Management and Mechanisms of Diarrhea Induced by Tyrosine Kinase Inhibitors in Human Epidermal Growth Factor Receptor-2-Positive Breast Cancer.

Breast cancer has the highest incidence among female malignancies, significantly impacting women's health. Recently, numerous HER2-targeted therapies have achieved excellent clinical outcomes. Currently, anti-HER2 drugs are divided into three main categories: monoclonal antibodies, small-molecule tyrosine kinase inhibitors, and antibody-coupled drugs (ADCs). The main toxic side effects of small molecule TKI-based therapy are diarrhea, hand-foot syndrome, rash, nausea, and vomiting. Diarrhea is a potential predictor of tumor response, affecting up to 95% of cancer patients treated with TKIs. Severe gastrointestinal toxicity can result in the need for dose reductions and treatment interruptions. This not only compromises the efficacy of TKIs but also deteriorates human nutrition and quality of life. The majority of individuals develop diarrhea within 7 days of starting treatment, with approximately 30% developing grade 3 or higher diarrhea within 2-3 days of starting treatment. The severity of diarrhea typically correlates with the dosage of most TKIs. Current prevention and management strategies are primarily empirical, focusing on symptom alleviation rather than addressing the toxicological mechanisms underlying TKI-induced diarrhea. Consequently, anti-diarrheal drugs are often less effective in managing this condition in cancer patients receiving TKIs. Moreover, our understanding of the toxicological mechanisms responsible for such diarrhea remains limited, underscoring the urgent need to identify these mechanisms in order to develop effective anti-diarrheal medications tailored to this specific context. This review aims to elucidate management approaches and mechanisms for diarrhea induced by TKIs during HER2-positive breast cance.

Breast cancer has the highest incidence among female malignancies, significantly impacting women's health. In recent years, numerous HER2-targeted therapies have been developed, including lapatinib, neratinib, tucatinib, and pyrotinib. However, second-generation tyrosine kinase inhibitors (TKIs) often cause severe gastrointestinal toxicity, necessitating dose reduction and treatment interruption. This not only compromises the efficacy of TKIs but also deteriorates nutritional status and quality of life. Diarrhea is a potential predictor of tumor response and is the second most common adverse event, affecting up to 95% of cancer patients treated with TKIs. Approximately 30% of these patients experience grade 3 or higher diarrhea within just 2-3 days of initiating TKI treatment. The severity of diarrhea typically correlates with the dosage of most TKIs. Current prevention and management strategies are primarily empirical, focusing on symptom alleviation rather than addressing the toxicological mechanisms underlying TKI-induced diarrhea. Consequently, anti-diarrheal drugs are often less effective in managing this condition in cancer patients receiving TKIs. Moreover, our understanding of the toxicological mechanisms responsible for such diarrhea remains limited, underscoring the urgent need to identify these mechanisms to develop effective antidiarrheal medications tailored for this specific context. This review aims to elucidate management approaches for diarrhea induced by HER2 tyrosine kinase inhibitors during breast cancer treatment.

Ictal-onset localization through effective connectivity analysis based on RNN-GC with intracranial EEG signals in patients with epilepsy.

Epilepsy is one of the most common clinical diseases of the nervous system. The occurrence of epilepsy will bring many serious consequences, and some patients with epilepsy will develop drug-resistant epilepsy. Surgery is an effective means to treat this kind of patients, and lesion localization can provide a basis for surgery. The purpose of this study was to explore the functional types and connectivity evolution patterns of relevant regions of the brain during seizures. We used intracranial EEG signals from patients with epilepsy as the research object, and the method used was GRU-GC. The role of the corresponding area of each channel in the seizure process was determined by the introduction of group analysis. The importance of each area was analysed by introducing the betweenness centrality and PageRank centrality. The experimental results show that the classification method based on effective connectivity has high accuracy, and the role of the different regions of the brain could also change during the seizures. The relevant methods in this study have played an important role in preoperative assessment and revealing the functional evolution patterns of various relevant regions of the brain during seizures.

Cellular RNA-binding proteins LARP4 and PABPC1 synergistically facilitate viral translation of coronavirus PEDV.

Coronaviruses are causing epizootic diseases and thus are a substantial threat for both domestic and wild animals. These viruses depend on the host translation machinery to complete their life cycle. The current paper identified cellular RNA-binding proteins (RBPs), La-related protein 4 (LARP4) and polyadenylate-binding protein cytoplasmic 1 (PABPC1), as critical regulators of efficient translation of the coronavirus porcine epidemic diarrhea virus (PEDV) mRNA. In Vero cells, PEDV infection caused LARP4 to migrate from the nucleus to the cytoplasm in a chromosome region maintenance1 (CRM1)-independent pathway. In the absence of the nuclear export signal of LARP4, viral translation was not promoted by LARP4. A further study unveiled that the cytoplasmic LARP4 binds to the 3'-terminal untranslated region (3'UTR) of PEDV mRNA with the assistance of PABPC1 to facilitate viral translation. LARP4 knockdown reduced the promotion of the PABPC1-induced 3'UTR translation activity. Moreover, the rabbit reticulocyte lysate (RRL) system revealed that the prokaryotic expressed protein LARP4 and PABPC1 enhance PEDV mRNA translation. To our knowledge, this is the first study demonstrating that PEDV induces nucleo-cytoplasmic shuttling of LARP4 to enhance its own replication, which broadens our insights into how viruses use host's RBPs for the efficient translation of viral mRNA.

A narrative review: research progress of adjuvant intensive endocrine therapy for early breast cancer.

Background and Objective: Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) is the most prevalent subtype of all BCs. The primary treatment modality is endocrine therapy (ET). Traditional adjuvant ET for early-stage breast cancer (EBC) has undergone extensive exploration and is relatively well-established. However, patients at high risk of recurrence may still experience early relapse, necessitating consideration of intensified adjuvant ET to reduce recurrence risk. The objective of this narrative review is to examine various strategies for intensifying adjuvant ET in EBC, thoroughly analyze key clinical studies, and summarize the most effective treatment approaches supported by current evidence-based medicine. Furthermore, it addresses unresolved challenges that necessitate further refinement and investigation. Methods: As of March 2024, a comprehensive literature search, compilation, and analysis were conducted across PubMed, Baidu Scholar, ClinicalTrials.gov, and relevant academic conferences. Key Content and Findings: There are numerous methods to intensify adjuvant ET: (I) combining ovarian function suppression (OFS) to reduce estrogen levels in the body and induce a state of artificial menopause to enhance the efficacy of ET; (II) individual extension of the duration of ET based on patients' varying risks of recurrence, with high-risk patients covering two peak recurrence periods; (III) the addition of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) can significantly extend invasive disease-free survival and reduce the risk of recurrence, serving as the main intensive treatment for high-risk patients; (IV) combination with bone-modifying drugs (BMD) can significantly reduce rates of bone metastasis and slightly enhance prognosis but is not commonly used in adjuvant settings; (V) combined with poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors, current studies only show a trend towards benefit in HR+ patients with germline BRCA1/2 mutations; more data are still needed to support its clinical benefit. This narrative review examines various strategies for intensifying adjuvant ET in EBC, critically evaluates key clinical studies, and summarizes the most effective treatment approaches supported by current evidence-based medicine. Furthermore, it addresses unresolved challenges that necessitate further refinement and investigation. Conclusions: In the context where traditional adjuvant ET is relatively well-established, the emergence of novel ET has notably addressed issues of endocrine resistance more effectively. Various intensified adjuvant ET has shown potential in further reducing recurrence risk among high-risk patients. However, additional research and time are essential to determine the optimal approaches for intensified adjuvant ET.

Chinese Society of Clinical Oncology (CSCO) Breast Cancer guidelines 2024.

Background: Developing guidelines for the diagnosis and treatment of common cancers in China based on the evidence-based practice, the availability of diagnosis and treatment products, and the up-to-date advances in precision medicine is one of the basic tasks of the Chinese Society of Clinical Oncology Breast Cancer (CSCO BC) Committee. Methods: Protocols with high evidence level and good availability are used as the Level I recommendations; protocols with relatively high evidence level but slightly lower expert consensus or with poor availability are used as the Level II recommendations; and protocols that are clinically applicable but with low evidence level are regarded as the Level III recommendations. Based on the findings of clinical research at home and abroad and the opinions of CSCO BC experts, the CSCO BC guidelines determine the levels of recommendations for clinical application. Results: For human epidermal growth factor receptor 2 (HER2)-positive breast cancer, a combination of trastuzumab and pertuzumab regimen were recommended as Level I recommendation for neoadjuvant and first line metastatic breast cancer. Pyrotinib is also recommended as Level I recommendation in first line and second line therapy according to the latest studies conducted in China. Antibody drug conjugates was also recommended for patients with trastuzumab progression. For triple negative breast cancer, immunotherapy in early and metastatic breast cancer was highlighted and listed as new chapters in this version of guideline. For hormone receptor (HR)-positive breast cancer, cyclin dependent kinase 4/6 (CDK4/6) was recommended in different stages, especially in adjuvant therapy. There was also a new chapter for HER2-low breast cancer stratified by HR status. Conclusions: We firmly believe that evidence-based, availability-concerned, and consensus-based guidelines will be more feasible for clinical practice in China and in other countries with similar situations.

AcornHRD: an HRD algorithm highly associated with anthracycline-based neoadjuvant chemotherapy in breast cancer in China.

PURPOSE: Our study aimed to develop and validate a homologous recombination deficiency (HRD) scoring algorithm in the Chinese breast cancer population. METHODS AND MATERIALS: Ninety-six in-house breast cancer (BC) samples and 6 HRD-positive standard cells were analyzed by whole-genome sequencing (WGS). Besides, 122 BCs from the TCGA database were down-sampled to ~ 1X WGS. We constructed an algorithm named AcornHRD for HRD score calculated based on WGS at low coverage as input data to estimate large-scale copy number alteration (LCNA) events on the genome. A clinical cohort of 50 BCs (15 cases carrying BRCA mutation) was used to assess the association between HRD status and anthracyclines-based neoadjuvant treatment outcomes. RESULTS: A 100-kb window was defined as the optimal size using 41 in-house cases and the TCGA dataset. HRD score high threshold was determined as HRD score ≥ 10 using 55 in-house BCs with BRCA mutation to achieve a 95% BRCA-positive agreement rate. Furthermore, the HRD status agreement rate of AcornHRD is 100%, while the ShallowHRD is 60% in standard cells. BRCA mutation was significantly associated with a high HRD score evaluated by AcornHRD and ShallowHRD (p = 0.008 and p = 0.003, respectively) in the TCGA dataset. However, AcornHRD showed a higher positive agreement rate than did the ShallowHRD algorithm (70% vs 60%). In addition, the BRCA-positive agreement rate of AcornHRD was superior to that of ShallowHRD (87% vs 13%) in the clinical cohort. Importantly, the high HRD score assessed by AcornHRD was significantly correlated with a residual cancer burden score of 0 or 1 (RCB0/1). Besides, the HRD-positive group was more likely to respond to anthracycline-based chemotherapy than the HRD-negative group (pCR [OR = 9.5, 95% CI 1.11-81.5, p = 0.040] and RCB0/1 [OR = 10.29, 95% CI 2.02-52.36, p = 0.005]). CONCLUSION: Using the AcornHRD algorithm evaluation, our analysis demonstrated the high performance of the LCNA genomic signature for HRD detection in breast cancers.

Combined analysis of transcriptomics with metabolomics provides insights into the resistance mechanism in winter jujube using L-Methionine.

Black rots lead to great economic losses in winter jujube industry. The objective of this research was to delve into the underlying mechanisms of enhanced resistance of winter jujube fruit to black rot by L-Methionine (Met) treatment. The findings revealed that the application of Met significantly curtailed lesion diameter and decay incidence in winter jujube fruit. The peroxidase (POD) activity in the Met-treated jujubes was 3.06-fold that in the control jujubes after 4 d of treatment. By day 8, the activities of phenylalanine ammonia-lyase (PAL), chitinase (CHI) and ß-1,3-glucanase (GLU) in the Met-treated jujubes had surged to their zenith, being 1.39, 1.22, and 1.52 times in the control group, respectively. At the end of storage, the flavonoid and total phenol content remained 1.58 and 1.06 times than that of the control group. Based on metabolomics and transcriptomics analysis, Met treatment upregulated 6 key differentially expressed metabolites (DEMs) (succinic acid, trans-ferulic acid, salicylic acid, delphinium pigments, (S)-abscisic acid, and hesperidin-7-neohesperidin), 12 key differentially expressed genes (DEGs) (PAL, CYP73A, COMT, 4CL, CAD, POD, UGT72E, ANS, CHS, IAA, TCH4 and PR1), which were involved in phenylpropanoid biosynthesis pathway, flavonoid biosynthesis pathway and plant hormone signal transduction pathway. Further analysis revealed that the most of the enzymes, DEMs and DEGs in this study were associated with both antioxidant and disease resistance. Consequently, Met treatment enhanced disease resistance of winter jujube fruit by elevating antioxidant capacity and triggering defense response. This study might provide theoretical support for utilizing Met in the management and prevention of post-harvest black rot in winter jujube.

Trastuzumab deruxtecan versus treatment of physician's choice in previously treated Asian patients with HER2-low unresectable/metastatic breast cancer: subgroup analysis of the DESTINY-Breast04 study.

BACKGROUND: In the global phase 3 DESTINY-Breast04 study (NCT03734029), the anti-human epidermal growth factor 2 (HER2) antibody-drug conjugate trastuzumab deruxtecan (T-DXd) demonstrated a statistically significant improvement in progression-free survival (PFS) and overall survival (OS), with manageable safety compared with treatment of physician's choice (TPC) in patients with HER2-low metastatic breast cancer (mBC) who had received 1-2 prior lines of chemotherapy. METHODS: This subgroup analysis examined the efficacy and safety of T-DXd versus TPC in 213 patients from Asian countries and regions who were enrolled in the DESTINY-Breast04 trial and randomized to T-DXd (n = 147) or TPC (n = 66). RESULTS: Median PFS with T-DXd and TPC was 10.9 and 5.3 months, respectively, in Asian patients with hormone receptor-positive mBC, and 10.9 and 4.6 months, respectively, in the overall Asian population. In both populations, median OS was not reached with T-DXd and was 19.9 months with TPC. The objective response rate was higher with T-DXd versus TPC in all Asian patients. Median treatment duration was 8.4 months with T-DXd and 3.5 months with TPC. The most common grade ≥ 3 drug-related treatment-emergent adverse events in Asian patients treated with T-DXd were neutropenia (16.3%), anemia (12.9%), and leukopenia (11.6%); the incidences of neutropenia and leukopenia were higher with TPC versus T-DXd. Adjudicated drug-related interstitial lung disease or pneumonitis with T-DXd was 14.3%; the majority of events were grade 1-2. CONCLUSIONS: T-DXd demonstrated clinically meaningful survival benefits versus TPC in Asian HER2-low mBC patients, regardless of hormone receptor status, with no new safety signals. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT03734029.

Disitamab vedotin, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpression and HER2-low advanced breast cancer: a phase I/Ib study.

BACKGROUND: Disitamab vedotin (DV; RC48-ADC) is an antibody-drug conjugate comprising a human epidermal growth factor receptor 2 (HER2)-directed antibody, linker and monomethyl auristatin E. Preclinical studies have shown that DV demonstrated potent antitumor activity in preclinical models of breast, gastric, and ovarian cancers with different levels of HER2 expression. In this pooled analysis, we report the safety and efficacy of DV in patients with HER2-overexpression and HER2-low advanced breast cancer (ABC). METHODS: In the phase I dose-escalation study (C001 CANCER), HER2-overexpression ABC patients received DV at doses of 0.5-2.5 mg/kg once every two weeks (Q2W) until unacceptable toxicity or progressive disease. The dose range, safety, and pharmacokinetics (PK) were determined. The phase Ib dose-range and expansion study (C003 CANCER) enrolled two cohorts: HER2-overexpression ABC patients receiving DV at doses of 1.5-2.5 mg/kg Q2W, with the recommended phase 2 dose (RP2D) determined, and HER2-low ABC patients receiving DV at doses of 2.0 mg/kg Q2W to explore the efficacy and safety of DV in HER2-low ABC. RESULTS: Twenty-four patients with HER2-overexpression ABC in C001 CANCER, 46 patients with HER2-overexpression ABC and 66 patients with HER2-low ABC in C003 CANCER were enrolled. At 2.0 mg/kg RP2D Q2W, the confirmed objective response rates were 42.9% (9/21; 95% confidence interval [CI]: 21.8%-66.0%) and 33.3% (22/66; 95% CI: 22.2%-46.0%), with median progression-free survival (PFS) of 5.7 months (95% CI: 5.3-8.4 months) and 5.1 months (95% CI: 4.1-6.6 months) for HER2-overexpression and HER2-low ABC, respectively. Common (≥5%) grade 3 or higher treatment-emergent adverse events included neutrophil count decreased (17.6%), gamma-glutamyl transferase increased (13.2%), asthenia (11.0%), white blood cell count decreased (9.6%), peripheral neuropathy such as hypoesthesia (5.9%) and neurotoxicity (0.7%), and pain (5.9%). CONCLUSION: DV demonstrated promising efficacy in HER2-overexpression and HER2-low ABC, with a favorable safety profile at 2.0 mg/kg Q2W.

Development and anatomy of petals with specialized nectar holder and pollen container in Fumarioideae (Papaveraceae).

MAIN CONCLUSION: Petal developmental characteristics in Fumarioideae were similar at early stages, and the specialized nectar holder/pollen container formed by the outer/inner petals. The micro-morphology of these two structures, however, shows diversity in seven species. Elaborate petals have been modified to form different types, including petal lobes, ridges, protuberances, and spurs, each with specialized functions. Nectar holder and pollen container presumably have a function in plant-pollinator interactions. In Fumarioideae, four elaborate petals of the disymmetric/zygomorphic flower present architecture forming the "nectar holder" and "pollen container" structure at the bottom and top separately. In the present study, the petals of seven species in Fumarioideae were investigated by scanning electron microscopy, light microscope, and transmission electron microscopes. The results show that petal development could divided into six stages: initiation, enlargement, adaxial/abaxial differentiation, elaborate specializations (sacs, spurs, and lobes formed), extension, and maturation, while the specialized "nectar holder" and "pollen container" structures mainly formed in stage 4. "Nectar holder" is developed from the shallow sac/spur differentiated at the base of the outer petal, eventually forming a multi-organized complex structure, together with staminal nectaries (1-2) with individual sizes. A semi-closed ellipsoidal "pollen container" is developed from the apical part of the 3-lobed inner petals fused by middle lobes and attain different sizes. The adaxial epidermis cells are specialized, with more distinct punctate/dense columnar protrusions or wavy cuticles presented on obviously thickening cell walls. In addition, a large and well-developed cavity appears between the inner and outer epidermis of the petals. As an exception, Hypecoum erectum middle lobes present stamen mimicry. Elaborate petal structure is crucial for comprehending the petal diversity in Fumarioideae and provides more evidence for further exploration of the reproductive study in Papaveraceae.

Tyrosine kinase inhibitors in HER2-positive metastatic breast cancer with trastuzumab emtansine resistance: insights from a multicenter retrospective real-world study.

The use of trastuzumab emtansine (T-DM1) has revealed significant efficacy in HER2-positive metastatic breast cancer (MBC). However, optimal therapeutic strategies following T-DM1 failure remain a subject of debate in clinical practice. In this multicenter, retrospective, real-world study, we sought to examine the effectiveness and safety of tyrosine kinase inhibitors (TKIs) as a therapeutic strategy in HER2-positive MBC who developed T-DM1 resistance. Between September 2018 and December 2022, 66 patients were enrolled. The median progression-free survival of TKIs-based therapy was 10.1 months (95% CI, 4.7-15.6). Objective response rate and clinical benefit rate were 18.2 and 66.7%, respectively. TKIs-based therapy demonstrated better effectiveness in patients who had previously derived benefit from T-DM1 and featured acquired resistance to trastuzumab. The most common adverse events were diarrhea (36, 54.5%), hand-foot syndrome (31, 47.0%), and leucopenia (30, 45.5%). In conclusion, TKIs-based therapy showed promising effectiveness and safety in HER2-positive MBC patients after T-DM1 failure.

BOLERO-5: a phase II study of everolimus and exemestane combination in Chinese post-menopausal women with ER + /HER2- advanced breast cancer.

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.

Investigating the impact of weather on stroke in summer.

The objective of this study is to explore how changes in weather contribute to an increase in hospital admissions for stroke in summer. We collected 96,509 cases of stroke hospitalization data in Tianjin from 2016 to 2022 summer, along with corresponding meteorological data. The generalized additive model and distributed lag nonlinear model were used to analyze the lag and cumulative effects of temperature on stroke hospitalization. The research results show both the cold effect and the heat effect in summer would increase the risk of hospitalization. The effect of daily maximum temperature on stroke hospitalization was immediate when the temperature was higher, and delayed when the temperature was lower. However, the risk of stroke hospitalization increased more significantly with increasing temperature than with decreasing temperature. In the presence of one or more of the following three weather changes: sharp temperature increase, sharp temperature decrease, continuous high temperature, the daily number of stroke inpatients were higher than the average in the same period. 83% of the Inpatient-heavy events within the study period were caused by a combination of dramatic temperature changes and continuous high temperatures. In 48% of Inpatient-heavy events, continuous high temperature weather above 30℃ for at least 4 consecutive days were observed. And 55% of high temperature weather was accompanied by high humidity. When the daily relative humidity was greater than 70% and the daily maximum temperature was between 26 and 28℃ or more than 34℃, or the daily maximum temperature changes over 10℃ within 48 h, the number of daily inpatients was more than 1.2 times of the average daily inpatients. More attention should be paid to the combined effects of continuous high temperature and sudden temperature changes in summer stroke prevention.

Calmodulin-like 5 promotes PEDV replication by regulating late-endosome synthesis and innate immune response.

The infection caused by porcine epidemic diarrhea virus (PEDV) is associated with high mortality in piglets worldwide. Host factors involved in the efficient replication of PEDV, however, remain largely unknown. Our recent proteomic study in the virus-host interaction network revealed a significant increase in the accumulation of CALML5 (EF-hand protein calmodulin-like 5) following PEDV infection. A further study unveiled a biphasic increase of CALML5 in 2 and 12 â€‹h after viral infection. Similar trends were observed in the intestines of piglets in the early and late stages of the PEDV challenge. Moreover, CALML5 depletion reduced PEDV mRNA and protein levels, leading to a one-order-of-magnitude decrease in virus titer. At the early stage of PEDV infection, CALML5 affected the endosomal trafficking pathway by regulating the expression of endosomal sorting complex related cellular proteins. CALML5 depletion also suppressed IFN-ß and IL-6 production in the PEDV-infected cells, thereby indicating its involvement in negatively regulating the innate immune response. Our study reveals the biological function of CALML5 in the virology field and offers new insights into the PEDV-host cell interaction.

Expert consensus on the clinical application of immunotherapy in breast cancer: 2024.

Background: Significant progress has been made in immunotherapy of breast cancer (BC) with the approval of multiple immune checkpoint inhibitors (ICIs), particularly in early and metastatic triple-negative breast cancer (TNBC) settings. Most guidelines have recommended immune therapy as the important approach in BC, yet several critical aspects still require further clarification, including proper patient selection, treatment duration, optimized chemotherapy partner, predictive biomarkers, and specific considerations for Chinese patients. Methods: (I) Establishment of expert group: the expert group consists of 32 experts from departments such as medical oncology, breast surgery, and pathology; (II) literature search: mainly conducted in English databases (such as PubMed, Embase, and Cochrane Library) and Chinese databases (such as China National Knowledge Infrastructure, China Biology Medicine disc, and Wanfang Database), with a search cutoff date of April 23, 2024; (III) assessment of evidence quality and recommendation strength: evidence quality and recommendation opinions are graded based on the evidence category and recommendation level of the Chinese Society of Clinical Oncology (CSCO) guidelines; (IV) consensus formulation: on the March 2, 2024, through online consensus meeting, the consensus content is thoroughly discussed, and opinions from all experts are solicited. Results: The consensus meeting has resulted in 15 detailed recommendations, providing clearer guidance on the clinical application of immunotherapy in BC management. The core suggestions are as follows: for early-stage II-III TNBC and metastatic TNBC (mTNBC) in the first-line setting, programmed cell death protein 1 (PD-1) inhibitors can be considered. However, for hormone receptor-positive/human epidermal growth factor receptor 2-negative BC (HR+/HER2- BC), HER2+ BC, and mTNBC in later lines of therapy, evidence is lacking to support the use of immunotherapy. Conclusions: This consensus provides a comprehensive overview of BC immunotherapy, including immunotherapy for early-stage BC and late-stage BC, immune related adverse event (irAE) management, biomarkers of immunotherapy, and future directions. The consensus consolidates these deliberations into 15 evidence-based recommendations, serving as a practical guide for clinicians to more scientifically and systematically manage the clinical application of immunotherapy.

The complete mitochondrial genome of Tauraco livingstonii (Musophagidae: Tauraco).

Livingstone's turaco, Tauraco livingstonii, belongs to the family Musophagidae. In this study, we obtained the complete mitochondrial genome sequence of Livingstone's turaco by high-throughput sequencing technology and constructed a phylogenetic tree. It was found that the mitochondria of this species are 19,015 bp in length and contain a total of 37 genes, comprising 13 protein-coding genes, 22 tRNA genes, and 2 rRNA genes. The base composition of the mitochondrial genome is 31.61% A, 24.22% T, 30.64% C, and 13.52% G, with a GC content of 44%. Notably, an intriguing phenomenon of mitochondrial genome rearrangements was observed, characterized by the duplication of the tRNA Glu-L-CR gene order. In addition, the results of the phylogenetic tree analysis shed light on the taxonomic position of Livingstone's turaco and supported the taxonomy of Otidimorphae. The study provides a basis for future phylogenetic and taxonomic investigations of Musophagiformes.

Case report: Emerging BRCA mutation confers benefit from olaparib after chemotherapy intolerance in advanced triple-negative breast cancer.

Key Clinical Message: In a patient with metastatic breast cancer, an acquired BRCA mutation in the BRCA gene was detected, resulting in benefits from olaparib treatment. This underscores the importance of ongoing genetic phenotype testing after paclitaxel chemotherapy. Abstract: Triple-negative breast cancer (TNBC) is associated with a poor prognosis and elevated mortality risk. BRCA mutations are commonly regarded as prevalent mutations in TNBC patients, strongly associated with congenital familial heredity. Dynamic changes in mutation sites, however, are rarely reported. In this case report, we report a 59-year-old TNBC patient who developed pulmonary metastases post-chemoradiotherapy. No BRCA mutations were detected through NGS. After 7.6 months of nab-paclitaxel treatment, the patient experienced progression of lung metastases, and BRCA mutations were detected through NGS testing. Subsequent administration of olaparib resulted in a reduction in lung metastasis, demonstrating significant therapeutic efficacy. This case underscores the infrequent occurrence of treatment-induced BRCA mutations and emphasizes the significance of dynamic NGS genetic testing for real-time assessment of a patient's mutational status.

Proteomic and metabolomic characterization of bone, liver, and lung metastases in plasma of breast cancer patients.

BACKGROUND: Breast cancer (BC) is the second leading cause of cancer-related deaths among women, primarily due to metastases to other organs rather than the primary tumor. METHODS: In this study, a comprehensive analysis of plasma proteomics and metabolomics was conducted on a cohort of 51 BC patients. Potential biomarkers were screened by the Least Absolute Shrinkage and Selection Operator (LASSO) regression and Random Forest algorithm. Additionally, enzyme-linked immunosorbent assay (ELISA) kits and untargeted metabolomics were utilized to validate the prognostic biomarkers in an independent cohort. RESULTS: In the study, extracellular matrix (ECM)-related functional enrichments were observed to be enriched in BC cases with bone metastases. Proteins dysregulated in retinol metabolism in liver metastases and leukocyte transendothelial migration in lung metastases were also identified. Machine learning models identified specific biomarker panels for each metastasis type, achieving high diagnostic accuracy with area under the curve (AUC) of 0.955 for bone, 0.941 for liver, and 0.989 for lung metastases. CONCLUSIONS: For bone metastasis, biomarkers such as leucyl-tryptophan, LysoPC(P-16:0/0:0), FN1, and HSPG2 have been validated. dUDP, LPE(18:1/0:0), and aspartylphenylalanine have been confirmed for liver metastasis. For lung metastasis, dUDP, testosterone sulfate, and PE(14:0/20:5) have been established.

PI3K/AKT/mTOR signaling pathway: an important driver and therapeutic target in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly heterogeneous tumor lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. It has higher aggressiveness and metastasis than other subtypes, with limited effective therapeutic strategies, leading to a poor prognosis. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway is prevalently over-activated in human cancers and contributes to breast cancer (BC) growth, survival, proliferation, and angiogenesis, which could be an interesting therapeutic target. This review summarizes the PI3K/AKT/mTOR signaling pathway activation mechanism in TNBC and discusses the relationship between its activation and various TNBC subtypes. We also report the latest clinical studies on kinase inhibitors related to this pathway for treating TNBC. Our review discusses the issues that need to be addressed in the clinical application of these inhibitors.