinoma (HNSCC) correlates to poor prognoses and influences treatment strategies. Deep learning may yield promising performance of predicting ENE in HNSCC but lack of transparency and interpretability. This work proposes an evolutionary learning method, called EL-ENE, to establish a more interpretable ENE prediction model for aiding clinical diagnosis. METHODS: There were 364 HNSCC patients who underwent neck lymph node (LN) dissection with pre-operative contrast-enhanced computerized tomography images. All the 778 LNs were divided into training and test sets with the ratio 8:2. EL-ENE uses an inheritable bi-objective combinatorial genetic algorithm for optimal feature selection and parameter setting of support vector machine. The diagnostic performances of the ENE prediction model and radiologists were compared using independent test datasets. RESULTS: The EL-ENE model achieved the test accuracy of 80.00%, sensitivity of 81.13%, and specificity of 79.44% for ENE detection. The three radiologists achieved the mean diagnostic accuracy of 70.4%, sensitivity of 75.6%, and specificity of 67.9%. The features of gray-level texture and 3D morphology of LNs played essential roles in predicting ENE. CONCLUSIONS: The EL-ENE method provided an accurate, comprehensible, and robust model to predict ENE in HNSCC with interpretable radiomic features for expanding clinical knowledge. The proposed transparent prediction models are more trustworthy and may increase their acceptance in daily clinical practice.

BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor-resistant BRCA-mutant ovarian cancer.

Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene (BRCA)-mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for improved therapeutic strategies. Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant BRCA-mutant HGSC cells and xenograft mouse models. CHK1i monotherapy induced DNA damage, apoptosis, and tumor size reduction. We then conducted a phase 2 study (NCT02203513) of prexasertib in patients with BRCA-mutant HGSC. The treatment was well tolerated but yielded an objective response rate of 6% (1 of 17; one partial response) in patients with previous PARPi treatment. Exploratory biomarker analyses revealed that replication stress and fork stabilization were associated with clinical benefit to CHK1i. In particular, overexpression of Bloom syndrome RecQ helicase (BLM) and cyclin E1 (CCNE1) overexpression or copy number gain/amplification were seen in patients who derived durable benefit from CHK1i. BRCA reversion mutation in previously PARPi-treated BRCA-mutant patients was not associated with resistance to CHK1i. Our findings suggest that replication fork-related genes should be further evaluated as biomarkers for CHK1i sensitivity in patients with BRCA-mutant HGSC.

Differential impacts of initial treatment status on long-term survival in patients with sarcomas treated in a referral center according to histologic type and anatomic site.

OBJECTIVE: The aim of this work was to estimate the magnitude of the differential impacts of initial treatment status relative to the impact of classic clinicopathologic factors on the long-term overall survival (OS) of sarcoma patients in a referral cancer center. METHODS: From the institutional database, we identified 2185 patients who presented to the institutional multidisciplinary team (MDT) prior to (N = 717, 32.8%) or after (N = 1468, 67.2%) initial treatment, with a first diagnosis of sarcoma from January 1999 to December 2018. Descriptive, univariate and multivariate analyses were applied to identify the factors related to OS. By performing propensity score matching of each completely MDT-treated patient to a referral patient with similar characteristics, the differential impacts of the identified risk and prognostic factors on OS in the 2 groups were estimated by the Kaplan‒Meier survival curves, log-rank test and Cox proportional hazard regression; the results were compared using calibrated nomograph models and forest plots. RESULTS: Adjusted for the clinicopathologic factors of patient age, sex, primary site, tumor grade, tumor size, resection margin and histology, hazard ratio-based modeling analysis indicated that the initial treatment status was an independent but intermediate prognostic factor associated with long-term OS. The major impacts of the initial and comprehensive MDT-based management on significant improvement of the 20-year OS of sarcomas were reflected in the subgroup of patients with stromal, undifferentiated pleomorphic, fibromatous, fibroepithelial, or synovial neoplasms and tumors in the breast, gastrointestinal tract, or soft tissues of limb and trunk. CONCLUSIONS: This retrospective study supports early referral of patients with soft tissue masses of unknown identity to a specialized MDT before biopsy and initial resection to reduce the risk of death but highlights an unmet need for a greater understanding of some of the most difficult sarcoma subtypes and subsites and their management.

Nicotine activates HIF-1α and regulates acid extruders through the nicotinic acetylcholine receptor to promote the Warburg effect in non-small cell lung cancer cells.

Cigarette smoking is the greatest risk factor for lung cancer, accounting for approximately 90% of all lung cancer-related deaths. Moreover, nicotine is associated with lung cancer onset and progression. Hypoxia-inducible factor 1α (HIF-1α) is involved in the metabolic reprogramming of cancer cells and accelerates cancer progression via regulation of pH and acid-base homeostasis. Previous studies have reported that nicotine upregulates HIF-1α expression. Therefore, we hypothesized that nicotine-mediated activation of HIF-1α regulates metabolic reprogramming and pH homeostasis in non-small cell lung cancer A549 cells and could potentially play a role in the progression of lung cancer. We examined the effects of nicotine on metabolic reprogramming and intracellular pH (pHi) homeostasis, which are critical for cancer progression. A549 cells were exposed to nicotine in the absence and presence of the nicotinic acetylcholine receptor antagonist, mecamylamine (MEC). We then analyzed glycolytic stress and the activity and expression of acid-extruder proteins, including the Na+-H+ exchanger 1 (NHE1) and monocarboxylate cotransporters 1 & 4 (MCT1 and MCT4, respectively). Nicotine promoted the Warburg effect, which is associated with accelerated migration of A549 cells through the activation of nicotinic acetylcholine receptors. Furthermore, nicotine upregulated the activities and expression of acid-extruder proteins, namely NHE1 and MCT4, and facilitated glycolysis. To the best of our knowledge, this is the first study to demonstrate that nicotine plays a pivotal regulatory role in metabolic reprogramming as well as regulation of pHi homeostasis in A549 cells via activation of nicotinic acetylcholine receptors and can therefore aggravate lung cancer progression.

Regorafenib induces damage-associated molecular patterns, cancer cell death and immune modulatory effects in a murine triple negative breast cancer model.

Damage associated molecular patterns (DAMPs), including calreticulin (CRT) exposure, high-mobility group box 1 protein (HMGB1) elevation, and ATP release, characterize immunogenic cell death (ICD) and may play a role in cancer immunotherapy. Triple negative breast cancer (TNBC) is an immunogenic subtype of breast cancer with higher lymphocyte infiltration. Here, we found that regorafenib, a multi-target angiokinase inhibitor previously known to suppress STAT3 signaling, induced DAMPs and cell death in TNBC cells. Regorafenib induced the expression of HMGB1 and CRT, and the release of ATP. Regorafenib-induced HMGB1 and CRT were attenuated following STAT3 overexpression. In a 4T1 syngeneic murine model, regorafenib treatment increased HMGB1 and CRT expression in xenografts, and effectively suppressed 4T1 tumor growth. Immunohistochemical staining revealed increased CD4+ and CD8+ tumor-infiltrating T cells in 4T1 xenografts following regorafenib treatment. Regorafenib treatment or programmed death-1 (PD-1) blockade using anti-PD-1 monoclonal antibody reduced lung metastasis of 4T1 cells in immunocompetent mice. While regorafenib increases the proportion of MHC II high expression on dendritic cells in mice with smaller tumors, the combination of regorafenib and PD-1 blockade did not show a synergistic effect on anti-tumor activity. These results suggest that regorafenib induces ICD and suppresses tumor progression in TNBC. It should be carefully evaluated when developing a combination therapy with an anti-PD-1 antibody and a STAT3 inhibitor.

The optimal intervention for preventing physical restraints among older adults living in the nursing home: A systematic review.

AIM: This study aimed to evaluate the effectiveness of restraint reduction programs for nursing home care providers in enforcing physical restraint on residents and identify the best strategies for such programs. DESIGN: Systematic Review. METHODS: We searched for randomized controlled trials published until February 2021 for systematic review. The systematic review captured multifactorial interventions, education and consultation measures, including nursing home residents' and care providers' results. Study quality was assessed using the Cochrane Collaboration criteria. RESULTS: In all seven trials, the interventions were led by a nurse specialist or unit leader and targeted at care providers. Five of the restraint reduction programs effectively reduced the rate of physical restraint use; two increased knowledge of restraint reduction for care providers; and one each promoted positive attitudes and behaviours. Duration of at least 6 weeks significantly improved the knowledge of care providers.

Distinct roles of treatment schemes and BRCA2 on the restoration of homologous recombination DNA repair and PARP inhibitor resistance in ovarian cancer.

Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a major advance in ovarian cancer, now as a treatment and as a maintenance therapy in the upfront and recurrent settings. However, patients often develop resistance to PARPis, underlining the importance of dissecting resistance mechanisms. Here, we report different dosing/timing schemes of PARPi treatment in BRCA2-mutant PEO1 cells, resulting in the simultaneous development of distinct resistance mechanisms. PARPi-resistant variants PEO1/OlaJR, established by higher initial doses and short-term PARPi treatment, develops PARPi resistance by rapidly restoring functional BRCA2 and promoting drug efflux activity. In contrast, PEO1/OlaR, developed by lower initial doses with long-term PARPi exposure, shows no regained BRCA2 function but a mesenchymal-like phenotype with greater invasion ability, and exhibits activated ATR/CHK1 and suppressed EZH2/MUS81 signaling cascades to regain HR repair and fork stabilization, respectively. Our study suggests that PARPi resistance mechanisms can be governed by treatment strategies and have a molecular basis on BRCA2 functionality. Further, we define different mechanisms that may serve as useful biomarkers to assess subsequent treatment strategies in PARPi-resistant ovarian cancer.

Interfering B cell receptor signaling via SHP-1/p-Lyn axis shows therapeutic potential in diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B cell lymphoma (DLBCL) is an aggressive and molecularly heterogeneous non-Hodgkin's lymphoma. The B cell receptor (BCR) signaling pathway in DLBCL emerges as a new drug target. Protein phosphatase SHP-1 negatively regulates several oncogenic tyrosine kinases and plays a tumor suppressive role. METHODS: The direct SHP-1 agonists were used to evaluate the potential therapeutic implication of SHP-1 in DLBCL. Immunohistochemical staining for SHP-1 was quantified by H-score. The SHP-1 phosphatase activity was determined using tyrosine phosphatase assay. In vitro studies, including MTT, western blot analysis and cell apoptosis, were utilized to examined biological functions of SHP-1. RESULTS: Oral administration of SHP-1 agonist showed the potent anti-tumor effects compared to a selective Bruton's tyrosine kinase (BTK) inhibitor ibrutinib in mice bearing U2932 xenografts. SHP-1 agonist increased SHP-1 activity as well as downregulated p-Lyn in vivo. Here, we demonstrated that immunohistochemical staining for SHP-1 expression was positive in 76% of DLBCL samples. SHP-1 agonist exerted anti-proliferative and apoptotic effects compared with ibrutinib in DLBCL cells. Mechanistically, SHP-1 agonist decreased BCR signaling, especially p-Lyn, and led to apoptosis. CONCLUSIONS: These data suggest that SHP-1 negatively regulates phosphorylation of Lyn, and targeting SHP-1/p-Lyn using SHP-1 agonist has therapeutic potential for treatment of DLBCL.

The Radiation Dose to the Left Supraclavicular Fossa is Critical for Anastomotic Leak Following Esophagectomy - A Dosimetric Outcome Analysis.

Purpose: For locally advanced esophageal cancer, definitive concurrent chemoradiotherapy (CCRT) with a radiation dose of 50-50.4 Gy/25-28 Fx is prescribed, followed by adjuvant esophagectomy for better local control or salvage treatment if locoregional recurrence occurs. However, radiation injury before surgery may delay wound healing. We performed cervical anastomosis directly inside the left supraclavicular fossa (SCF), the irradiation target for esophageal cancer. The significance of radiation injury in patients with cervical anastomotic leak (AL) remains unclear. Thus, we assessed the influence of radiation on cervical AL in patients undergoing preoperative CCRT followed by esophagectomy. Patients and Methods: We defined the SYC zone, a portion of the region overlapping the left SCF. The radiation dose to the SYC zone was analyzed and correlated with AL in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who were administered preoperative CCRT (radiation dose with 50-50.4 Gy/25-28 Fx to the primary esophageal tumor) followed by esophagectomy between October 2009 and January 2018. Receiver operating characteristic curve analysis and logistic regression were used to identify the optimal radiation factor to predict AL and the cutoff value. Results: The optimal radiation factor to predict AL was the mean dose to the SYC zone (area under the curve (AUC)=0.642), and the cutoff point of the mean dose was 48.55 Gray (Gy). For a mean SYC zone dose ≥48.55 Gy, the AL risk was sevenfold greater than that for <48.55 Gy (OR = 7.805; 95% CI: 1.184 to 51.446; P value = 0.033). Conclusion: Recognizing the SYC zone as an organ at risk and performing radiation evaluation are meaningful. A reduced mean dose of the SYC zone below 48.55 Gy results in a lower cervical AL rate following esophagectomy.

The Impact of Weight Loss during Chemoradiotherapy for Unresectable Esophageal Cancer: Real-World Results.

Weight loss is a common phenomenon presented in unresectable esophageal cancer (EC) patients during their definitive chemoradiotherapy (dCRT) treatment course. This study explored the prognostic value of weight changes during dCRT in unresectable EC patients. From 2009 to 2017, 69 cT4b thoracic EC patients undergoing complete curative dCRT without baseline malnutrition were included. Clinical factors were analyzed via the Cox proportional hazards model and survival was analyzed by the Kaplan−Meier method. During dCRT, the median weight loss percentage was 5.51% (IQR = 2.77−8.85%), and the lowest body weight was reached at 35 days (IQR = 23−43 days). Median OS of these patients was 13.5 months. Both univariate and multivariate analysis demonstrated that weight loss ≤ 4% during dCRT was significantly associated with superior OS with a hazard ratio of 2.61 (95% CI: 1.40−4.85, p = 0.002). The median OS for patients with weight loss ≤ 4% and >4% during dCRT was 59.6 months and 9.7 months, respectively (p = 0.001). Our study demonstrated that weight loss ≤ 4% during dCRT course is a favorable prognostic factor for cT4b EC patients. This index could serve as a nutrition support reference for unresectable EC patients receiving dCRT in the future.

Overexpression of multiple epidermal growth factor like domains 11 rescues anoikis survival through tumor cells-platelet interaction in triple negative breast Cancer cells.

AIMS: The aim of this study was to test the hypothesis that overexpression of the Multiple Epidermal Growth Factor Like Domains 11 (MEGF11) gene in TNBC cells increases tumor cell survival against anoikis via interaction with platelets. MAIN METHODS: The role of MEGF11 was studied in human TNBC MDA-MB-231 and MDA-MB-468 cells by overexpressing MEGF11 (o/e MEGF11) using non-attached culture. Mouse wild type 4 T1 and Δmegf11-4 T1 cells were implanted into the mammary fat pad of BALB/c mice. Circulating tumor cells were isolated and cultured. Plasma platelets were added to these cell lines to carry out a platelet binding assay by confocal microscopy. Anoikis was observed by Live/Dead staining and a quantitative PBMC-specific cytotoxic assay (with/without platelets) was carried out to measure calcein release. The protein levels of MEGF11, Akt, and caspase 3 were assessed by Western blotting. KEY RESULTS: Reduced number of circulating Δmegf11 4 T1 cells, and 4 T1-platelet clusters and reduced p-Akt expression, accompanied by increased specific calcein release, were observed in the Δmegf11 4T1group compared to the 4 T1 wild type group. There was significant increased cancer-platelet binding using the o/e MEGF11 MDA-MB-231/468 lines. Cell survival, caspase 3 activation and PBMC-specific cytotoxicity in the o/e MEGF11 MDA-MB-468 cells, but not in the MDA-MB-231 cells, could be rescued by platelet binding (+), compared to the platelet (-) group. SIGNIFICANCE: We conclude that MEGF11 overexpression in TNBC cells rescues tumor cells from anoikis via interaction with platelets in mouse 4 T1 cells and human MDA-MB-468 cells.

Vacuum ultraviolet nonlinear metalens.

Vacuum ultraviolet (VUV) light plays an essential role across science and technology, from molecular spectroscopy to nanolithography and biomedical procedures. Realizing nanoscale devices for VUV light generation and control is critical for next-generation VUV sources and systems, but the scarcity of low-loss VUV materials creates a substantial challenge. We demonstrate a metalens that both generates-by second-harmonic generation-and simultaneously focuses the generated VUV light. The metalens consists of 150-nm-thick zinc oxide (ZnO) nanoresonators that convert 394 nm (~3.15 eV) light into focused 197-nm (~6.29 eV) radiation, producing a spot 1.7 µm in diameter with a 21-fold power density enhancement as compared to the wavefront at the metalens surface. The reported metalens is ultracompact and phase-matching free, allowing substantial streamlining of VUV system design and facilitating more advanced applications. This work provides a useful platform for developing low-loss VUV components and increasing the accessibility of the VUV regime.

Cell cycle checkpoints and beyond: Exploiting the ATR/CHK1/WEE1 pathway for the treatment of PARP inhibitor-resistant cancer.

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) have become a mainstay of therapy in ovarian cancer and other malignancies, including BRCA-mutant breast, prostate, and pancreatic cancers. However, a growing number of patients develop resistance to PARPis, highlighting the need to further understand the mechanisms of PARPi resistance and develop effective treatment strategies. Targeting cell cycle checkpoint protein kinases, e.g., ATR, CHK1, and WEE1, which are upregulated in response to replication stress, represents one such therapeutic approach for PARPi-resistant cancers. Mechanistically, activated cell cycle checkpoints promote cell cycle arrest, replication fork stabilization, and DNA repair, demonstrating the interplay of DNA repair proteins with replication stress in the development of PARPi resistance. Inhibitors of these cell cycle checkpoints are under investigation in PARPi-resistant ovarian and other cancers. In this review, we discuss the cell cycle checkpoints and their roles beyond mere cell cycle regulation as part of the arsenal to overcome PARPi-resistant cancers. We also address the current status and recent advancements as well as limitations of cell cycle checkpoint inhibitors in clinical trials.

Comparison between the use of hypofractionated and conventionally fractionated radiotherapy in early breast cancer: A single-center real-world study in Taiwan.

BACKGROUND/PURPOSE: This study aimed to analyze the long-term outcomes of hypofractionated whole-breast irradiation (WBI) (HF-WBI) compared with those of conventionally fractionated WBI (CF-WBI) for early breast cancer treated with breast-conservation surgery (BCS) and adjuvant WBI in Taiwan. METHODS: This study included patients treated at our institution between 2012 and 2016. All patients with early breast cancer received BCS (pT1-2, pN0, M0) and adjuvant WBI through one of two treatment schemes. Propensity score matching analysis was conducted to create comparable cohorts. The major result is ipsilateral breast tumor recurrence (IBTR) rates and overall survival rates. RESULTS: A total of 869 patients with early-stage breast cancer received adjuvant HF-WBI or CF-WBI were included. After matching, 718 patients were separated into two groups of the same number. With a median follow-up of 66 months, seven cases of IBTR were noted (three for CF, four for HF). There were no significant differences between the HF-WBI and CF-WBI groups in 5-year IBTR rates (0.9% vs 0.6%, P = 0.3887, 95% CI [0.25-7.79]) and 5-year overall survival rates (98.1% vs 98.9%, P = 0.4702, 95% CI [0.32-3.49]). In our institution, the use of HF-WBI increased significantly from 5% before 2012 (Q3) to 92% in 2016 (Q4). There was no significant difference in grade 1-2 toxicity between the two treatment groups. Fewer cases of grade 3 skin toxicity noted in the HF-WBI group (zero vs four events). CONCLUSION: HF-WBI had similar IBTR, OS and toxicity to CF-WBI.