Genome-wide CRISPR screening identifies tyrosylprotein sulfotransferase-2 as a target for augmenting anti-PD1 efficacy.

BACKGROUND: Immune checkpoint therapy (ICT) provides durable responses in select cancer patients, yet resistance remains a significant challenge, prompting the exploration of underlying molecular mechanisms. Tyrosylprotein sulfotransferase-2 (TPST2), known for its role in protein tyrosine O-sulfation, has been suggested to modulate the extracellular protein-protein interactions, but its specific role in cancer immunity remains largely unexplored. METHODS: To explore tumor cell-intrinsic factors influencing anti-PD1 responsiveness, we conducted a pooled loss-of-function genetic screen in humanized mice engrafted with human immune cells. The responsiveness of cancer cells to interferon-γ (IFNγ) was estimated by evaluating IFNγ-mediated induction of target genes, STAT1 phosphorylation, HLA expression, and cell growth suppression. The sulfotyrosine-modified target gene of TPST2 was identified by co-immunoprecipitation and mass spectrometry. The in vivo effects of TPST2 inhibition were evaluated using mouse syngeneic tumor models and corroborated by bulk and single-cell RNA sequencing analyses. RESULTS: Through in vivo genome-wide CRISPR screening, TPST2 loss-of-function emerged as a potential enhancer of anti-PD1 treatment efficacy. TPST2 suppressed IFNγ signaling by sulfating IFNγ receptor 1 at Y397 residue, while its downregulation boosted IFNγ-mediated signaling and antigen presentation. Depletion of TPST2 in cancer cells augmented anti-PD1 antibody efficacy in syngeneic mouse tumor models by enhancing tumor-infiltrating lymphocytes. RNA sequencing data revealed TPST2's inverse correlation with antigen presentation, and increased TPST2 expression is associated with poor prognosis and altered cancer immunity across cancer types. CONCLUSIONS: We propose TPST2's novel role as a suppressor of cancer immunity and advocate for its consideration as a therapeutic target in ICT-based treatments.

Hybrid Nanogenerators for Ocean Energy Harvesting: Mechanisms, Designs, and Applications.

The ocean holds vast potential as a renewable energy source, but harnessing its power has been challenging due to low-frequency and high-amplitude stimulation. However, hybrid nanogenerators (HNGs) offer a promising solution to convert ocean energy into usable power efficiently. With their high sensitivity and flexible design, HNGs are ideal for low-frequency environments and remote ocean regions. Combining triboelectric nanogenerators (TENGs) with piezoelectric nanogenerators (PENGs) and electromagnetic nanogenerators (EMGs) creates a unique hybrid system that maximizes energy harvesting. Ultimately, hybrid energy-harvesting systems offer a sustainable and reliable solution for growing energy needs. This study provides an in-depth review of the latest research on ocean energy harvesting by hybrid systems, focusing on self-powered applications. The article also discusses primary hybrid designs for devices, powering self-powered units such as wireless communication systems, climate monitoring systems, and buoys as applications. The potential of HNGs is enormous, and with rapid advancements in research and fabrication, these systems are poised to revolutionize ocean energy harvesting. It outlines the pros and cons of HNGs and highlights the major challenges that must be overcome. Finally, future outlooks for hybrid energy harvesters are also discussed.

Evaluation of patient satisfaction for telehealth (telephone and video) in rheumatology outpatients during COVID-19 pandemic.

BACKGROUND: Telehealth in rheumatology has been a topic of interest for many years, but the COVID-19 pandemic placed it in the forefront. AIMS: To evaluate patient perception of rheumatology telehealth and determine predictive factors for future telehealth acceptability. METHODS: A questionnaire containing 30 questions was sent to public and private rheumatology patients who attended telehealth appointments between April and May 2020. The questionnaire aimed to obtain information on baseline demographics, traditional appointment details, telehealth appointment details and appointment satisfaction using a 5-point Likert scale. Descriptive statistical analysis was conducted. RESULTS: The questionnaire was sent to 1452 patients, of whom 494 (34%) patients responded. More than 70% of responses indicated overall satisfaction in specialist care through telehealth, and 88.7% perceived this suitable during a pandemic. Less than 50% of patients were agreeable for future telehealth either through telephone or video conference after the pandemic is over. Higher odds ratio for future telehealth acceptability was associated with visual impairment, perceived cost-effectiveness and previous time lost at work for a face-to-face appointment. CONCLUSION: During the unprecedented time of the pandemic, telehealth appointments (telephone/video) assisted in providing ongoing patient care remotely, with high level of satisfaction seen in this study. The patient's experience and perception of telehealth was strongly influenced by financial incentives, and certain subgroups of patients were more accepting for future telehealth appointments. Nevertheless, low level of future telehealth acceptability also highlighted the potential dissatisfaction among patients in telehealth compared with the traditional appointments.

Convenience store visitors recall cigarette advertisements even if they do not purchase cigarettes.

BACKGROUND: This study examined the extent to which visitors to convenience stores remember the cigarette advertisements they encounter in these stores and investigated the relationships between how advertisements are recalled and attitudes toward them. METHODS: Exit surveys of 1007 visitors to three convenience stores located in Seoul, Korea, were conducted between 25 November 2015 and 7 December 2015. RESULTS: Of the respondents, 23.4% (n = 236) freely recalled the cigarette advertisement in the store just visited. However, the percentage of participants who correctly recalled the advertisement increased to 55.2% (n = 556) after we presented them with a card showing options for the advertisement (i.e. a cued recall task). Regardless of sex or purchasing cigarettes, free recall performance was significantly associated with age, number of weekly visits to the convenience store and current smoking status. In addition, free recall increased with having a positive attitude toward cigarette advertisements. CONCLUSIONS: Repeated visits to convenience stores may continue to expose individuals to cigarettes and their advertisements; such exposure may subconsciously affect recall of the advertisements and maintenance of a positive attitude toward cigarette advertisements. Therefore, to denormalize smoking in society, cigarette advertising and displays at points of sale including convenience stores, should be banned.

MicroRNA-Let-7a regulates the function of microglia in inflammation.

Microglia have multiple functions in cerebrovascular and neurodegenerative diseases. Regulation of microglial function during inflammatory stress is important for treatment of central nervous system (CNS) diseases because microglia secrete various substances that affect neurons and glia. MicroRNA-Let-7a (miR-Let-7a) is a tumor suppressor miRNA that has been reported to target transcripts that encode proteins involved in apoptosis. In the present study, we examined the essential role of miR-Let-7a in inflammatory stress by over-expressing miR-Let-7a to investigate its role in determining the BV2 microglial phenotype, a cell line often used as a model of activated microglia. We found that inflammatory factors and Reactive Oxygen Species (ROS) production levels were altered according to miR-Let-7a expression level as measured by Western blot analysis, reverse transcription PCR, quantitative real time PCR, the measurement of nitrite (indicative of the nitric oxide (NO) pathway), and immunocytochemistry (ICC). Our results suggest that miR-Let-7a is involved in the function of microglia in the setting of inflammatory injury. In response to inflammation, miR-Let-7a participates in the reduction of nitrite production and the expression of inducible nitric oxide synthase (iNOS), interleukin (IL)-6 and is involved in increased expression of brain derived neurotrophic factor (BDNF), interleukin (IL)-10, and IL-4 in microglia. Thus, miRNA-Let-7a could act as a regulator of the function of microglia in inflammation.

Let7a involves in neural stem cell differentiation relating with TLX level.

Neural stem cells (NSCs) have the potential for differentiation into neurons known as a groundbreaking therapeutic solution for central nervous system (CNS) diseases. To resolve the therapeutic efficiency of NSCs, recent researchers have focused on the study on microRNA's role in CNS. Some micro RNAs have been reported significant functions in NSC self-renewal and differentiation through the post-transcriptional regulation of neurogenesis genes. MicroRNA-Let7a (Let7a) has known as the regulator of diverse cellular mechanisms including cell differentiation and proliferation. In present study, we investigated whether Let7a regulates NSC differentiation by targeting the nuclear receptor TLX, which is an essential regulator of NSC self-renewal, proliferation and differentiation. We performed the following experiments: western blot analysis, TaqMan assay, RT-PCR, and immunocytochemistry to confirm the alteration of NSCs. Our data showed that let7a play important roles in controlling NSC fate determination. Thus, manipulating Let-7A and TLX could be a novel strategy to enhance the efficiency of NSC's neuronal differentiation for CNS disorders.

Yellow nail syndrome in anti-SSA and anti-SSB positive primary Sjögren's syndrome.

Yellow nail syndrome (YNS) is a rare, acquired condition, characterised by at least two of the three clinical criteria: nail changes, respiratory tract disease and lymphoedema. Currently, the aetiology of YNS remains unknown; however, it is believed to be caused by impaired lymphatic drainage. Currently, there remain no definitive treatment options available and no prospective trials evaluating this. Management includes supportive care and symptomatic treatment. The presence of YNS has been described alongside various conditions, including autoimmune diseases, malignancies and drug exposures. To strengthen the literature on this topic, we present the case of a female patient with a history of anti-SSA and anti-SSB positive primary Sjögren's syndrome, who developed YNS in the immediate postpartum period.

Polyhexamethylene guanidine aerosol causes irreversible changes in blood proteins that associated with the severity of lung injury.

Polyhexamethylene guanidine (PHMG) is a positively charged polymer used as a disinfectant that kills microbes but can cause pulmonary fibrosis if inhaled. After the long-term risks were confirmed in South Korea, it became crucial to measure toxicity through diverse surrogate biomarkers, not only proteins, especially after these hazardous chemicals had cleared from the body. These biomarkers, identified by their biological functions rather than simple numerical calculations, effectively explained the imbalance of pulmonary surfactant caused by fibrosis from PHMG exposure. These long-term studies on children exposed to PHMG has shown that blood protein indicators, primarily related to apolipoproteins and extracellular matrix, can distinguish the degree of exposure to humidifier disinfectants (HDs). We defined the extreme gradient boosting models and computed reflection scores based on just ten selected proteins, which were also verified in adult women exposed to HD. The reflection scores successfully discriminated between the HD-exposed and unexposed groups in both children and adult females (AUROC: 0.957 and 0.974, respectively) and had a strong negative correlation with lung function indicators. Even after an average of more than 10 years, blood is still considered a meaningful specimen for assessing the impact of environmental exposure to toxic substances, with proteins providing in identifying the pathological severity of such conditions.

Willingness to Use and Pay for Digital Health Care Services According to 4 Scenarios: Results from a National Survey.

BACKGROUND: Smartphones and their associated technology have evolved to an extent where these devices can be used to provide digital health interventions. However, few studies have been conducted on the willingness to use (WTU) and willingness to pay (WTP) for digital health interventions. OBJECTIVE: The purpose of this study was to investigate how previous service experience, the content of the services, and individuals' health status affect WTU and WTP. METHODS: We conducted a nationwide web-based survey in 3 groups: nonusers (n=506), public service users (n=368), and private service users (n=266). Participants read scenarios about an imagined health status (such as having a chronic illness) and the use of digital health intervention models (self-management, expert management, and medical management). They were then asked to respond to questions on WTU and WTP. RESULTS: Public service users had a greater intention to use digital health intervention services than nonusers and private service users: scenario A (health-risk situation and self-management), nonusers=odd ratio [OR] .239 (SE .076; P<.001) and private service users=OR .138 (SE .044; P<.001); scenario B (health-risk situation and expert management), nonusers=OR .175 (SE .040; P<.001) and private service users=OR .219 (SE .053; P<.001); scenario C (chronic disease situation and expert management), nonusers=OR .413 (SE .094; P<.001) and private service users=OR .401 (SE .098; P<.001); and scenario D (chronic disease situation and medical management), nonusers=OR .480 (SE .120; P=.003) and private service users=OR .345 (SE .089; P<.001). In terms of WTP, in scenarios A and B, those who used the public and private services had a higher WTP than those who did not (scenario A: ß=-.397, SE .091; P<.001; scenario B: ß=-.486, SE .098; P<.001). In scenario C, private service users had greater WTP than public service users (ß=.264, SE .114; P=.02), whereas public service users had greater WTP than nonusers (ß=-.336, SE .096; P<.001). In scenario D, private service users were more WTP for the service than nonusers (ß=-.286, SE .092; P=.002). CONCLUSIONS: We confirmed that the WTU and WTP for digital health interventions differed based on individuals' prior experience with health care services, health status, and demographics. Recently, many discussions have been made to expand digital health care beyond the early adapters and fully into people's daily lives. Thus, more understanding of people's awareness and acceptance of digital health care is needed.

Generating Detailed Spectral Libraries for Canine Proteomes Obtained from Serum and Urine.

Domestic dogs (Canis lupus familiaris) are popular companion animals. Increase in medical expenses associated with them and demand for extending their lifespan in a healthy manner has created the need to develop new diagnostic technology. Companion dogs also serve as important animal models for non-clinical research as they can provide various biological phenotypes. Proteomics have been increasingly used on dogs and humans to identify novel biomarkers of various diseases. Despite the growing applications of proteomics in liquid biopsy in veterinary medicine, no publicly available spectral assay libraries have been created for the proteome of canine serum and urine. In this study, we generated spectral assay libraries for the two-representative liquid-biopsy samples using mid-pH fractionation that allows in-depth understanding of proteome coverage. The resultant canine serum and urine spectral assay libraries include 1,132 and 4,749 protein groups and 5,483 and 25,228 peptides, respectively. We built these complimentary accessible resources for proteomic biomarker discovery studies through ProteomeXchange with the identifier PXD034770.

Gut bacteria-derived 3-phenylpropionylglycine mitigates adipocyte differentiation of 3T3-L1 cells by inhibiting adiponectin-PPAR pathway.

BACKGROUND: Gut microbiota provide numerous types of metabolites that humans cannot produce and have a huge influence on the host metabolism. Accordingly, gut bacteria-derived metabolites can be employed as a resource to develop anti-obesity and metabolism-modulating drugs. OBJECTIVE: This study aimed to examine the anti-adipogenic effect of 3-phenylpropionylglycine (PPG), which is a glycine conjugate of bacteria-derived 3-phenylpropionic acid (PPA). METHODS: The effect of PPG on preadipocyte-to-adipocyte differentiation was evaluated in 3T3-L1 differentiation models and the degree of the differentiation was estimated by Oil red O staining. The molecular mechanisms of the PPG effect were investigated with transcriptome analyses using RNA-sequencing and quantitative real-time PCR. RESULTS: PPG suppressed lipid droplet accumulation during the adipogenic differentiation of 3T3-L1 cells, which is attributed to down-regulation of lipogenic genes such as acetyl CoA carboxylase 1 (Acc1) and fatty acid synthase (Fasn). However, other chemicals with chemical structures similar to PPG, including cinnamoylglycine and hippuric acid, had little effect on the lipid accumulation of 3T3-L1 cells. In transcriptomic analysis, PPG suppressed the expression of adipogenesis and metabolism-related gene sets, which is highly associated with downregulation of the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Protein-protein association network analysis suggested adiponectin as a hub gene in the network of genes that were differentially expressed genes in response to PPG treatment. CONCLUSION: PPG inhibits preadipocyte-to-adipocyte differentiation by suppressing the adiponectin-PPAR pathway. These data provide a potential candidate from bacteria-derived metabolites with anti-adipogenic effects.

Polo-Like Kinase 1 Regulates Chromosomal Instability and Paclitaxel Resistance in Breast Cancer Cells.

PURPOSE: Chromosomal instability (CIN) contributes to intercellular genetic heterogeneity and has been implicated in paclitaxel (PTX) resistance in breast cancer. In this study, we explored polo-like kinase 1 (PLK1) as an important regulator of mitotic integrity and as a useful predictive biomarker for PTX resistance in breast cancer. METHODS: We performed PTX resistance screening using the human kinome CRISPR/Cas9 library in breast cancer cells. In vitro cell proliferation and apoptosis assays and in vivo xenograft experiments were performed to determine the effects of PLK1 on breast cancer cells. Immunofluorescence microscopy was used to measure the degree of multipolar cell division. RESULTS: Kinome-wide CRISPR/Cas9 screening identified various kinases involved in PTX resistance in breast cancer cells; among these, PLK1 was chosen for further experiments. PLK1 knockdown inhibited the proliferation of MDA-MB-231 and MDA-MB-468 cells in vitro and in vivo. Moreover, PLK1 silencing sensitized breast cancer cells and mouse xenograft tumor models to PTX cytotoxicity. Silencing of PLK1 induced the formation of multipolar spindles and increased the percentage of multipolar cells. In addition, PLK1 silencing resulted in the downregulation of BubR1 and Mad2 in breast cancer cells. Furthermore, PLK1 upregulation in primary breast cancer was associated with decreased overall patient survival based on the analysis of The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium databases. CONCLUSION: PLK1 plays an important role in PTX resistance by regulating CIN in breast cancer cells. Targeting PLK1 may be an effective treatment strategy for PTX-resistant breast cancers.

Augmentation of the RNA m6A reader signature is associated with poor survival by enhancing cell proliferation and EMT across cancer types.

N6-Methyladenosine (m6A) RNA modification plays a critical role in the posttranscriptional regulation of gene expression. Alterations in cellular m6A levels and m6A-related genes have been reported in many cancers, but whether they play oncogenic or tumor-suppressive roles is inconsistent across cancer types. We investigated common features of alterations in m6A modification and m6A-related genes during carcinogenesis by analyzing transcriptome data of 11 solid tumors from The Cancer Genome Atlas database and our in-house gastric cancer cohort. We calculated m6A writer (W), eraser (E), and reader (R) signatures based on corresponding gene expression. Alterations in the W and E signatures varied according to the cancer type, with a strong positive correlation between the W and E signatures in all types. When the patients were divided according to m6A levels estimated by the ratio of the W and E signatures, the prognostic effect of m6A was inconsistent according to the cancer type. The R and especially the R2 signatures (based on the expression of IGF2BPs) were upregulated in all cancers. Patients with a high R2 signature exhibited poor prognosis across types, which was attributed to enrichment of cell cycle- and epithelial-mesenchymal transition-related pathways. Our study demonstrates common features of m6A alterations across cancer types and suggests that targeting m6A R proteins is a promising strategy for cancer treatment.

The National Health Plan 2030: Its Purpose and Directions of Development.

The National Health Plan 2030 (HP2030) started to be prepared in 2017 and was completed and announced in December 2020. This study presents an overview of how it was established, the major changes in policies, its purpose, and future directions. This study analyzed the steps taken in the past 4 years to establish HP2030 and reviewed major issues at the international and governmental levels based on an evaluation of HP2020 and its content. HP2030 establishes 6 divisions and 28 topic areas, and it will continue to expand investments in health with a total budget of 2.5 trillion Korean won. It also established goals to enhance health equity for the first time, with the goal of calculating healthy life expectancy in a way that reflects the circumstances of Korea and reducing the gap in income and healthy life expectancy between regions. The establishment of HP2030 is significant in that it constitutes a sustainable long-term plan with sufficient preparation, contains policy measures that everyone participates in and makes together, and works towards improvements in universal health standards and health equity. With the announcement of HP2030, which includes goals and directions of the national health policy for the next 10 years, it will be necessary to further strengthen collaboration with relevant ministries, local governments, and agencies in various fields to concretize support for prevention-centered health management as a national task and to develop a health-friendly environment that considers health in all policy areas.

Targeting antioxidant enzymes enhances the therapeutic efficacy of the BCL-XL inhibitor ABT-263 in KRAS-mutant colorectal cancers.

Cancer chemotherapeutic drugs exert cytotoxic effects by modulating intracellular reactive oxygen species (ROS) levels. However, whether ROS modulates the efficacy of targeted therapeutics remains poorly understood. Previously, we reported that upregulation of the anti-apoptotic protein, BCL-XL, by KRAS activating mutations was a potential target for KRAS-mutant colorectal cancer (CRC) treatment. Here, we demonstrated that the BCL-XL targeting agent, ABT-263, increased intracellular ROS levels and targeting antioxidant pathways augmented the therapeutic efficacy of this BH3 mimetic. ABT-263 induced expression of genes associated with ROS response and increased intracellular ROS levels by enhancing mitochondrial superoxide generation. The superoxide dismutase inhibitor, 2-methoxyestradiol (2-ME), exhibited synergism with ABT-263 in KRAS-mutant CRC cell lines. This synergistic effect was attributed to the inhibition of mTOR-dependent translation of the anti-apoptotic MCL-1 protein via caspase 3-mediated cleavage of AKT and S6K. In addition, combination treatment of ABT-263 and 2-ME demonstrated a synergistic effect in in vivo patient-derived xenografts harboring KRAS mutations. Our data suggest a novel role for ROS in BH3 mimetic-based targeted therapy and provide a novel strategy for treatment of CRC patients with KRAS mutations.

CRISPR screens identify a novel combination treatment targeting BCL-XL and WNT signaling for KRAS/BRAF-mutated colorectal cancers.

Metastatic or recurrent colorectal cancer (CRC) patients require systemic chemotherapy, but the therapeutic options of targeted agents remain limited. CRC patients with KRAS or BRAF gene mutations exhibit a worse prognosis and are resistant to anti-EGFR treatment. Previous studies have shown that the expression of anti-apoptotic protein BCL-XL is increased in CRC patients with KRAS/BRAF mutations, suggesting BCL-XL as a therapeutic target for this subgroup. Here, we performed genome-wide CRISPR/Cas9 screens of cell lines with KRAS mutations to investigate the factors required for sensitivity to BCL-XL inhibitor ABT-263 using single-guide RNAs (sgRNAs) that induce loss-of-function mutations. In the presence of ABT-263, sgRNAs targeting negative regulators of WNT signaling (resulting in WNT activation) were enriched, whereas sgRNAs targeting positive regulators of WNT signaling (resulting in WNT inhibition) were depleted in ABT-263-resistant cells. The activation of WNT signaling was highly associated with an increased expression ratio of anti- to pro-apoptotic BCL-2 family genes in CRC samples. Genetic and pharmacologic inhibition of WNT signaling using ß-catenin short hairpin RNA or TNIK inhibitor NCB-0846, respectively, augmented ABT-263-induced cell death in KRAS/BRAF-mutated cells. Inhibition of WNT signaling resulted in transcriptional repression of the anti-apoptotic BCL-2 family member, MCL1, via the functional inhibition of the ß-catenin-containing complex at the MCL1 promoter. In addition, the combination of ABT-263 and NCB-0846 exhibited synergistic effects in in vivo patient-derived xenograft (PDX) models with KRAS mutations. Our data provide a novel targeted combination treatment strategy for the CRC patient subgroup with KRAS or BRAF mutations.

Soluble Fas ligand drives autoantibody-induced arthritis by binding to DR5/TRAIL-R2.

To date, no study has demonstrated that soluble Fas ligand (sFasL)-mediated inflammation is regulated via interaction with Fas in vivo. We found that FasL interacts specifically with tumor necrosis factor receptor superfamily (TNFRSF)10B, also known as death receptor (DR)5. Autoantibody-induced arthritis (AIA) was attenuated in FasL (Faslgld/gld)- and soluble FasL (FaslΔs/Δs)-deficient mice, but not in Fas (Faslpr/lpr and Fas-/-)- or membrane FasL (FaslΔm/Δm)-deficient mice, suggesting sFasL promotes inflammation by binding to a Fas-independent receptor. Affinity purification mass spectrometry analysis using human (h) fibroblast-like synovial cells (FLSCs) identified DR5 as one of several proteins that could be the elusive Fas-independent FasL receptor. Subsequent cellular and biochemical analyses revealed that DR5 interacted specifically with recombinant FasL-Fc protein, although the strength of this interaction was approximately 60-fold lower than the affinity between TRAIL and DR5. A microarray assay using joint tissues from mice with arthritis implied that the chemokine CX3CL1 may play an important downstream role of the interaction. The interaction enhanced Cx3cl1 transcription and increased sCX3CL1 production in FLSCs, possibly in an NF-κB-dependent manner. Moreover, the sFasL-DR5 interaction-mediated CX3CL1-CX3CR1 axis initiated and amplified inflammation by enhancing inflammatory cell influx and aggravating inflammation via secondary chemokine production. Blockade of FasL or CX3CR1 attenuated AIA. Therefore, the sFasL-DR5 interaction promotes inflammation and is a potential therapeutic target.

Plasma Proteome Signature to Predict the Outcome of Breast Cancer Patients Receiving Neoadjuvant Chemotherapy.

The plasma proteome of 51 non-metastatic breast cancer patients receiving neoadjuvant chemotherapy (NCT) was prospectively analyzed by high-resolution mass spectrometry coupled with nano-flow liquid chromatography using blood drawn at the time of diagnosis. Plasma proteins were identified as potential biomarkers, and their correlation with clinicopathological variables and survival outcomes was analyzed. Of 51 patients, 20 (39.2%) were HR+/HER2-, five (9.8%) were HR+/HER2+, five (9.8%) were HER2+, and 21 (41.2%) were triple-negative subtype. During a median follow-up of 52.0 months, there were 15 relapses (29.4%) and eight deaths (15.7%). Four potential biomarkers were identified among differentially expressed proteins: APOC3 had higher plasma concentrations in the pathological complete response (pCR) group, whereas MBL2, ENG, and P4HB were higher in the non-pCR group. Proteins statistically significantly associated with survival and capable of differentiating low- and high-risk groups were MBL2 and P4HB for disease-free survival, P4HB for overall survival, and MBL2 for distant metastasis-free survival (DMFS). In the multivariate analysis, only MBL2 was a consistent risk factor for DMFS (HR: 9.65, 95% CI 2.10-44.31). The results demonstrate that the proteomes from non-invasive sampling correlate with pCR and survival in breast cancer patients receiving NCT. Further investigation may clarify the role of these proteins in predicting prognosis and thus their therapeutic potential for the prevention of recurrence.

Multicentre retrospective cohort study assessing the incidence of serious infections in patients with lupus nephritis, compared with non-renal systemic lupus erythematosus.

OBJECTIVES: The incidence of serious infections is poorly defined in patients with lupus nephritis (LN). It is also unclear if LN influences risk of serious infections in a longitudinal analysis. The aim of this study was to determine the incidence of serious infections in patients with SLE and LN, compared with patients with SLE without LN. METHODS: A multicentre retrospective cohort study was conducted. Patients with LN identified at two tertiary centres were matched where possible with age and gender-matched patients with SLE without LN.Any infection requiring inpatient admission, occurring in the 6 months following index clinical visit, was considered serious. Cox regression was employed to investigate the association between risk of serious infection and LN status, and other relevant covariates. RESULTS: A total of 173 patients were included within the analysis (n=87 LN, n=86 SLE only). A total of 9.2% (n=8) of patients with LN experienced at least one serious infection within the study period, compared with 5.8% (n=5) of patients without LN, equivalent to 19.5 and 12.0 infections per 100 patient-years with and without LN, respectively. Univariable and multivariable analyses found no significant increased risk of serious infection in patients with LN versus controls (HR 1.61; 95% CI 0.53 to 4.92 and adjusted HR (aHR) 0.91; 95% CI 0.27 to 3.06, respectively). Increased prednisone dose and modified SLE comorbidity index were strongly associated with serious infection (aHR (per 5 mg) 1.21; 95% CI 1.07 to 1.37; p=0.003 and aHR 1.13; 95% CI 1.02 to 1.25; p=0.018, respectively). CONCLUSIONS: In this cohort, adjusting for cofactors, the presence of LN alone does not appear to increase the risk of serious infections compared with patients with SLE without LN. However, increased prednisone dose at baseline visit and increasing comorbidity were independently associated with the incidence of serious infection.