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Abstract How to extend the photoresponse of perovskite solar cells (PVSCs) to the region of near‐infrared (NIR)/infrared light has become an appealing research subject in this field since it can better harness the solar irradiation. Herein, the typical fullerene electron‐transporting layer (ETL) of an inverted PVSC is systematically engineered to enhance device's NIR photoresponse. A low bandgap nonfullerene acceptor (NFA) is incorporated into the fullerene ETL aiming to intercept the NIR light passing through the device. However, despite forming type II charge transfer with fullerene, the blended NFA cannot enhance the device's NIR photoresponse, as limited by the poor dissociation of photoexciton induced by NIR light. Fortunately, it can be addressed by adding a p‐type polymer. The ternary bulk‐heterojunction (BHJ) ETL is demonstrated to effectively enhance the device's NIR photoresponse due to the better cascade‐energy‐level alignment and increased hole mobility. By further optimizing the morphology of such a BHJ ETL, the derived PVSC is finally demonstrated to possess a 40% external quantum efficiency at 800 nm with photoresponse extended to the NIR region (to 950 nm), contributing ≈9% of the overall photocurrent. This study unveils an effective and simple approach for enhancing the NIR photoresponse of inverted PVSCs.

Abstract cFLIP, a master anti-apoptotic regulator, targets the FADD-induced DED complexes of procaspase-8 in death receptor and ripoptosome signaling pathways. Several tumor cells maintain relatively high levels of cFLIP in achieving their immortality. However, understanding the three-dimensional regulatory mechanism initiated or mediated by elevated levels of cFLIP has been limited by the absence of the atomic coordinates for cFLIP-induced DED complexes. Here we report the crystal plus cryo-EM structures to uncover an unconventional mechanism where cFLIP and procaspase-8 autonomously form a binary tandem DED complex, independent of FADD. This complex gains the ability to recruit FADD, thereby allosterically modulating cFLIP assembly and partially activating caspase-8 for RIPK1 cleavage. Our structure-guided mutagenesis experiments provide critical insights into these regulatory mechanisms, elucidating the resistance to apoptosis and necroptosis in achieving immortality. Finally, this research offers a unified model for the intricate bidirectional hierarchy-based processes using multiprotein helical assembly to govern cell fate decisions.

ABSTRACT Acetaminophen (APAP) overdose can cause severe liver injury and life‐threatening conditions that may lead to multiple organ failure without proper treatment. N‐acetylcysteine (NAC) is the accepted and prescribed treatment for detoxification in cases of APAP overdose. Nonetheless, in acute liver failure (ALF), particularly when the ingestion is substantial, NAC may not fully restore liver function. NAC administration in ALF has limitations and potential adverse effects, including nausea, vomiting, diarrhoea, flatus, gastroesophageal reflux, and anaphylactoid reactions. Mesenchymal stromal cell (MSC)‐based therapies using paracrine activity show promise for treating ALF, with preclinical studies demonstrating improvement. Recently, MSC‐derived extracellular vesicles (EVs) have emerged as a new therapeutic option for liver injury. MSC‐derived EVs can contain various therapeutic cargos depending on the cell of origin, participate in physiological processes, and respond to abnormalities. However, most therapeutic EVs lack a distinct orientation upon entering the body, resulting in a lack of targeting specificity. Therefore, enhancing the precision of natural EV delivery systems is urgently needed. Thus, we developed an advanced targeting technique to deliver modified EVs within the body. Our strategy aims to employ bioorthogonal click chemistry to attach a targeting molecule to the surface of small extracellular vesicles (sEVs), creating exogenous chimeric antigen receptor‐modified sEVs (CAR‐sEVs) for the treatment. First, we engineered azido‐modified sEVs (N3‐sEVs) through metabolic glycoengineering by treating MSCs with the azide‐containing monosaccharide N‐azidoacetyl‐mannosamine (Ac4ManNAz). Next, we conjugated N3‐sEVs with a dibenzocyclooctyne (DBCO)‐tagged single‐chain variable fragment (DBCO‐scFv) that targets the asialoglycoprotein receptor (ASGR1), thus producing CAR‐sEVs for precise liver targeting. The efficacy of CAR‐sEV therapy in ALF models by targeting ASGR1 was validated. MSC‐derived CAR‐sEVs reduced serum liver enzymes, mitigated liver damage, and promoted hepatocyte proliferation in APAP‐induced injury. Overall, CAR‐sEVs exhibited enhanced hepatocyte specificity and efficacy in ameliorating liver injury, highlighting the significant advancements achievable with cell‐free targeted therapy.

Bevacizumab is widely used in various clinical indications, but investigations into its optimal dosage for treating CNS metastases remain limited. The BEEP regimen, comprising bevacizumab, etoposide, and cisplatin, has recently demonstrated promising clinical outcomes for patients with breast cancer brain metastasis (BCBM) or leptomeningeal metastasis (LM). This study aimed to evaluate the exposure-response relationship of bevacizumab in BCBM patients and to explore the improved CNS penetration of chemotherapy by bevacizumab with LM patients. Twenty-two BCBM patients and six LM patients receiving the BEEP regimen were enrolled. For BCBM patients, blood samples were drawn at trough level of cycles 1 and 6 to investigate the association between bevacizumab concentrations and clinical outcomes. For LM patients, plasma and cerebrospinal fluid (CSF) concentrations of bevacizumab and etoposide were measured to investigate the enhancement of etoposide penetration provided by bevacizumab. Concentration evaluation revealed that bevacizumab plasma concentrations substantially varied between individuals. Additionally, concentrations increased after 6 cycles, indicating bevacizumab accumulation during treatment. Although bevacizumab concentrations did not associate with therapeutic response and progression-free survival, patients with higher bevacizumab concentrations exhibited longer overall survival (adjusted HR 0.78; p = 0.039). Furthermore, a positive correlation was observed between time-weighted average concentration of plasma bevacizumab and CSF penetration of etoposide on day 2 (post-bevacizumab) relative to day 1 (pre-bevacizumab) (r = 0.83; p = 0.042). These findings offer valuable insights into the application of therapeutic drug monitoring of bevacizumab to improve survival outcomes in BCBM patients. Further studies are warranted to determine the optimal bevacizumab concentration.

Abstract Regulatory T cells (Tregs) are crucial immune cells for tissue repair and regeneration. However, their potential as a cell-based regenerative therapy is not yet fully understood. Here, we show that local delivery of exogenous Tregs into injured mouse bone, muscle, and skin greatly enhances tissue healing. Mechanistically, exogenous Tregs rapidly adopt an injury-specific phenotype in response to the damaged tissue microenvironment, upregulating genes involved in immunomodulation and tissue healing. We demonstrate that exogenous Tregs exert their regenerative effect by directly and indirectly modulating monocytes/macrophages (Mo/MΦ) in injured tissues, promoting their switch to an anti-inflammatory and pro-healing state via factors such as interleukin (IL)-10. Validating the key role of IL-10 in exogenous Treg-mediated repair and regeneration, the pro-healing capacity of these cells is lost when Il10 is knocked out. Additionally, exogenous Tregs reduce neutrophil and cytotoxic T cell accumulation and IFN-γ production in damaged tissues, further dampening the pro-inflammatory Mo/MΦ phenotype. Highlighting the potential of this approach, we demonstrate that allogeneic and human Tregs also promote tissue healing. Together, this study establishes exogenous Tregs as a possible universal cell-based therapy for regenerative medicine and provides key mechanistic insights that could be harnessed to develop immune cell-based therapies to enhance tissue healing.

Abstract Background Although tumor cells undergoing epithelial–mesenchymal transition (EMT) typically exhibit spindle morphology in experimental models, such histomorphological evidence of EMT has predominantly been observed in rare primary spindle carcinomas. The characteristics and transcriptional regulators of spontaneous EMT in genetically unperturbed non-spindled carcinomas remain underexplored. Methods We used primary culture combined with RNA sequencing (RNA-seq), single-cell RNA-seq (scRNA-seq), and in situ RNA-seq to explore the characteristics and transcription factors (TFs) associated with potential spontaneous EMT in non-spindled breast carcinoma. Results Our primary culture revealed carcinoma cells expressing diverse epithelial–mesenchymal traits, consistent with epithelial–mesenchymal plasticity. Importantly, carcinoma cells undergoing spontaneous EMT did not necessarily exhibit spindle morphology, even when undergoing complete EMT. EMT was a favored process, whereas mesenchymal–epithelial transition appeared to be crucial for secondary tumor growth. Through scRNA-seq, we identified TFs that were sequentially and significantly upregulated as carcinoma cells progressed through the EMT process, which correlated with increasing VIM expression. Once upregulated, the TFs remained active throughout the EMT process. ZEB1 was a key initiator and sustainer of EMT, as indicated by its earliest significant upregulation in the EMT process, its exact correlation with VIM expression, and the reversal of EMT and downregulation of EMT-upregulated TFs upon ZEB1 knockdown. The correlation between ZEB1 and vimentin expression in triple-negative breast cancer and metaplastic breast carcinoma tumor cohorts further highlighted its role. The immediate upregulation of ZEB2 following that of ZEB1, along with the observation that the knockdown of ZEB1 or ZEB2 downregulates both ZEB1 and ZEB2 concomitant with the reversal of EMT, suggests their functional cooperation in EMT. This finding, together with that of a lack of correlation of SNAI1, SNAI2, and TWIST1 expression with the mesenchymal phenotype, indicated EMT-TFs have a context-dependent role in EMT. Upregulation of EMT-related gene signatures during EMT correlated with poor patient outcomes, highlighting the biological importance of the model. Elevated EMT gene signatures and increased ZEB1 and ZEB2 expression in vimentin-positive compared to vimentin-negative carcinoma cells within the corresponding primary tumor tissue confirmed ZEB1 and ZEB2 as intrinsic, instead of microenvironmentally-induced, EMT regulators, and vimentin as an in vivo indicator of EMT. Conclusions Our findings provide insights into the characteristics and transcriptional regulators of spontaneous EMT in primary non-spindled carcinoma.

Abstract Regulatory T cells (Tregs) are key immune regulators that have shown promise in enhancing cardiac repair post-MI, although the mechanisms remain elusive. Here, we show that rapidly increasing Treg number in the circulation post-MI via systemic administration of exogenous Tregs improves cardiac function in male mice, by limiting cardiomyocyte death and reducing fibrosis. Mechanistically, exogenous Tregs quickly home to the infarcted heart and adopt an injury-specific transcriptome that mediates repair by modulating monocytes/macrophages. Specially, Tregs lead to a reduction in pro-inflammatory Ly6CHi CCR2+ monocytes/macrophages accompanied by a rapid shift of macrophages towards a pro-repair phenotype. Additionally, exogenous Treg-derived factors, including nidogen-1 and IL-10, along with a decrease in cardiac CD8+ T cell number, mediate the reduction of the pro-inflammatory monocyte/macrophage subset in the heart. Supporting the pivotal role of IL-10, exogenous Tregs knocked out for IL-10 lose their pro-repair capabilities. Together, this study highlights the beneficial use of a Treg-based therapeutic approach for cardiac repair with important mechanistic insights that could facilitate the development of novel immunotherapies for MI.

Abstract Palbociclib combined with endocrine therapy is approved for treating patients with hormone-receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer; however, data on palbociclib combined with tamoxifen are limited. We investigated the efficacy and safety of palbociclib–tamoxifen in patients with HR+/HER2− advanced breast cancer. This double-blind phase 3 study included 184 women who were randomly assigned 1:1 to receive palbociclib–tamoxifen or placebo–tamoxifen. Pre/perimenopausal women also received goserelin. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Median PFS was 24.4 months (95% confidence interval [CI], 13.1–32.4) with palbociclib–tamoxifen and 11.1 months (95% CI, 7.4–14.6) with placebo–tamoxifen (hazard ratio [HR], 0.60; 95% CI, 0.43–0.85; P = 0.002). Palbociclib–tamoxifen improved PFS in patients who were treated with first-line or second-line endocrine therapy and pre-, peri-, and postmenopausal patients. Though OS data are still immature (median not reached in both groups), an overall risk reduction of 27% (HR, 0.73; 95% CI, 0.44–1.21) with palbociclib–tamoxifen was observed at the time of PFS analysis. The most common grade 3/4 adverse event with palbociclib–tamoxifen was neutropenia (89.0% [none were febrile] versus 1.1% with placebo–tamoxifen). There were no deaths owing to adverse events in either group. Among patients with HR+/HER2− advanced breast cancer, palbociclib–tamoxifen resulted in significantly longer PFS than tamoxifen alone. Early OS data showed a trend favoring palbociclib–tamoxifen. Trial registration: ClinicalTrials.gov number, NCT03423199. Study registration date: February 06, 2018.

Abstract Hepatocellular carcinoma (HCC) is characterized by a notable sex disparity in incidence and tumor aggressiveness. Revealing differences in genetic landscapes between male and female HCCs may expand the understanding of sexual disparities mechanisms and assist the development of precision medicine. Although reports on the sex disparity of HCC are accumulated, studies focusing on sex-related biomarkers among Asian populations remain limited. Here, we conducted a comprehensive genomic profiling analysis to explore differences between male and female patients within a cohort of 195 Taiwanese HCC patients. We did not detect any sex-biased genomic alterations. However, when our investigation extended to the TCGA dataset, we found higher frequencies of gene copy gains in CCNE2 and mutations in CTNNB1 and TP53 among male patients. Besides, we further evaluated the associations between genomic alterations and patients’ prognosis by sex. The results showed that female patients harboring tumors with STAT3 gain and alterations in the JAK–STAT pathway displayed a poor prognosis. These two factors remained independently associated with unfavorable prognosis even after adjusting for the patient’s age and stage characteristics (Hazard ratio = 10.434, 95% CI 3.331–32.677, P

Abstract Searching for topological superconductors that host topological charge-neutral Majorana zero-modes at edges has become a central problem in condensed matter research due to their potential applications for quantum computations. Meanwhile, electron correlations in solid-state materials enhance quantum fluctuations and give rise to various quantum many-body phases. Whether these electron correlations alone would lead to topological superconductivity is a fundamentally important open problem. Here, we theoretically find the correlation-driven topological superconductivity in a class of Kondo lattice materials. Therein, the odd-parity Kondo hybridization mediates ferromagnetic spin-spin coupling and leads to spin-triplet pairing between local moments. Triplet $$p\pm i{p}^{{\prime} }$$ p ± i p ′ -wave topological superconductivity with Majorana zero modes at edges is reached when Kondo hybridization co-exists with the triplet pairings. Our results offer a detailed understanding of the experimental observations on UTe2, a ferromagnetic heavy-electron triplet superconductor. Our approach to topological superconductivity shows advantages over the heterostructure approach by proximity effect.

Abstract Background Immunohistochemistry (IHC) and in situ hybridization (ISH) remain standard biomarkers for therapeutic decisions in human epidermal growth factor 2 (HER2)-positive breast cancers (BCs); however, they are insufficient to explain the heterogeneous anti-HER2 response. Methods We aimed to investigate the correlation of in situ HER2 RNA expression (isHRE), using RNAscope, with HER2 biomarkers and the impact of isHRE on the pathological complete response (pCR) rates of 278 patients with HER2 IHC/fluorescence ISH (FISH)-positive BC receiving neoadjuvant chemotherapy and anti-HER2 targeted treatment (NCTT). Results We validated HER2 RNAscope scoring as a semiquantitative method to determine isHRE and showed a positive correlation between RNAscope scores and pCR rates, with particularly different rates between patients with a score of 5 versus 1–4 BCs (66.7% vs. 15.9%, p

Abstract Fas-associated protein with death domain (FADD), procaspase-8, and cellular FLICE-inhibitory proteins (cFLIP) assemble through death-effector domains (DEDs), directing death receptor signaling towards cell survival or apoptosis. Understanding their three-dimensional regulatory mechanism has been limited by the absence of atomic coordinates for their ternary DED complex. By employing X-ray crystallography and cryogenic electron microscopy (cryo-EM), we present the atomic coordinates of human FADD-procaspase-8-cFLIP complexes, revealing structural insights into these critical interactions. These structures illustrate how FADD and cFLIP orchestrate the assembly of caspase-8-containing complexes and offer mechanistic explanations for their role in promoting or inhibiting apoptotic and necroptotic signaling. A helical procaspase-8-cFLIP hetero-double layer in the complex appears to promote limited caspase-8 activation for cell survival. Our structure-guided mutagenesis supports the role of the triple-FADD complex in caspase-8 activation and in regulating receptor-interacting protein kinase 1 (RIPK1). These results propose a unified mechanism for DED assembly and procaspase-8 activation in the regulation of apoptotic and necroptotic signaling across various cellular pathways involved in development, innate immunity, and disease.

Abstract Background Myocarditis substantially increases the risk of ventricular arrhythmia. Approximately 30% of all ventricular arrhythmia cases in patients with myocarditis originate from the right ventricular outflow tract (RVOT). However, the role of NLRP3 signaling in RVOT arrhythmogenesis remains unclear. Methods Rats with myosin peptide–induced myocarditis (experimental group) were treated with an NLRP3 inhibitor (MCC950; 10 mg/kg, daily for 14 days) or left untreated. Then, they were subjected to electrocardiography and echocardiography. Ventricular tissue samples were collected from each rat’s RVOT, right ventricular apex (RVA), and left ventricle (LV) and examined through conventional microelectrode and histopathologic analyses. In addition, whole-cell patch-clamp recording, confocal fluorescence microscopy, and Western blotting were performed to evaluate ionic currents, intracellular Ca2+ transients, and Ca2+-modulated protein expression in individual myocytes isolated from the RVOTs. Results The LV ejection fraction was lower and premature ventricular contraction frequency was higher in the experimental group than in the control group (rats not exposed to myosin peptide). Myocarditis increased the infiltration of inflammatory cells into cardiac tissue and upregulated the expression of NLRP3; these observations were more prominent in the RVOT and RVA than in the LV. Furthermore, experimental rats treated with MCC950 (treatment group) improved their LV ejection fraction and reduced the frequency of premature ventricular contraction. Histopathological analysis revealed higher incidence of abnormal automaticity and pacing-induced ventricular tachycardia in the RVOTs of the experimental group than in those of the control and treatment groups. However, the incidences of these conditions in the RVA and LV were similar across the groups. The RVOT myocytes of the experimental group exhibited lower Ca2+ levels in the sarcoplasmic reticulum, smaller intracellular Ca2+ transients, lower L-type Ca2+ currents, larger late Na+ currents, larger Na+–Ca2+ exchanger currents, higher reactive oxygen species levels, and higher Ca2+/calmodulin-dependent protein kinase II levels than did those of the control and treatment groups. Conclusion Myocarditis may increase the rate of RVOT arrhythmogenesis, possibly through electrical and structural remodeling. These changes may be mitigated by inhibiting NLRP3 signaling.

Abstract Background Due to cardiotoxicity concerns, the concurrent use of epirubicin and trastuzumab has not been fully studied. This study aimed to examine the cardiotoxicity and pathological complete response (pCR) rate associated with the concurrent regimens in patients with human epidermal growth factor receptor 2 (HER2)‐positive early breast cancer (EBC). Methods We conducted a systematic search for relevant literature in the NCBI/PubMed, the Cochrane database, and international conference abstracts for phase II or III randomized controlled trials between January 1, 2000, and February 28, 2021, focusing on the concurrent regimens in patients with HER2‐positive EBC. To compare the risk of cardiotoxicity and the odds of the pCR rate, we performed linear meta‐regression analyses to investigate the effects of multiple covariates. Results We analyzed 7 neoadjuvant trials involving the concurrent use of epirubicin and trastuzumab with 1797 patients. The median cumulative dose of epirubicin used was 300 mg/m2, with a total of 96 reported adverse cardiac events. The concurrent regimens did not result in a significant increase in cardiotoxicity compared to nonconcurrent regimens (risk ratio [RR] = 1.18, 95% confidence interval [CI] = 0.68–2.05). Compared with nonconcurrent or non‐anthracycline‐containing regimens, concurrent regimens were associated with a significant increase in the pCR rate (odds ratio = 1.48, 95% CI = 1.04–2.12). The linear fixed‐effects meta‐regression analysis indicated that in trials including more patients with hormone receptor‐positive EBC, the RR of cardiotoxicity significantly increased with concurrent regimens, and the pCR rate became less significant. Conclusions The combination of trastuzumab and a low dose of epirubicin positively impacted the pCR rate without a significant increase in cardiotoxicity. We recommend exploring concurrent regimens for HR‐negative, HER2‐positive tumors to enhance pCR rates, with caution advised for HR‐positive tumors due to potential cardiotoxicity.

Abstract Background Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are the two most common immune checkpoints targeted in triple-negative breast cancer (BC). Refining patient selection for immunotherapy is non-trivial and finding an appropriate digital pathology framework for spatial analysis of theranostic biomarkers for PD-1/PD-L1 inhibitors remains an unmet clinical need. Methods We describe a novel computer-assisted tool for three-dimensional (3D) imaging of PD-L1 expression in immunofluorescence-stained and optically cleared BC specimens (n = 20). The proposed 3D framework appeared to be feasible and showed a high overall agreement with traditional, clinical-grade two-dimensional (2D) staining techniques. Additionally, the results obtained for automated immune cell detection and analysis of PD-L1 expression were satisfactory. Results The spatial distribution of PD-L1 expression was heterogeneous across various BC tissue layers in the 3D space. Notably, there were six cases (30%) wherein PD-L1 expression levels along different layers crossed the 1% threshold for admitting patients to PD-1/PD-L1 inhibitors. The average PD-L1 expression in 3D space was different from that of traditional immunohistochemistry (IHC) in eight cases (40%). Pending further standardization and optimization, we expect that our technology will become a valuable addition for assessing PD-L1 expression in patients with BC. Conclusion Via a single round of immunofluorescence imaging, our approach may provide a considerable improvement in patient stratification for cancer immunotherapy as compared with standard techniques.

The development of bionic organ-on-a-chip technology relies heavily on advancements in in situ sensors and biochip packaging. By integrating precise biological and fluid condition sensing with microfluidics and electronic components, long-term dynamic closed-loop culture systems can be achieved. This study aims to develop biocompatible heterogeneous packaging and laser surface modification techniques to enable the encapsulation of electronic components while minimizing their impact on fluid dynamics. Using a kidney-on-a-chip as a case study, a non-toxic packaging process and fluid interface control methods have been successfully developed. Experimentally, miniature pressure sensors and control circuit boards were encapsulated using parylene-C, a biocompatible material, to isolate biochemical fluids from electronic components. Ultraviolet laser processing was employed to fabricate structures on parylene-C. The results demonstrate that through precise control of processing parameters, the wettability of the material can be tuned freely within a contact angle range of 60° to 110°. Morphological observations and MTT assays confirmed that the material and the processing methods do not induce cytotoxicity. This technology will facilitate the packaging of various miniature electronic components and biochips in the future. Furthermore, laser processing enables rapid and precise control of interface conditions across different regions within the chip, demonstrating a high potential for customized mass production of biochips. The proposed innovations provide a solution for in situ sensing in organ-on-a-chip systems and advanced biochip packaging. We believe that the development of this technology is a critical step toward realizing the concept of “organ twin”.

An origami-based tactile sensory ring utilizing multilayered conductive paper substrates presents an innovative approach to wearable health applications. By harnessing paper’s flexibility and employing origami folding, the sensors integrate structural stability and self-packaging without added encapsulation layers. Knot-shaped designs create loop-based systems that secure conductive paper strips and protect sensing layers. Demonstrating a sensitivity of 3.8 kPa−1 at subtle pressures (0–0.05 kPa), the sensors detect both minimal stimuli and high-pressure inputs. Electrical modeling of various origami configurations identifies designs with optimized performance with a pentagon knot offering higher sensitivity to support high-sensitivity needs. Meanwhile a square knot provides greater precision and quicker recovery, balancing sensitivity and stability for real-time feedback devices. The enhanced elastic modulus from folds remains within human skin’s elasticity range, ensuring comfort. Applications include grip strength monitoring and pulse rate detection from the thumb, capturing pulse transit time (PTT), an essential cardiovascular biomarker. This design shows the potential of origami-based tactile sensors in creating versatile, cost-effective wearable health monitoring systems.

Abstract Background Immune checkpoint inhibitors have revolutionized the treatment of malignancies. However, disproportionate enrollment among races and ethnicities places the generalizability of global trial results in doubt. Methods In this systematic review, phase 3 randomized controlled trials investigating pembrolizumab in advanced cancers and providing subgroup analyses of Asian and non‐Asian participants were included. The primary and secondary effect measures were the mean differences (MDs) in the natural logarithms of the hazard ratios (HRs) for overall survival (OS) and progression‐free survival (PFS) between these two subgroups, respectively. We used random‐effects meta‐analysis to calculate the pooled ratios of HRs (i.e., exp(MD)) and implemented a meta‐regression analysis to identify significant covariates. Results A total of 17 and 11 trials were included in the meta‐analyses of OS and PFS, respectively. These trials included 2732 (25.49%) Asian and 7000 (65.32%) non‐Asian participants in the OS analysis and 1438 (22.5%) Asian and 4129 (64.61%) non‐Asian participants in the PFS analysis. The pooled ratio of HRs for OS was 0.87 (95% CI: 0.76–0.99; p = 0.0391), favoring Asian participants, but no significant difference was found in PFS (pooled ratio of HRs: 0.93; 95% CI: 0.82–1.07; p = 0.2391). Both linear meta‐regression analyses revealed an open‐label design as a crucial covariate, which indicated more benefits for non‐Asian participants. Conclusions Compared with non‐Asian patients, Asian patients with advanced cancers may derive superior OS benefits from pembrolizumab. Although the results warrant further exploration, this meta‐analysis provides insight into clinical research design.

Abstract Background Breast cancer is a heterogeneous disease categorized based on molecular characteristics, including hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression levels. The emergence of profiling technology has revealed multiple driver genomic alterations within each breast cancer subtype, serving as biomarkers to predict treatment outcomes. This study aimed to explore the genomic landscape of breast cancer in the Taiwanese population through comprehensive genomic profiling (CGP) and identify diagnostic and predictive biomarkers. Methods Targeted next‐generation sequencing‐based CGP was performed on 116 archived Taiwanese breast cancer specimens, assessing genomic alterations (GAs), including single nucleotide variants, copy number variants, fusion genes, tumor mutation burden (TMB), and microsatellite instability (MSI) status. Predictive variants for FDA‐approved therapies were evaluated within each subtype. Results In the cohort, frequent mutations included PIK3CA (39.7%), TP53 (36.2%), KMT2C (9.5%), GATA3 (8.6%), and SF3B1 (6.9%). All subtypes had low TMB, with no MSI‐H tumors. Among HR + HER2− patients, 42% (27/65) harbored activating PIK3CA mutations, implying potential sensitivity to PI3K inhibitors and resistance to endocrine therapies. HR + HER2− patients exhibited intrinsic hormonal resistance via FGFR1 gene gain/amplification (15%), exclusive of PI3K/AKT pathway alterations. Aberrations in the PI3K/AKT/mTOR and FGFR pathways were implicated in chemoresistance, with a 52.9% involvement in triple‐negative breast cancer. In HER2+ tumors, 50% harbored GAs potentially conferring resistance to anti‐HER2 therapies, including PIK3CA mutations (32%), MAP3K1 (2.9%), NF1 (2.9%), and copy number gain/amplification of FGFR1 (18%), FGFR3 (2.9%), EGFR (2.9%), and AKT2 (2.9%). Conclusion This study presents CGP findings for treatment‐naïve Taiwanese breast cancer, emphasizing its value in routine breast cancer management, disease classification, and treatment selection.

Summary: Immune checkpoint blockade (ICB) is a promising therapy for solid tumors, but its effectiveness depends on biomarkers that are not precise. Here, we utilized genome-wide association study to investigate the association between genetic variants and tumor mutation burden to interpret ICB response. We identified 16 variants (p

Cytomegalovirus (CMV) infection is associated with significant morbidity and mortality in both immunocompetent and immunocompromised patients. CMV is a ubiquitous Herpesviridae virus with a wide spectrum of pathologies in humans. Immunocompetent patients generally develop a benign, self-limited mononucleosis-like syndrome, whereas gastrointestinal tissue-invasive disease is more frequently seen in immunocompromised. The clinical manifestations of CMV colitis or proctitis are demarcated by bloody diarrhea, ulcerations, ulcero-infiltrative changes, and pseudomembranous formation on colonoscopy. Gastrointestinal CMV infections complicated with deep rectal ulcer and fistula formation are rare in patients with systemic lupus erythematosus. Ganciclovir is also the gold standard therapy for CMV colitis or proctitis.