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Eigenspace estimation is a fundamental tool in data analytics, which has found applications in PCA, dimension reduction, and clustering, among others. The modern machine learning community usually involves data that come from and belong to different organizations. The low communication power and possible data privacy breaches make the eigenspace estimation challenging. To address these issues, we propose a class of algorithms called FedPower within the federated learning (FL) framework. FedPower leverages the well-known power method by alternating multiple local power iterations and a global aggregation step, thus improving communication efficiency. In the aggregation, we propose to weight each local eigenvector matrix with Orthogonal Procrustes Transformation (OPT) for better alignment. We add Gaussian noise in each iteration to ensure strong privacy protection by adopting the notion of differential privacy (DP). We provide convergence bounds for FedPower composed of different interpretable terms corresponding to the effects of Gaussian noise, parallelization, and random sampling of local machines. Additionally, we conduct experiments to demonstrate the effectiveness of our proposed algorithms. [ABSTRACT FROM AUTHOR]

Background: To assess the distribution characteristics of immune infiltration and lymphovascular invasion in breast cancer skin recurrence patients. Methods: We retrospectively analyzed the clinicopathological data of patients who underwent radical surgery for primary breast cancer and experienced skin recurrence between January 2001 and April 2019. Immune and lymphovascular biomarkers were quantified in primary breast cancers, skin lesions and visceral metastatic lesions. Differences in biomarkers distribution between matched tissues were statistically analyzed using the Wilcoxon signed-rank test and Kruskal–Wallis one-way ANOVA. Results: A total of 71 female breast cancer patients were reviewed in this study. Our study found that the expression levels of various lymphocyte immune markers in primary tumor specimens were higher than those in skin recurrences. The expression of CD8, CD57 and CD31 in primary breast cancer was higher than those in the skin. Compared to visceral metastatic lesions, D2-40 was highly expressed in the skin, while CD8 tended to decrease. In the skin specimens, the expression of CD8 (P < 0.001), FOXP3 (P = 0.006) and CD68 (P < 0.001) in the intratumoral area was higher, while the expression of CD57 (P < 0.001) was higher in the peritumoral area. Analyzing specimens from the same patient at different time points of skin progression, it was found that the expression of peritumoral CD4 decreased (P = 0.044) as the disease progressed. The low expression of D2-40 and CD163 in the skin lesions suggested a decrease in DFS. Conclusion: The immune microenvironment of breast cancer skin recurrence may be in a state of suppression, and this suppression may intensify with disease progression. The pattern of skin recurrence may be more inclined toward lymphatic invasion. Our study provides new insights into the biological behaviors of this disease and its response to immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Young patients with breast ductal carcinoma in situ (DCIS) often face a poorer prognosis. The genomic intricacies in young-onset DCIS, however, remain underexplored. Methods: To address this gap, we undertook a comprehensive study encompassing exome, transcriptome, and vmethylome analyses. Our investigation included 20 DCIS samples (including 15 young-onset DCIS) and paired samples of normal breast tissue and blood. Results: Through RNA sequencing, we identified two distinct DCIS subgroups: "immune hot" and "immune cold". The "immune hot" subgroup was characterized by increased infiltration of lymphocytes and macrophages, elevated expression of PDCD1 and CTLA4, and reduced GATA3 expression. This group also exhibited active immunerelated transcriptional regulators. Mutational analysis revealed alterations in TP53 (38%), GATA3 (25%), and TTN (19%), with two cases showing mutations in APC, ERBB2, and SMARCC1. Common genomic alterations, irrespective of immune status, included gains in copy numbers at 1q, 8q, 17q, and 20q, and losses at 11q, 17p, and 22q. Signature analysis highlighted the predominance of signatures 2 and 1, with "immune cold" samples showing a significant presence of signature 8. Our methylome study on 13 DCIS samples identified 328 hyperdifferentially methylated regions (DMRs) and 521 hypo-DMRs, with "immune cold" cases generally showing lower levels of methylation. Conclusion: In summary, the molecular characteristics of young-onset DCIS share similarities with invasive breast cancer (IBC), potentially indicating a poor prognosis. Understanding these characteristics, especially the immune microenvironment of DCIS, could be pivotal in identifying new therapeutic targets and preventive strategies for breast cancer. [ABSTRACT FROM AUTHOR]

Background: The global BOLERO-2 trial established the efficacy and safety of combination everolimus (EVE) and exemestane (EXE) in the treatment of estrogen receptor positive (ER +), HER2-, advanced breast cancer (ABC). BOLERO-5 investigated this combination in a Chinese population (NCT03312738). Methods: BOLERO-5 is a randomized, double-blind, multicenter, placebo controlled, phase II trial comparing EVE (10 mg/day) or placebo (PBO) in combination with EXE (25 mg/day). The primary endpoint was progression-free survival (PFS) per investigator assessment. Secondary endpoints included PFS per blinded independent review committee (BIRC), overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), pharmacokinetics, and safety. Results: A total of 159 patients were randomized to EVE + EXE (n = 80) or PBO + EXE (n = 79). By investigator assessment, treatment with EVE + EXE prolonged median PFS by 5.4 months (HR 0.52; 90% CI 0.38, 0.71), from 2.0 months (PBO + EXE; 90% CI 1.9, 3.6) to 7.4 months (EVE + EXE; 90% CI 5.5, 9.0). Similar results were observed following assessment by BIRC, with median PFS prolonged by 4.3 months. Treatment with EVE + EXE was also associated with improvements in ORR and CBR. No new safety signals were identified in BOLERO-5, with the incidence of adverse events in Chinese patients consistent with the safety profile of both drugs. Conclusion: The efficacy and safety results of BOLERO-5 validate the findings from BOLERO-2, and further support the use of EVE + EXE in Chinese post-menopausal women with ER + , HER2- ABC. NCT03312738, registered 18 October 2017. [ABSTRACT FROM AUTHOR]

Currently approved HER2-targeting antibody-drug conjugates (ADCs) for HER2-positive breast cancer (BC) are associated with safety concerns. In this multicenter, single-arm, dose-escalation (phase 1a) and dose-expansion (phase 1b) phase 1 trial (NCT03944499), patients with HER2-expressing advanced solid tumors received FS-1502 (an anti-HER2 ADC) with a 3 + 3 design in phase 1a; patients with metastatic HER2-positive BC received FS-1502 at the recommended phase 2 dose (RP2D) in phase 1b. The primary end points were dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and RP2D for phase 1a and objective response rate (ORR) for phase 1b. A total of 150 patients with HER2-expressing solid tumors (n = 5) and BC (n = 145) were enrolled (female, n = 146, 97.3%). One DLT each was reported at 3.0 and 3.5 mg/kg; the MTD was not reached. The RP2D was 2.3 mg/kg once every 3 weeks. Five (3.3%) patients experienced pneumonitis; four (2.7%) had grade 3 reversible ocular events. Of 67 HER2-positive BC patients receiving the RP2D, the best ORR was 53.7% (95% CI, 41.1-66.0%), including PRs confirmed (confirmed ORR, 37.5%) and pending for confirmation. FS-1502 was well tolerated with limited ocular and pulmonary findings and demonstrated promising antitumor activity in HER2-positive BC patients. Safety concerns limit the success of HER2-targeting antibody-drug conjugates (ADCs) for the treatment of HER2-postive breast cancer. Here, the authors present a phase 1a/b trial reporting the safety and preliminary efficacy of FS-1502, an anti-HER2 ADC with a cancer-selective cleavable linker, for the treatment of HER2-positive metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Background: Deciduous forests in eastern North America experienced a widespread and intense spongy moth (Lymantria dispar) infestation in 2021. This study quantified the impact of this spongy moth infestation on carbon (C) cycle in forests across the Great Lakes region in Canada, utilizing high-resolution (10 × 10 m2) Sentinel-2 satellite remote sensing images and eddy covariance (EC) flux data. Study results showed a significant reduction in leaf area index (LAI) and gross primary productivity (GPP) values in deciduous and mixed forests in the region in 2021. Results: Remote sensing derived, growing season mean LAI values of deciduous (mixed) forests were 3.66 (3.18), 2.74 (2.64), and 3.53 (2.94) m2 m−2 in 2020, 2021 and 2022, respectively, indicating about 24 (14)% reduction in LAI, as compared to pre- and post-infestation years. Similarly, growing season GPP values in deciduous (mixed) forests were 1338 (1208), 868 (932), and 1367 (1175) g C m−2, respectively in 2020, 2021 and 2022, showing about 35 (22)% reduction in GPP in 2021 as compared to pre- and post-infestation years. This infestation induced reduction in GPP of deciduous and mixed forests, when upscaled to whole study area (178,000 km2), resulted in 21.1 (21.4) Mt of C loss as compared to 2020 (2022), respectively. It shows the large scale of C losses caused by this infestation in Canadian Great Lakes region. Conclusions: The methods developed in this study offer valuable tools to assess and quantify natural disturbance impacts on the regional C balance of forest ecosystems by integrating field observations, high-resolution remote sensing data and models. Study results will also help in developing sustainable forest management practices to achieve net-zero C emission goals through nature-based climate change solutions. [ABSTRACT FROM AUTHOR]

In diabetes, macrophages and inflammation are increased in the islets, along with β-cell dysfunction. Here, we demonstrate that galectin-3 (Gal3), mainly produced and secreted by macrophages, is elevated in islets from both high-fat diet (HFD)-fed and diabetic db/db mice. Gal3 acutely reduces glucose-stimulated insulin secretion (GSIS) in β-cell lines and primary islets in mice and humans. Importantly, Gal3 binds to calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1) and inhibits calcium influx via the cytomembrane and subsequent GSIS. β-Cell CACNG1 deficiency phenocopies Gal3 treatment. Inhibition of Gal3 through either genetic or pharmacologic loss of function improves GSIS and glucose homeostasis in both HFD-fed and db/db mice. All animal findings are applicable to male mice. Here we show a role of Gal3 in pancreatic β-cell dysfunction, and Gal3 could be a therapeutic target for the treatment of type 2 diabetes. Galectin-3, mainly produced and secreted by macrophages, is elevated in diabetes. Here, the authors show that galectin-3 directly interacts with voltage-gated channel auxiliary subunit gamma 1 (CACNG1) and blocks calcium transients and subsequent insulin secretion. [ABSTRACT FROM AUTHOR]

The randomized, multicenter, double-blind, placebo-controlled, phase III PEONY trial (NCT02586025) demonstrated significantly improved total pathologic complete response (primary endpoint) with dual HER2 blockade in HER2-positive early/locally advanced breast cancer, as previously reported. Here, we present the final, long-term efficacy (secondary endpoints: event-free survival, disease-free survival, overall survival) and safety analysis (62.9 months' median follow-up). Patients (female; n = 329; randomized 2:1) received neoadjuvant pertuzumab/placebo with trastuzumab and docetaxel, followed by adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, then pertuzumab/placebo with trastuzumab until disease recurrence or unacceptable toxicity, for up to 1 year. Five-year event-free survival estimates are 84.8% with pertuzumab and 73.7% with placebo (hazard ratio 0.53; 95% confidence interval 0.32–0.89); 5-year disease-free survival rates are 86.0% and 75.0%, respectively (hazard ratio 0.52; 95% confidence interval 0.30–0.88). Safety data are consistent with the known pertuzumab safety profile and generally comparable between arms, except for diarrhea. Limitations include the lack of ado-trastuzumab emtansine as an option for patients with residual disease and the descriptive nature of the secondary, long-term efficacy endpoints. PEONY confirms the positive benefit:risk ratio of neoadjuvant/adjuvant pertuzumab, trastuzumab, and docetaxel treatment in this patient population. Previously, the authors reported the primary analysis of a phase III randomized control trial investigating dual HER2 blockade in HER2-positive early/locally advanced breast cancer. Here, the authors report the long-term efficacy and safety analysis of this trial. [ABSTRACT FROM AUTHOR]

This study aimed to reveal the soil reinforcement by shrub root systems after repeated stress from external forces, such as high winds and runoff, for extended periods in the wind-hydraulic compound erosion zone. Using the widely distributed Shandong mine area soil and water-conserving plant species, Caragana microphylla, Hippophae rhamnoides, and Artemisia ordosica, cyclic loading tests were conducted on taproots of the three plant species (1–5 mm diameter) via a TY8000 servo-type machine to investigate the taproots' tensile properties response to repeated loading–unloading using simulated high wind pulling and runoff scouring. Our study revealed that the tensile force was positively correlated with the root diameter but the tensile strength was negatively correlated under monotonic and cyclic loading of the three plants' taproots. However, after cyclic loading, the three plant species' taproots significantly enhanced the tensile force and strength more than monotonic loading (P < 0.05). The taproot force–displacement hysteresis curves of the three plant species revealed obvious cyclic characteristics. Structural equation modeling analysis revealed that root diameter and damage method directly affected the taproots' survival rate, reflecting their sustainable soil reinforcement capacity. The damage method significantly influenced the soil reinforcement more than the root diameter. Our findings reveal that the plant species' taproots can adapt more to the external environment and enhance their resistance to erosion after natural low perimeter erosion damage, effectively inducing soil reinforcement. Particularly, the taproots of Caragana microphylla have superior soil-fixing ability and can be used for ecological restoration. [ABSTRACT FROM AUTHOR]

β-Cell dysfunction and β-cell loss are hallmarks of type 2 diabetes (T2D). Here, we found that trimethylamine N-oxide (TMAO) at a similar concentration to that found in diabetes could directly decrease glucose-stimulated insulin secretion (GSIS) in MIN6 cells and primary islets from mice or humans. Elevation of TMAO levels impairs GSIS, β-cell proportion, and glucose tolerance in male C57BL/6 J mice. TMAO inhibits calcium transients through NLRP3 inflammasome-related cytokines and induced Serca2 loss, and a Serca2 agonist reversed the effect of TMAO on β-cell function in vitro and in vivo. Additionally, long-term TMAO exposure promotes β-cell ER stress, dedifferentiation, and apoptosis and inhibits β-cell transcriptional identity. Inhibition of TMAO production improves β-cell GSIS, β-cell proportion, and glucose tolerance in both male db/db and choline diet-fed mice. These observations identify a role for TMAO in β-cell dysfunction and maintenance, and inhibition of TMAO could be an approach for the treatment of T2D.β-Cell dysfunction is a hallmark of type 2 diabetes. Here, the authors show that trimethylamine N-oxide (TMAO (a microbiota metabolite)) induces β-cell dysfunction and type 2 diabetes in mice through NLRP3 inflammasome activation and calcium transients. [ABSTRACT FROM AUTHOR]

In zero-shot relation extraction, existing methods usually learn semantic features from seen relations to infer unseen relations. However, because there is no instance of unseen relation that can be used for training, it is still a challenge for the existing models to learn the semantic gap between seen relations and unseen relations, resulting in poor generalization performance of the learned semantic features. Therefore, we propose a Semantic Max-Divergence Metric (SMDM) based method to measure the distances between relations from both direct and indirect semantic differences. For that, we learn multiple binary feature reference-spaces to extract the semantic divergences of each unseen relation instance relative to each seen relation, which can be converted to a relative-affinity (RA) matrix as indirect semantic metrics. Furthermore, we combine RA with direct semantic metrics based on BERT to maximum the divergences between unseen relation instances and get clearer unseen relation boundaries. Empirical results on benchmark datasets demonstrate SMDM can the superior improvement on F1-score and external indicators of SMDM compared to the state-of-the-art methods. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of malignant tumor-related deaths worldwide. The presence of tumor-initiating cells in lung cancer leads to tumor recurrence, metastasis, and resistance to conventional treatment. Cleavage and polyadenylation specificity factor 4 (CPSF4) activation in tumor cells contributes to the poor prognosis of lung cancer. However, the precise biological functions and molecular mechanisms of CPSF4 in the regulation of tumor-initiating cells remain unclear. We demonstrated that CPSF4 promotes tumor-initiating phenotype and confers chemoresistance to paclitaxel both in vitro and in vivo. Mechanistically, we showed that CPSF4 binds to the promoters of vascular endothelial growth factor (VEGF) and neuropilin-2 (NRP2) and activated their transcription. In addition, we showed that CPSF4/VEGF/NRP2-mediated tumor-initiating phenotype and chemoresistance through TAZ induction. Furthermore, analysis of clinical data revealed that lung cancer patients with high CPSF4 expression exhibit high expression levels of VEGF, NRP2, and TAZ and that expression of these proteins are positively correlated with poor prognosis. Importantly, selective inhibition of VEGF, NRP2, or TAZ markedly suppressed CPSF4-mediated tumor-initiating phenotype and chemoresistance. Our findings reveal the mechanism of CPSF4 modulating tumor-initiating phenotype and chemoresistance in lung cancer and indicate that the CPSF4-VEGF-NRP2-TAZ signaling pathway may be a prognosis marker and therapeutic target in lung cancer. [ABSTRACT FROM AUTHOR]

Purpose: Findings from randomized clinical trials have shown that survival in patients with sentinel lymph node (SLN)-negative breast cancer is noninferior with SLN biopsy (SLNB) alone versus further axillary lymph node dissection (ALND). However, the long-term outcome of these two surgical approaches in pN0 breast cancer patients in real-world setting remains uncertain. Methods: We included patients diagnosed with pathologically staged T1-2N0M0 breast cancer between 2000 and 2015 in surveillance, epidemiology, and end results 18-registry database. Patients were considered to have undergone SLNB alone if they had ≤ 5 examined lymph nodes (ELNs), and ALND if they had ≥ 10 ELNs. The outcomes included overall survival (OS) and breast cancer-specific survival. Propensity score analyses by weighting and matching and multivariable Cox regression analysis were performed to minimize treatment selection bias. Results: We included 309,430 patients (253,501 SLNB and 55,929 ALND). In the weighted cohort, ALND was associated with significantly lower OS (hazard ratio [HR] 1.13; 95% confidence interval [CI] 1.10–1.16) and BCSS (HR 1.16; 95% CI 1.10–1.22) compared with SLNB alone. Both the propensity score-matching model and multivariable Cox model demonstrated a survival benefit for SLNB when compared with ALND. Subgroup analyses for key variables did not change these findings. Conclusion: We found statistically significant differences in OS and BCSS between SLNB and ALND, though the magnitude of these differences was small. Our findings further support that SLNB alone should be the standard of care for patients who do not have metastatic lymph nodes identified during breast cancer surgery. [ABSTRACT FROM AUTHOR]

2205 duplex stainless steel (DSS) has good corrosion resistance due to its typical duplex organization, but the increasingly harsh CO2-containing oil and gas environment leads to different degrees of corrosion, especially pitting corrosion, which seriously threatens the safety and reliability of oil and gas development. In this paper, the effect of temperature on the corrosion behavior of 2205 DSS in a simulated solution containing 100 g/L Cl− and saturated CO2 was investigated with immersion tests and electrochemical tests and combined with characterization techniques such as laser confocal microscopy and X-ray photoelectron spectroscopy. The results show that the average critical pitting temperature of 2205 DSS was 66.9 °C. When the temperature was higher than 66.9 °C, the pitting breakdown potential, passivation interval, and self-corrosion potential decreased, while the dimensional passivation current density increased, and the pitting sensitivity was enhanced. With a further increase in temperature, the capacitive arc radius of 2205 DSS decreased, the film resistance and charge transfer resistance gradually decreased, the carrier density of the donor and acceptor in the product film layer with n + p bipolar characteristics also increased and the inner layer of the film with Cr oxide content decreased, while the outer layer with Fe oxide content increased, the dissolution of the film layer increased, the stability decreased, and the number and pore size of pits increased. [ABSTRACT FROM AUTHOR]

Platinum is recommended in combination with gemcitabine in the treatment of metastatic triple-negative breast cancer (mTNBC). We conduct a randomized phase 3, controlled, open-label trial to compare nab-paclitaxel/cisplatin (AP) with gemcitabine/cisplatin (GP) in mTNBC patients (ClinicalTrials.gov NCT02546934). 254 patients with untreated mTNBC randomly receive AP (nab-paclitaxel 125 mg/m² on day 1, 8 and cisplatin 75 mg/m² on day 1) or GP (gemcitabine 1250 mg/m² on day 1, 8 and cisplatin 75 mg/m² on day 1) intravenously every 3 weeks until progression disease, intolerable toxicity or withdrawal of consent. The primary endpoint is progression-free survival (PFS); secondary endpoints are objective response rate (ORR), safety and overall survival (OS). The trial has met pre-specified endpoints. The median PFS is 9.8 months with AP as compared to 7.4 months with GP (stratified HR, 0.67; 95% CI, 0.50–0.88; P = 0.004). AP significantly increases ORR (81.1% vs. 56.3%, P < 0.001) and prolongs OS (stratified HR, 0.62; 95% CI, 0.44–0.90; P = 0.010) to GP. Of grade 3 or 4 adverse events, a significantly higher incidence of neuropathy in AP and thrombocytopenia in GP is noted. These findings warrant further assessment of adding novel agents to the nab-paclitaxel/platinum backbone due to its high potency for patients with mTNBC. Platinum agents, such as carboplatin and cisplatin, have been recommended in combination with gemcitabine for the treatment of metastatic triple negative breast cancer (TNBC). Here the authors report the results of a randomized phase 3 trial to compare the efficacy of first-line nab-paclitaxel/cisplatin to gemcitabine/cisplatin in patients with TNBC. [ABSTRACT FROM AUTHOR]

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Purpose: This phase 1, open-label, single-arm clinical trial evaluated pharmacokinetics, safety, and biomarker activity of palbociclib-letrozole as first-line treatment for estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) in postmenopausal Chinese women to support palbociclib approval in China.Methods: Patients received palbociclib 125 mg once daily (3/1 schedule) plus letrozole 2.5 mg once daily. Blood samples were collected predose and ≤ 120 h after single and multiple doses of palbociclib. The incidence and severity of adverse events were reported. Skin biopsy tissues and blood samples were collected for biomarker assessments.Results: By 31 July 2018, 26 patients were enrolled. After single and multiple dosing, palbociclib maximum plasma concentration was 82.14 and 139.7 ng/mL, apparent clearance was 52.40 and 49.97 L/h, AUCτ was 1217 and 2501 ng∙h/mL, and t½ was 23.46 and 27.26 h, respectively. Levels of Ki67, retinoblastoma protein, and thymidine kinase decreased after palbociclib treatment. A similar safety profile as previously reported was observed.Conclusions: Pharmacokinetic and pharmacodynamic effects of palbociclib were well characterized in Chinese patients with ABC. Despite higher exposure, pharmacokinetic parameters were similar to those of a previously studied non-Asian population. No palbociclib dose adjustment based on Chinese ethnicity is needed. Palbociclib-letrozole had a manageable safety profile.Clinical Trial Registration: NCT02499146. [ABSTRACT FROM AUTHOR]

Purpose: In the KATHERINE study (NCT01772472), patients with HER2-positive early breast cancer (EBC) and residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy who were treated with adjuvant trastuzumab emtansine (T-DM1) had a 50% reduction in the risk of an invasive disease-free survival (IDFS) event compared to patients treated with adjuvant trastuzumab. In metastatic disease, T-DM1 has resulted in higher rates of thrombocytopenia in Asian versus non-Asian patients. Here, we report safety and efficacy in Chinese patients from KATHERINE. Methods: Patients with HER2-positive EBC and residual invasive disease after taxane- and trastuzumab-containing neoadjuvant chemotherapy followed by surgery were randomized 1:1 to 14 cycles of adjuvant T-DM1 or trastuzumab. The primary endpoint was time to an IDFS event. Results: Among Chinese patients (T-DM1 n = 51, trastuzumab n = 50), T-DM1 treatment resulted in a 43% reduction in risk of an IDFS event compared to trastuzumab (HR = 0.57; 95% CI 0.25–1.31), with similar results for secondary endpoints. As in the global population, Chinese patients receiving T-DM1 versus trastuzumab had more grade ≥ 3 adverse events (AEs; 39.2% versus 4.1%) and AEs leading to treatment discontinuation (27.5% versus 0%). The most common grade ≥ 3 AE with T-DM1 was thrombocytopenia (21.6%), a frequency higher than the frequency in the global population (5.7%). Grade ≥ 3 hemorrhage was reported in 1 patient (T-DM1 arm). Conclusions: In the KATHERINE study, T-DM1 demonstrated increased efficacy compared to trastuzumab in Chinese patients. Consistent with previous data in Asian patients, T-DM1 was associated with more grade ≥ 3 AEs, and AEs leading to discontinuation, which was driven by an increase in thrombocytopenia. [ABSTRACT FROM AUTHOR]

Background: HLX02 is an approved biosimilar of trastuzumab. Objective: This study aimed to evaluated the efficacy, safety, and immunogenicity of HLX02 compared with reference trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer. Patients and Methods: This randomized, double-blind, phase III study was conducted at 89 centers in China, the Philippines, Poland, and Ukraine. Eligible patients were randomized (1:1) to receive HLX02 or European Union (EU)-sourced trastuzumab (initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for up to 12 months) in combination with docetaxel intravenously. The primary endpoint was overall response rate up to week 24 (ORR24). Equivalence was declared if the 95% confidence interval (CI) of difference was within ± 13.5%. Safety and immunogenicity were evaluated in patients who received at least one dose of study medication. Results: Between 11 November 2016 and 10 July 2019, a total of 649 patients were enrolled. The ORR24 was 71.3 and 71.4% in the HLX02 (n = 324) and EU-trastuzumab (n = 325) groups, with a difference of − 0.1% (95% CI − 7 to 6.9), which fell entirely in the predefined equivalence margins. No statistically significant differences were observed in all secondary efficacy analyses. Safety profiles and immunogenicity were comparable in HLX02 and EU-trastuzumab groups. In total, 98.8% of patients in each group experienced at least one treatment-emergent adverse event (TEAE), 23.8 and 24.9% experienced serious TEAEs, and 0.6% in each group had antidrug antibodies. Conclusions: Among patients with HER2-positive recurrent or metastatic breast cancer, HLX02 demonstrated equivalent efficacy and similar safety and immunogenicity to reference trastuzumab. Clinical Trial Registration: Chinadrugtrials.org CTR20160526 (12 September 2016), ClinicalTrials.gov NCT03084237 (20 March 2017), EudraCT 2016-000206-10 (27 April 2017). Plain Language Summary: Trastuzumab is a biologic drug used to treat patients with certain types of breast cancer and stomach cancer. Biosimilars are medications that are almost identical to and indistinguishable from original biologic drugs but usually less expensive and more accessible. The main purpose of this study was to evaluate the efficacy (treatment effects) of HLX02 (trastuzumab biosimilar) compared with reference trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer. Other objectives were to evaluate the safety of HLX02 by monitoring adverse events and assessing its potential to induce antibody production (which can prevent a drug from being effective). Patients with HER2-positive recurrent or metastatic breast cancer were randomly allocated to receive HLX02 (n = 324) or European Union (EU)-sourced trastuzumab (n = 325). Study drugs (HLX02 or EU-trastuzumab) were given intravenously, with an initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for up to 12 months. Statistical analyses showed that HLX02 was equivalent to trastuzumab in efficacy evaluations. Adverse events observed in the HLX02 treatment group were consistent with those seen with trastuzumab in the current and previous clinical studies. Additionally, no statistically significant differences were seen in the tendency to stimulate antibody production between the two study drugs. To conclude, HLX02 and reference trastuzumab had similar efficacy and safety profiles. These data support the approval of HLX02 as a trastuzumab biosimilar. [ABSTRACT FROM AUTHOR]

Assessing the status and trend of potential evaporation (PE) is essential for investigating the climate change impact on the terrestrial water cycle. Despite recent advances, evaluating climate change impacts on PE using pan evaporation (Epan) data in cold regions is hindered by the unavailability of Epan measurements in cold seasons due to the freezing of water and sparse spatial distribution of sites. This study generated long-term PE datasets in Canada for 1979–2016 by integrating the dynamic evolutions of water–ice–snow processes into estimation in the Ecological Assimilation of Land and Climate Observations (EALCO) model. The datasets were compared with Epan before the spatial variations and trends were analyzed. Results show that EALCO PE and Epan measurements demonstrate similar seasonal variations and trends in warm seasons in most areas. Annual PE in Canada varied from 100 mm in the Northern Arctic to approximately 1000 mm in southern Canadian Prairies, southern Ontario, and East Coast, with about 600 mm for the entire landmass. Annual PE shows an increasing trend at a rate of 1.5–4 mm/year in the Northern Arctic, East, and West Canada. The increase is primarily associated with the elevated air temperature and downward longwave and shortwave radiation, with some regions contributed by augmented wind speed. The increase of annual PE is mainly attributed to the augmentation of PE in warm seasons. [ABSTRACT FROM AUTHOR]

Programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) interaction plays a crucial role in tumor-associated immune escape. Here, we verify that triple-negative breast cancer (TNBC) has higher PD-L1 expression than other subtypes. We then discover that nucleophosmin (NPM1) binds to PD-L1 promoter specifically in TNBC cells and activates PD-L1 transcription, thus inhibiting T cell activity in vitro and in vivo. Furthermore, we demonstrate that PARP1 suppresses PD-L1 transcription through its interaction with the nucleic acid binding domain of NPM1, which is required for the binding of NPM1 at PD-L1 promoter. Consistently, the PARP1 inhibitor olaparib elevates PD-L1 expression in TNBC and exerts a better effect with anti-PD-L1 therapy. Together, our research has revealed NPM1 as a transcription regulator of PD-L1 in TNBC, which could lead to potential therapeutic strategies to enhance the efficacy of cancer immunotherapy. PD-L1 is highly expressed in triple-negative breast cancers (TNBC). Here, the authors show that nucleophosmin 1 (NPM1) transcriptionally activates PD-L1 expression and inhibits T cell activity in TNBC. [ABSTRACT FROM AUTHOR]

Summary: Background We examined the efficacy of mirtazapine in preventing delayed nausea and vomiting following highly emetogenic chemotherapy (HEC). Patients and methods Patients who had experienced delayed emesis and would be subsequently scheduled for at least three more cycles of the same chemotherapy were randomly assigned to either a mirtazapine (15 mg daily on days 2–4) or a control group. In addition, both groups received a standard triplet regimen comprising aprepitant, a 5-HT3 receptor antagonist, and dexamethasone (7.5 mg on days 2–4). The chemotherapy regimens were either an epirubicin plus cyclophosphamide regimen or cisplatin-containing regimens. The primary end point was a complete response (no emesis and no rescue treatment) to the delayed phase (25–120 h post-chemotherapy) during Cycle 1. The impact on quality of life (QOL) was assessed using the Functional Living Index–Emesis (FLIE) questionnaire. Results Of 95 enrolled patients, 46 were assigned to the mirtazapine group and 49 to the control group. The complete response rate in the delayed phase during Cycle 1 was significantly higher with mirtazapine than in the control group (78.3% versus 49.0%, P = 0.003). The main adverse effects of mirtazapine were mild to moderate somnolence and weight gain. Mean total FLIE scores were similar between the two arms. Conclusions This is the first randomized prospective study to show that adding mirtazapine has a substantial and statistically significant benefit with good tolerance in patients with breast cancer who have experienced delayed emesis following the same prior HEC. (Trial registration: ClinicalTrials.gov NCT02336750). [ABSTRACT FROM AUTHOR]

Purpose: Ovarian function is important for optimizing endocrine treatment in patients with hormone receptor-positive (HR+) early breast cancer (eBC). The aim of the study was to determine whether patients' pretreatment levels of anti-Mullerian hormone (AMH) were associated with menses status after chemotherapy and to build a predictive nomogram model for amenorrhea in women with HR+ eBC.Methods: Between August 2013 and December 2014, 120 premenopausal patients with HR+ eBC were included retrospectively. The associations among age, prechemotherapy levels of AMH, follicle-stimulating hormone (FSH),and estradiol (E2) and the 2-year postchemotherapy menses status were analyzed. We determined the cutoff values of hormone levels by using the biostatistical tool (Cutoff Finder). A novel nomogram was established to predict the 2-year amenorrhea status based on the logistic analysis. Concordance index (C-index) was used to validate the capacity.Results: One hundred nine women (90.8%) experienced amenorrhea after chemotherapy. AMH < 0.965 ng/ml predicted amenorrhea at 2 years (AUC 0.84, sensitivity 74% and specificity 81.8%), independent of age. The predictive nomogram based on age and pretreatment AMH and FSH levels was developed to predict the probability of 2-year postchemotherapy amenorrhea with a C-index of 0.88 (95% CI 0.84-0.91).Conclusions: In premenopausal patients with HR+ eBC, prechemotherapy AMH concentration was associated with the patient's 2-year amenorrhea status, independent of age. The nomogram model based on age and pretreatment AMH and FSH levels accurately predicted the 2-year amenorrhea status. [ABSTRACT FROM AUTHOR]

Hand-foot-genital syndrome (HFGS) is a rare autosomal dominant inherited syndrome characterized by limb malformations and urogenital defects. HFGS is caused by mutations in the HOXA13 gene. The aim of this study was to identify causative mutations in individuals and to explore the molecular pathogenesis in a Chinese family with HFGS. We performed Sanger sequencing and identified a recurrent missense mutation in the homeodomain (c.1123G>T, p.V375F) of HOXA13, molecular modelling predicted the mutation would affect DNA binding, and a luciferase reporter assay indicated that it impaired the ability of HOXA13 to activate transcription of the human EPHA7 promoter. This is the first report of the molecular basis for HFGS caused by missense mutations of HOXA13. [ABSTRACT FROM AUTHOR]

Purpose: Endocrine therapy is associated with improved disease-free survival (DFS) in hormone receptor-positive breast cancer, but it is also associated with many adverse events. The aim of this study was to clarify the association between endocrine treatment-related symptoms and treatment efficacy in patients receiving adjuvant endocrine therapy. Method: EMBASE, Web of Science, PubMed, and CENTRAL databases were searched for studies that compared treatment efficacy between patients in whom adverse events did and did not occur during hormone therapy. Hazard ratios (HRs) and associated 95 % confidence intervals (CIs) for DFS and overall survival were estimated and pooled using random-effects models. Results: Of 4665 citations identified, ten studies incorporating 32,192 patients were included in the meta-analysis. The presence of endocrine treatment-related symptoms was associated with improved DFS (HR 0.76; 95 % CI 0.68-0.85). Similar results were observed in patients with vasomotor symptoms (HR 0.76; 95 % CI 0.66-0.87) or musculoskeletal symptoms (HR 0.75; 95 % CI 0.60-0.94), in patients taking an aromatase inhibitor (HR 0.69; 95 % CI 0.57-0.85) or tamoxifen (HR 0.74; 95 % CI 0.60-0.93), and in patients with symptoms at 3-month (HR 0.74; 95 % CI 0.66-0.83), 6-month (HR 0.80; 95 % CI 0.66-0.96), or 12-month follow-up visits (HR 0.75; 95 % CI 0.68-0.83). However, no significant difference in overall survival was observed between patients with or without endocrine treatment-related symptoms (HR 0.82; 95 % CI 0.60-1.11). Sensitivity analysis excluding studies with heterogeneous factors yielded consistent results. No evidence of publication bias was observed. Conclusion: In our meta-analysis, endocrine treatment-related symptoms were shown to correlate with superior DFS and may therefore be useful in predicting treatment efficacy in patients with breast cancer receiving hormone therapy. [ABSTRACT FROM AUTHOR]

Ecosystem responses to rising CO2 concentrations are a major source of uncertainty in climate change projections. Data from ecosystem-scale Free-Air CO2 Enrichment (FACE) experiments provide a unique opportunity to reduce this uncertainty. The recent FACE Model-Data Synthesis project aimed to use the information gathered in two forest FACE experiments to assess and improve land ecosystem models. A new 'assumption-centred' model intercomparison approach was used, in which participating models were evaluated against experimental data based on the ways in which they represent key ecological processes. By identifying and evaluating the main assumptions causing differences among models, the assumption-centred approach produced a clear roadmap for reducing model uncertainty. Here, we explain this approach and summarize the resulting research agenda. We encourage the application of this approach in other model intercomparison projects to fundamentally improve predictive understanding of the Earth system. [ABSTRACT FROM AUTHOR]

The aim of this study is to analyze the prognostic value of androgen receptor (AR) expression for patients with triple-negative breast cancer (TNBC). Clinical data of these patients were collected and analyzed, and immunohistochemical staining for AR was performed on tissue microarrays of operable breast cancer from 287 patients with TNBC, who were treated at Sun Yat-sen University Cancer Center from January 1995 to December 2008. AR expression was found in 25.8% of the cases with TNBC. TNBC patients with AR negative have a higher proportion of positive lymph node. A significant correlation was found between AR expression and disease-free survival (DFS) and overall survival (OS). Univariated analysis indicated that AR expression had a significant prognostic value in TNBC patients, whereas multivariate analysis indicated that AR was a significant independent prognostic factor of DFS ( P = 0.032) in all patients. Our results suggested that AR was a favorable prognostic factor of DFS and OS in patients with TNBC. Therefore, TNBC may be further divided into two subtypes according to AR status. [ABSTRACT FROM AUTHOR]

The aim of this study was to analyze the prognostic value of EGFR expression for patients with triple-negative breast cancer (TNBC). Clinical data of these patients were collected and analyzed, and immunohistochemical staining for EGFR was performed on tissue microarrays of operable breast cancer from 287 patients with TNBC, who were treated at Sun Yat-sen University Cancer Center from January 1995 to December 2008. EGFR expression was found in 36.2% of the cases with TNBC. A significant correlation was found between EGFR expression and disease-free survival (DFS). Univariated analysis indicated that EGFR expression had a significant prognostic value in TNBC patients, whereas multivariate analysis indicated that EGFR was a significant independent prognostic factor of DFS ( P = 0.011) in all patients. Our results suggested that EGFR was an independent prognostic factor of DFS in patients with TNBC. Therefore, EGFR could become a good therapeutic target in the treatment of TNBC. [ABSTRACT FROM AUTHOR]

Patients suffering from triple-negative breast cancer (TNBC) have poor prognosis mainly because no standard treatment is currently available. Our objectives were to explore the prognostic factors for first relapse of patients with TNBC. A cohort of 687 patients with TNBC, diagnosed and treated between January 1995 and December 2008 at Sun Yat-sen University Cancer Center, were retrospectively analyzed. Cox proportional hazards models were fitted to explore factors that predict relapse development. Survival rate was computed using the Kaplan-Meier product limit method. The median age of the 687 patients was 46 (range 16-76 years), and 64.8% of the patients were pre-menopausal. The median follow-up time was 56 months (range 14-156 months), in which 194 patients had recurrence, and 115 died. The median recurrence-free time was 25 months (range 4-143 months), with 118 (60.8%) of the cases first relapsing at a single site. The three- and five-year disease-free survival rates were 79.7 and 72.6%, respectively. Primary tumor size at diagnosis, lymph node status, and type of regimen used in the (neo)adjuvant chemotherapy were considered independent predictors of first relapse. CMF-containing adjuvant chemotherapy significantly decreased recurrence compared with the anthracycline- or taxane-based regimens (RR = 0.66, 95%; CI 0.45-0.96; P = 0.030). The median time from first relapse to death was 26 months (range 2-121 months). The two- and five-year survival rates were 60.6 and 36.6%, respectively. Liver metastasis at first recurrence and progression-free survival over 12 months after first-line therapy were two important factors that affected survival rate after recurrence. The median relapse time of TNBC was about 2 years after diagnosis. CMF regimens for TNBC patients may be more effective than anthracycline- or taxane-based regimens. Liver metastasis at first recurrence signifies unfavorable prognosis. [ABSTRACT FROM AUTHOR]

The article presents a study on the relationship between the mutations of vitamin D 1α hydroxylase gene (CYP27BI) and the clinical findings of vitamin-D-dependent rickets type I (VDDR-I). The study used the laboratory tests and x-ray examinations from a 13-month-old Chinese boy who was diagnosed of 1α-hydroxylase deficiency and a DNA sequencing was performed. Results showed that a small deletion and a missense mutation were found in the mutations of CYP27BI in the patient.

The South-to-North Water Transfer (SNWT) Project of China is the largest of its kind ever implemented. Of its three routes (i.e., East, Middle and West), the middle one will transfer 14 billion m3 of water annually from the Han River, a tributary of the Yangtze and the water supplying area, to Beijing by 2030. Thus water quality in the 95,000 km2 upper Han River basin is of great concern. A watershed management initiative has been implemented in the basin, and the ultimate objectives are to quantify basin’s ecosystem functioning and to develop an integrated management system with respect to water resources conservation. Specifically, the program includes five activities: characterization of riparian ecosystems, detection of land use and land cover change, quantification of nutrient cycling of representative ecosystems, determination of spatial and temporal variations of water quality, and finally development of a watershed management system for water conservation. This article provides the justifications of the watershed management initiative and the initial results are comprehended with respect to the water conservation in the Han River basin. [ABSTRACT FROM AUTHOR]

A new canopy radiation transfer and surface albedo scheme is developed as part of the land surface model EALCO (Ecological Assimilation of Land and Climate Observations). The model uses a gap probability-based successive orders of scattering approach that explicitly includes the heterogeneities of stands and crown elements and the radiation multiple scattering. The model uses the optical parameters of ecosystem elements and physically represents ecosystem processes in surface albedo dynamics. Model tests using measurements from a boreal deciduous forest ecosystem show that the model well reproduced the observed diurnal and seasonal albedo dynamics under different weather and ecosystem conditions. The annual mean absolute errors between modeled and measured daily albedo and reflected radiation are 0.01 and 1.33 W m−2, respectively. The model results provide a quantitative assessment of the impacts of plant shading and sky conditions on surface albedo observed in high-latitude ecosystems. The contribution of ground snow to surface albedo in winter was found to be less than 0.1 even though the canopy is leafless during this time. The interception of snow by the leafless canopy can increase the surface albedo by 0.1–0.15. The model results show that the spectral properties of albedo have large seasonal variations. In summer, the near infrared component is substantially larger than visible, and surface albedo is less sensitive to sky conditions. In winter, the visible band component is markedly increased and can exceed the near infrared proportion under cloudy conditions or when snow exists on the canopy. The spectral properties of albedo are also found to have large diurnal variations under the clear-sky conditions in winter. [ABSTRACT FROM AUTHOR]

The prognosis of relapsed or refractory B-cell lymphoma is poor, with a short-term survival after conventional second-line chemotherapy. Rituximab, a chimeric anti-CD20 antigen, in combination with CHOP or CHOP-like chemotherapy may improve both disease free survival (DFS) and overall survival (OS) of naive patients, but its role in the second-line therapy for relapsed non-Hodgkin’s Lymphoma (NHL) remains to be defined. This study aimed to evaluate the efficacy of rituximab-containing salvage regimens for relapsed or refractory NHL, and observe the toxicities. The clinical data of 54 patients, who were with relapsed or refractory NHL and treated in the Cancer Center of Sun Yat-sen University, were analyzed retrospectively. Of the 54 patients, 29 were man, 25 were women, with a median age of 52.5 years old (range 18 to 75); 50 patients (92.6%) scored 0–1 for the ECOG performance status; for second-line international prognostic index (sIPI), 21 (38.9%) scored 0–1, 30 (55.6%) scored 2 to 3, and 3 (5.6%) scored 4–5; 40 cases were diffuse large B-cell lymphoma (DLBCL), accounting for 74.1% of all subtypes. Rituximab was administered intravenously at a dose of 375 mg/m2 at the day before each chemotherapy cycle. The second or third-line salvage regimens included EPOCH, CHOP, DHAP, DICE, IVAC, IMVP-16 and FND. Of the 54 patients, 49 received retuximab-containing salvage regimens. The objective response rate of the 45 evaluable cases was 68.8%, with a complete remission (CR) rate of 37.7%; 3 patients achieved CR after radiotherapy following rituximab-based regimens and 3 achieved CR after autologous hematopoietic stem cell transplantation. The most frequent adverse events were leucopenia, nausea and alopecia. The addition of rituximab to chemotherapy only elevated the occurrence of mild infusion-related reactions, such as chills, fever and pruritus. The median follow-up time was 18 months (range 2–86 months); 5 patients were lost, 24 were dead (23 died of lymphoma, and 1 died of severe hepatitis), the other patients remained alive. The median survival time was 32 months (range 2–86 months, 95% confidential interval 16–48 months). The 1-, 2-and 3-year OS rates were 70.6%, 53.6% and 41.5%, respectively. The median TTP was 6 months (range 0–52 months). The median PFS was 10 months (range 0–47 months, 95% CI 0–26 months). The 1-and 2-year PFS were 49.3% and 41.3%. Rituximab-containing salvage regimens are effective and well tolerated therapy for patients with relapsed or refractory B-cell NHL, even those were extensively treated. [ABSTRACT FROM AUTHOR]

Human pluripotent stem cell-derived islets (hPSC islets) are a promising alternative to primary human islets for the treatment of insulin-deficient diabetes. We previously demonstrated the feasibility of this approach in nonhuman primates; however, the therapeutic effects of hPSC islets can be limited by the maladaptive processes at the transplantation site. Here, we demonstrate successful implantation of hPSC-derived islets in a new transplantation site in the abdomen, the subanterior rectus sheath, in eight nonhuman primates (five male and three female). In this proof-of-principle study, we find that hPSC islets survive and gradually mature after transplantation, leading to improved glycemic control in diabetic primates. Notably, C-peptide secretion responds to meal challenge from 6 weeks post-transplantation (wpt), with stimulation indices comparable to those of native islets. The average post-prandial C-peptide level reaches approximately 2.0 ng ml -1 from 8 wpt, which is five times higher than the peak value we previously obtained after portal vein infusion of hPSC islets and was associated with a decrease of glycated hemoglobin levels by 44% at 12 wpt. Although additional studies in larger cohorts involving long-term follow-up of transplants are needed, our results indicate that the subanterior rectus sheath supports functional maturation and maintenance of hPSC islets, suggesting that it warrants further exploration as a transplantation target site in the context of for hPSC-based cell-replacement therapies., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)