Clinical and Genotypic Insights Into Higher Prevalence of Palbociclib Associated Neutropenia in Asian Patients.

BACKGROUND: CDK4/6 inhibitors (CDK4/6i) have shown great efficacy in prolonging progression-free survival and is the current standard of care for hormone positive (HR(+)) metastatic breast cancer (mBC). Despite well tolerability and ease of use, the most common side effect of CDK4/6i is myelosuppression, with neutropenia the most prevalent adverse effect. Studies show that the prevalence and severity of neutropenia are more marked in Asian patients, although details remain obscure. METHODS: In this study, we retrospectively analyzed 105 Taiwanese patients who received palbociclib for HR(+) HER2(-) mBC at the Taipei Veterans General Hospital. To investigate a possible genetic association for high prevalence of neutropenia, we queried the Taiwan Biobank with publicly available germline databases (ALFA, gnomAD, ExAC, 1000 Genomes project, HapMap), for the allele frequencies of 4 neutropenia-related SNPs (ABCB1_rs1045642, ABCB1_rs1128503, ERCC1_rs3212986, ERCC1_rs11615) and compared between different ethnicities. In addition, one of the patients was a long-term patient with peritoneal dialysis. We quantified the levels of palbociclib in her serum and peritoneal fluid by liquid chromatography-mass spectrometry (LC-MS). RESULTS: Interestingly, in our cohort, early neutropenia nadir (occurred within 56 days of start) was associated with worse treatment outcome, while occurrence of grade 3/4 neutropenia was associated with better outcome. We observed an extremely high incidence of neutropenia (96.2% any grade, 70.4% grade 3/4). In the analyzed germline databases, we discovered a higher SNP frequency of the T allele in ABCB1_rs1128503, a lower frequency of T allele in ABCB1_rs1045642, and a higher SNP frequency of G allele in ERCC1_rs11615. We observed that palbociclib levels in peritoneal dialysate ranged from around 20-50 ppb, and serum levels reached 100-110 ppb during drug administration and decreased to <10 ppb during discontinuation. CONCLUSION: Our retrospective analysis of real world palbociclib use reveals an association with grade 3/4 neutropenia with better outcome and early neutropenia nadir with worse outcome. Our findings of Asian specific SNPs support a predisposition toward profound and prevalent neutropenia in Asian patients under CDK4/6i. We also report the first pharmacokinetics analysis on a patient with peritoneal dialysis receiving CDK4/6i. In summary, our study provides novel clinical and genotypic insights into CDK4/6i associated neutropenia.

Peripheral blood stem cell harvesting in young children weighing less than 15 kg.

Autologous peripheral blood stem cell (PBSC) transplantation is crucial in pediatric cancer treatment, and tandem transplantation is beneficial in certain malignancies. Collecting PBSCs in small children with low body weight is challenging. We retrospectively analyzed data of pediatric cancer patients weighing <15 kg who underwent autologous PBSC harvesting in our hospital. Collections were performed in the pediatric intensive care unit over 2 or 3 consecutive days, to harvest sufficient stem cells (goal ≥2 × 106 CD34+ cells/kg per apheresate). From April 2006 to August 2021, we performed 129 collections after 50 mobilizations in 40 patients, with a median age of 1.9 (range, 0.6-5.6) years and a body weight of 11.0 (range, 6.6-14.7) kg. The median CD34+ cells in each apheresate were 4.2 (range, 0.01-40.13) × 106/kg. 78% and 56% of mobilizations achieved sufficient cell dose for single or tandem transplantation, respectively, without additional aliquoting. The preapheresis hematopoietic progenitor cell (HPC) count was highly correlated with the CD34+ cell yield in the apheresate (r = 0.555, P < 0.001). Granulocyte colony-stimulating factor alone was not effective for mobilization in children ≥2 years of age, even without radiation exposure. By combining the preapheresis HPC count ≥20/µL and the 3 significant host factors, including age <2 years, no radiation exposure and use of chemotherapy, the prediction rate of goal achievement was increased (area under the curve 0.787).

Comparing transfusion reactions between pre-storage and post-storage leukoreduced apheresis platelets: an analysis using propensity score matching.

Transfusion reactions induced by platelet transfusions may be reduced and alleviated by leukocyte reduction of platelets. Although leukoreduction of apheresis platelets can be performed either pre-storage or post-storage, seldom studies directly compare the incidence of transfusion reaction in these two different blood products. We conducted a retrospective study to compare the transfusion reactions between pre-storage and post-storage leukoreduced apheresis platelets. We reviewed the general characteristics and the transfusion reactions, symptoms, and categories for inpatients who received pre-storage or post-storage leukoreduced apheresis platelets. Propensity-score matching was performed to adjust for baseline differences between groups. A total of 40,837 leukoreduction apheresis platelet orders were reviewed. 116 (0.53%) transfusion reactions were reported in 21,884 transfusions with pre-storage leukoreduction, and 174 (0.91%) reactions were reported in 18,953 transfusions with post-storage leukoreduction. Before propensity-score matching, the odds ratio for transfusion reactions in the pre-storage group relative to the post-storage group was 0.57 (95% confidence interval [CI] 0.45-0.72, P < 0.01); the odds ratio after matching was 0.63 (95% CI 0.49-0.80, P < 0.01). A two-proportion z-test revealed pre-storage leukoreduction significantly decreases the symptoms of chills, fever, itching, urticaria, dyspnea, and hypertension as compared with those in post-storage leukoreduction. Pre-storage leukoreduced apheresis platelet significantly decreased febrile non-hemolytic transfusion reaction as compared with post-storage groups. This study suggests pre-storage leukoreduction apheresis platelet significantly decreases the transfusion reaction as compared with those in post-storage leukoreduction.

Risk factors of early disease progression and decreased survival for multiple myeloma patients after upfront autologous stem cell transplantation.

Multiple myeloma (MM) stands as the second most prevalent hematological malignancy, constituting approximately 10% of all hematological malignancies. Current guidelines recommend upfront autologous stem cell transplantation (ASCT) for transplant-eligible MM patients. This study seeks to delineate factors influencing post-ASCT outcomes in MM patients. Our cohort comprised 150 MM patients from Taipei Veterans General Hospital, with progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint. A Cox proportional hazards model was employed to discern potential predictive factors for survival. ASCT age ≥ 65 (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.08-3.47) and the presence of extramedullary disease (HR 2.53, 95% CI 1.53-4.19) negatively impacted PFS. Conversely, treatment response ≥ VGPR before ASCT (HR 0.52, 95% CI 0.31-0.87) and total CD34+ cells collected ≥ 4 × 106 cells/kg on the first stem cell harvesting (HR 0.52, 95% CI 0.32-0.87) were positively associated with PFS. For OS, patients with ISS stage III (HR 2.06, 95% CI 1.05-4.04), the presence of extramedullary disease (HR 3.92, 95% CI 2.03-7.58), light chain ratio ≥ 100 before ASCT (HR 7.08, 95% CI 1.45-34.59), post-ASCT cytomegalovirus infection (HR 9.43, 95% CI 3.09-28.84), and a lower conditioning melphalan dose (< 140 mg/m2; HR 2.75, 95% CI 1.23-6.17) experienced shorter OS. In contrast, post-ASCT day + 15 absolute monocyte counts (D15 AMC) > 500/µl (HR 0.36, 95% CI 0.17-0.79) and post-ASCT day + 15 platelet counts (D15 PLT) > 80,000/µl (HR 0.48, 95% CI 0.24-0.94) were correlated with improved OS. Significantly, early PLT and AMC recovery on day + 15 predicting longer OS represents a novel finding not previously reported. Other factors also align with previous studies. Our study provides real-world insights for post-ASCT outcome prediction beyond clinical trials.

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.

Genomic Alterations of Tumors in HER2-Low Breast Cancers.

The aim of this study was to elucidate molecular profiling in HER2-low tumors based on a promising dataset. A total of 615 consecutive HER2-negative breast cancer samples were assayed. The genomic mutations in the two groups with different HER2 expression levels (HER2-0 vs. HER2-low) were compared. The mutation types obtained via next-generation targeted sequencing were correlated with the clinicopathological features of the patients with HER2-0 and HER2-low breast cancer. The results showed that there was a significantly higher percentage of receptor-positive (ER/PR) tumors and more low-level Ki-67 tumors, but a lower incidence of stage I/II tumors in the HER2-low group compared to the HER2-0 group. There was a significantly higher frequency of 17.62% (65/369) for PIK3CA_SNA in the HER2-low group than in the HER2-0 group, which had a frequency of only 9.35% (23/246) (p = 0.006). When the called gene alterations in the triple-negative breast cancer (TNBC) group were compared with those in the luminal-like breast cancer group, there was a significantly high frequency of 28.17% (140/497) for ERBB2_SNA in a luminal-like group than in the TNBC group(16.95% (20/118)).We conclude that the early detection of PIK3CA mutations is likely to be important and might help therapeutic decision making in patients with HER2-low tumors.

Integration of Metal Catalysis and Organocatalysis in a Metal Nanocluster with Anchored Proline.

Chiral metal nanoclusters have recently been attracting great attention. It is challenging to realize asymmetric catalysis via atomically precise metal nanoclusters. Herein, we report the synthesis and total structure determination of chiral clusters [Au7Ag8(dppf)3(l-/d-proline)6](BF4)2 (l-/d-Au7Ag8). Superatomic clusters l-/d-Au7Ag8 display intense and mirror-image Cotton effects in their CD spectra. Density functional theory (DFT) calculations were carried out to understand the correlation between electronic structures and the optical activity of the enantiomeric pair. Surprisingly, the incorporation of proline in a metal nanocluster can significantly promote the catalytic efficiency in asymmetric Aldol reactions. The increase of catalytic activity of Au7Ag8 in comparison with organocatalysis by proline is attributed to the cooperative effect of the metal core and prolines, showing the advantages of the integration of metal catalysis and organocatalysis in a metal nanocluster.

Prevalence of BRCA1, BRCA2, and PALB2 genomic alterations among 924 Taiwanese breast cancer assays with tumor-only targeted sequencing: extended data analysis from the VGH-TAYLOR study.

BACKGROUND: The homologous recombination (HR) repair pathway for DNA damage, particularly the BRCA1 and BRCA2 genes, has become a target for cancer therapy, with poly ADP-ribose polymerase (PARP) inhibitors showing significant outcomes in treating germline BRCA1/2 (gBRCA1/2) mutated breast cancer. Recent studies suggest that some patients with somatic BRCA1/2 (sBRCA1/2) mutation or mutations in HR-related genes other than BRCA1/2 may benefit from PARP inhibitors as well, particularly those with PALB2 mutations. The current analysis aims to evaluate the prevalence of genetic alterations specific to BRCA1, BRCA2, and PALB2 in a large cohort of Taiwanese breast cancer patients through tumor-targeted sequencing. METHODS: A total of 924 consecutive assays from 879 Taiwanese breast cancer patients underwent tumor-targeted sequencing (Thermo Fisher Oncomine Comprehensive Assay v3). We evaluated BRCA1, BRCA2, and PALB2 mutational profiles, with variants annotated and curated by the ClinVAR, the Oncomine™ Knowledgebase Reporter, and the OncoKB™. We also conducted reflex germline testing using either whole exome sequencing (WES) or whole genome sequencing (WGS), which is ongoing. RESULTS: Among the 879 patients analyzed (924 assays), 130 had positive mutations in BRCA1 (3.1%), BRCA2 (8.6%), and PALB2 (5.2%), with a total of 14.8% having genetic alterations. Co-occurrence was noted between BRCA1/BRCA2, BRCA1/PALB2, and BRCA2/PALB2 mutations. In BRCA1-mutated samples, only p.K654fs was observed in three patients, while other variants were observed no more than twice. For BRCA2, p.N372H was the most common (26 patients), followed by p.S2186fs, p.V2466A, and p.X159_splice (5 times each). For PALB2, p.I887fs was the most common mutation (30 patients). This study identified 176 amino acid changes; 60.2% (106) were not documented in either ClinVAR or the Oncomine™ Knowledgebase Reporter. Using the OncoKB™ for annotation, 171 (97.2%) were found to have clinical implications. For the result of reflex germline testing, three variants (BRCA1 c.1969_1970del, BRCA1 c.3629_3630del, BRCA2 c.8755-1G > C) were annotated as Pathogenic/Likely pathogenic (P/LP) variants by ClinVar and as likely loss-of-function or likely oncogenic by OncoKB; while one variant (PALB2 c.448C > T) was not found in ClinVar but was annotated as likely loss-of-function or likely oncogenic by OncoKB. CONCLUSION: Our study depicted the mutational patterns of BRCA1, BRCA2, and PALB2 in Taiwanese breast cancer patients through tumor-only sequencing. This highlights the growing importance of BRCA1/2 and PALB2 alterations in breast cancer susceptibility risk and the treatment of index patients. We also emphasized the need to meticulously annotate variants in cancer-driver genes as well as actionable mutations across multiple databases.

The association of trastuzumab with atrial fibrillation and heart failure in breast cancer patients in routine clinical practice: a population-based propensity score matching and competing risk model analysis.

PURPOSE: Trastuzumab, a potent anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody, is conditionally reimbursed by the Taiwan National Health Insurance (NHI) for HER2-positive breast cancer (BC). Trastuzumab-induced cardiotoxicity studies have well characterized heart failure (HF) but fewer addressed arrhythmia, particularly the association of potential life threatening atrial fibrillation (Af) is poorly characterized. We aimed to study the trastuzumab-related risk of Af and HF using the claimed data of Taiwan NHI. METHODS: A nationwide retrospective cohort of patients with BC from the Taiwan NHI reimbursement database from January 2007 to December 2016 was analyzed. Propensity score matching and competing risk model analysis were used for adjusting confounding concurrent medication or comorbidities and competing events. The HF study was used to validate the method used. RESULTS: For Af, 12,472 trastuzumab users were matched with 12,472 non-trastuzumab users. For HF, 12,241 trastuzumab users and 12,241 non-users were enrolled. We found that trastuzumab users had significantly worse HF-free survival but not Af-free survival than non-trastuzumab users. In the competing risk analysis, the use of trastuzumab did not increase the risk of Af (hazard ratio [HR] 0.76, P = 0.0006) but was associated with HF (HR 1.19, P = 0.0052). The risk trends among stratifications by comorbidities and concurrent medication remained in similar directions for both Af and HF. CONCLUSION: Trastuzumab in real-world practice was associated with an increased risk of HF, but was not associated with an increased risk of Af in BC patients. Trastuzumab-induced arrhythmogenic effects may be masked by concurrent heart-protecting measures, more prominent roles of comorbidities or concurrent medications under real-world settings. Further studies are required.

Management of cancer-related fatigue in Taiwan: an evidence-based consensus for screening, assessment and treatment.

BACKGROUND: Cancer-related fatigue is one of the most common and persistent issues experienced by cancer patients. Cancer-related fatigue is a distinct form of fatigue that is subjective, long-lasting and unalleviated by rest or sleep. Studies have shown that almost all cancer patients experience severe fatigue that disrupts the quality of life and physical function, but cancer-related fatigue remains under-addressed in clinical care, and only about half of all patients receive treatment. METHODS: To increase the awareness of cancer-related fatigue and improve current management, the Taiwan Society of Cancer Palliative Medicine and the Taiwan Oncology Nursing Society convened a consensus committee to develop recommendations for the screening, assessment and treatment of cancer-related fatigue. RESULTS: Thirteen consensus recommendations were subsequently developed based on the best available evidence and the clinical experience of committee members. CONCLUSIONS: These recommendations are expected to facilitate the standardization of cancer-related fatigue management across Taiwan and may also serve as a reference for other clinicians.

Risk Factors and Outcomes of Stem Cell Mobilization Failure in Multiple Myeloma Patients.

Introduction: Autologous hematopoietic stem cell transplantation (ASCT) is a well-established treatment for patients with multiple myeloma (MM), and adequate stem cell collection must be assured before ASCT. However, prediction of poor mobilizers (PMs) is still difficult despite several risk factors for mobilization failure having been identified. Methods: We retrospectively analyzed MM patients at Taipei Veterans General Hospital in Taiwan who underwent stem cell collection between October 2006 and August 2020. A CD34+ cell collection of <1 × 106 cells/kg was defined as a mobilization failure. The primary endpoint was mobilization failure. The secondary endpoint was overall survival (OS). Odds ratios (ORs) and 95% confidence intervals (CIs) for mobilization failure were calculated using a logistic regression model. The cumulative incidence of mortality was estimated using the Kaplan-Meier method. Results: In the multivariate analysis, absolute monocyte count <500/µL (adjusted OR 10.75, 95% CI: 1.82-63.57, p = 0.009), platelet count <150,000/µL (adjusted OR 12.49, 95% CI: 2.65-58.89, p = 0.001) before mobilization, and time interval from diagnosis to stem cell harvest ≥180 days (adjusted OR 7.69, 95% CI: 1.61-36.87, p = 0.011) were risk factors for PMs. PM patients had poorer OS compared to patients with successful stem cell collection in the univariate analysis (log-rank test p = 0.027). The predicted probability of PMs was estimated by the multiple logistic regression model with a sensitivity of 84.6% and a specificity of 84.0%. Conclusion: Absolute monocyte count <500/µL, platelet count <150,000/µL, and treatment duration more than 180 days before stem cell mobilization are risk factors for unsuccessful stem cell collection. Our prediction models have high sensitivity and specificity for mobilization failure prediction and allow for early interventions for possible PMs.

Disc-Like Silver Nanocluster Ag93 Built with Bicapped Hexagonal Prismatic Ag15 and Ino Decahedral Ag13 Units.

The reduction of alkynyl-silver and phosphine-silver precursors with a weak reducing reagent Ph2 SiH2 led to the formation of a novel silver nanocluster [Ag93 (PPh3 )6 (C≡CR)50 ]3+ (R=4-CH3 OC6 H4 ), which is the largest structurally characterized cluster of clusters. This disc-shaped cluster has a Ag69 kernel consisting of a bicapped hexagonal prismatic Ag15 unit wrapped by six Ino decahedra through edge-sharing. This is the first time that Ino decahedra are used as a building block to assemble a cluster of clusters. Moreover, the central silver atom has a coordination number of 14, which is the highest in metal nanoclusters. This work provides a diverse metal packing pattern in metal nanoclusters, which is helpful for understanding metal cluster assembling mechanisms.

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.

Impact of BRCA mutation on the survival and risk of contralateral breast cancer in Asian breast cancer patients.

PURPOSE: Breast cancer is increasing around the globe, including Asia. We aimed to examine the survival and risk of contralateral breast cancer (CBC) in Asian breast cancer patients with BRCA mutations. METHODS: A total of 128 breast cancer patients with germline BRCA mutations and 4,754 control breast cancer patients were enrolled. Data on clinical-pathologic characteristics, survival, and CBC were collected from the medical record. The rates of survival and CBC were estimated by Kaplan-Meier method. RESULTS: The mean age of onset in BRCA mutation carriers was significantly younger than control patients (BRCA vs. Non-BRCA: 43.9 vs. 53.2 years old). BRCA mutation carriers had a higher proportion of triple-negative breast cancer (TNBC) (52%) than control patients (12%, p < 0.001). The risk of CBC was significantly higher in BRCA mutation patients than in control cases (hazard ratio (HR) = 3.95, 95% CI 2.71-5.75); when stratified by genotype, the HRs (95%CI) were 4.84 (3.00-7.82) for BRCA1 and 3.13 (1.78-5.49) for BRCA2 carriers, respectively. Moreover, BRCA1 mutation patients with triple-negative breast cancer (TNBC) as their first breast cancer had the highest risk of CBC (HR = 5.55, 95% CI 3.29-9.34). However, we did not observe any differences in relapse-free survival and overall survival between mutation carriers and control patients. CONCLUSION: Our study suggest that BRCA patients had a significantly higher risk of developing CBC, particularly for BRCA1 mutation carriers with TNBC as the first breast cancer.

The meV XUV-RIXS facility at UE112-PGM1 of BESSY II.

Resonant inelastic X-ray scattering in the XUV-regime has been implemented at BESSY II, pushing for a few-meV bandwidth in inelastic X-ray scattering at transition metal M-edges, rare earth N-edges and the K-edges of light elements up to carbon with full polarization control. The new dedicated low-energy beamline UE112-PGM1 has been designed to provide 1 µm vertical and 20 µm horizontal beam dimensions that serve together with sub-micrometre solid-state sample positioning as the source point for a high-resolution plane grating spectrometer and a high-transmission Rowland spectrometer for rapid overview spectra. The design and commissioning results of the beamline and high-resolution spectrometer are presented. Helium autoionization spectra demonstrate a resolving power of the beamline better than 10 000 at 64 eV with a 300 lines mm-1 grating while the measured resolving power of the spectrometer in the relevant energy range is 3000 to 6000.

Prevalence of Tumor Genomic Alterations in Homologous Recombination Repair Genes Among Taiwanese Breast Cancers.

PURPOSE: Deleterious germline BRCA1/2 mutations are among the most highly pathogenic variants in hereditary breast and ovarian cancer syndrome. Recently, genes implicated in homologous recombination repair (HRR) pathways have been investigated extensively. Defective HRR genes may indicate potential clinical benefits from PARP (poly ADP ribose polymerase) inhibitors beyond BRCA1/2 mutations. METHODS: We evaluated the prevalence of BRCA1/2 mutations as well as alterations in HRR genes with targeted sequencing. A total of 648 consecutive breast cancer samples were assayed, and HRR genes were evaluated for prevalence in breast cancer tissues. RESULTS: Among 648 breast cancers, there were 17 truncating and 2 missense mutations in BRCA1 and 45 truncating and 1 missense mutation in BRCA2, impacting 3% and 5% of the study population (collectively altered in 6%) with cooccurrence of BRCA1/2 in 7 breast cancers. On the other hand, HRR genes were altered in 122 (19%) breast cancers, while TBB (Talazoparib Beyond BRCA) trial-interrogated genes (excluding BRCA1/2) were mutated in 107 (17%) patients. Beyond BRCA1/2, the most prevalent HRR mutant genes came from ARID1A (7%), PALB2 (7%), and PTEN (6%). Collectively, 164 (25%) of the 648 Taiwanese breast cancer samples harbored at least one mutation among HRR genes. CONCLUSIONS: The prevalence of BRCA1/2 mutations was far below one tenth, while the prevalence of HRR mutations was much higher and approached one-fourth among Taiwanese breast cancers. Further opportunities to take advantage of defective HRR genes for breast cancer treatment should be sought for the realization of precision medicine.

Two-Stage Structural and Slowing-Down Percolation Transitions in the Densifying Cancer Cell Monolayer.

We experimentally demonstrate the two-stage structural and slowing-down percolating transitions, followed by the confluent transition in the densifying cancer cell monolayers from the dilute state, and investigate their impacts on collective cell dynamics. It is found that cells aggregate into clusters at low cell density. With increasing cell number density, the structural percolation through the formation of a large cell cluster percolating through the space precedes the dynamical percolation transition of forming a percolating cluster of slow cell elements. Both percolating transitions exhibit scale-free scaling behaviors of cluster size distributions and fractal structures, similar to those of the universality class of 2D nonequilibrium systems governed by percolation theory. Dynamically, at low cell density, cell aggregation enhances cooperative motion. The structural percolation leads to slower motion, especially with stronger suppression for the high-frequency modes in the turbulent-like velocity power spectra. The following slowing-down percolation associated with the onset of cell crowding in regions occupied by cells further enhances dynamical slowing-down, and suppresses the increasing trend of dynamical heterogeneity and the steepening of the power spectrum of motion, until their reversions after the confluent transition.

Nitrogen Donor Protection for Atomically Precise Metal Nanoclusters.

Surface organic ligands are critical in dictating the structures and properties of atomically precise metal nanoclusters. In contrast to the conventionally used thiolate, phosphine and alkynyl ligands, nitrogen donor ligands have not been used in the protection for well-defined metal nanoclusters until recently. This review focuses on recent developments in atomically precise metal nanoclusters stabilized by different types of nitrogen donor ligands, in which the synthesis, total structure determination and various properties are covered. We hope that this review will provide insights into the rational design of N donor-protected metal nanoclusters in terms of structural and functional modulation.

Influence of diabetes mellitus on the diagnostic performance of machine learning-based coronary CT angiography-derived fractional flow reserve: a multicenter study.

OBJECTIVES: To examine the diagnostic accuracy of machine learning-based coronary CT angiography-derived fractional flow reserve (FFRCT) in diabetes mellitus (DM) patients. METHODS: In total, 484 patients with suspected or known coronary artery disease from 11 Chinese medical centers were retrospectively analyzed. All patients underwent CCTA, FFRCT, and invasive FFR. The patients were further grouped into mild (25~49 %), moderate (50~69 %), and severe (≥ 70 %) according to CCTA stenosis degree and Agatston score < 400 and Agatston score ≥ 400 groups according to coronary artery calcium severity. Propensity score matching (PSM) was used to match DM (n  = 112) and non-DM (n  = 214) groups. Sensitivity, specificity, accuracy, and area under the curve (AUC) with 95 % confidence interval (CI) were calculated and compared. RESULTS: Sensitivity, specificity, accuracy, and AUC of FFRCT were 0.79, 0.96, 0.87, and 0.91 in DM patients and 0.82, 0.93, 0.89, and 0.89 in non-DM patients without significant difference (all p > 0.05) on a per-patient level. The accuracies of FFRCT had no significant difference among different coronary stenosis subgroups and between two coronary calcium subgroups (all p > 0.05) in the DM and non-DM groups. After PSM grouping, the accuracies of FFRCT were 0.88 in the DM group and 0.87 in the non-DM group without a statistical difference (p > 0.05). CONCLUSIONS: DM has no negative impact on the diagnostic accuracy of machine learning-based FFRCT. KEY POINTS: • ML-based FFRCT has a high discriminative accuracy of hemodynamic ischemia, which is not affected by DM. • FFRCT was superior to the CCTA alone for the detection of ischemia relevance of coronary artery stenosis in both DM and non-DM patients. • Coronary calcification had no significant effect on the diagnostic accuracy of FFRCT to detect ischemia in DM patients.

Spontaneous multi-scale void formation and closure in densifying epithelial and fibroblast monolayers from the sub-confluent state.

Using time-lapse phase contrast microscopy, the formation and closure of spontaneously generated voids in the densifying monolayers of isotropic epithelial cells (ECs) and elongated fibroblast cells (FCs) through proliferation from the sub-confluent state are investigated. It is found that, in both types of monolayers after forming a connected network composed of nematic patches with different orientations, numerous multi-scale voids can be spontaneously formed and gradually close with increasing time. The isotropic fluctuations of deformation and crawling of ECs and the anisotropic axial motion/alignment polarizations of FCs are the two keys leading to the following different generic dynamical behaviors. In EC monolayers, voids exhibit irregular boundary fluctuations and easier cell re-orientation of front layer cells (FLCs) surrounding void boundaries. Void closures are mainly through pinching the gap between the opposite fluctuating void boundaries, and the inward crawling of FLCs to reduce void area associated with topological rearrangement to reduce FLC number. In FC monolayers, large voids have piecewise smooth convex boundaries, and cusp-shaped concave boundaries with cells orienting toward the void at cusp tips. The extension of a thin cell bridge from the cusp tip can bisect a large void into smaller voids. For smaller FC voids dominated by convex boundaries, along which cell alignment prohibits inward crawling, the reduction of FLC number through successive outward squeezing of single FLCs by neighboring FLCs sliding along the void boundary plays an important role for topological rearrangement and void closure. Unlike those surrounding artificial wounds in dense EC monolayers, the absence of ring-like purse-strings surrounding EC and FC voids allows topological rearrangements for reducing void perimeter and void area.