Cocirculation and coinfection of multiple respiratory viruses during autumn and winter seasons of 2023 in Beijing, China: A retrospective study.

China experienced severe epidemics of multiple respiratory pathogens in 2023 after lifting "Zero-COVID" policy. The present study aims to investigate the changing circulation and infection patterns of respiratory pathogens in 2023. The 160 436 laboratory results of influenza virus and respiratory syncytial virus (RSV) from February 2020 to December 2023, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from June 2020 to December 2023, Mycoplasma pneumoniae, adenovirus, and human rhinovirus from January 2023 to December 2023 were analyzed. We observed the alternating epidemics of SARS-CoV-2 and influenza A virus (IAV), as well as the out-of-season epidemic of RSV during the spring and summer of 2023. Cocirculation of multiple respiratory pathogens was observed during the autumn and winter of 2023. The susceptible age range of RSV in this winter epidemic (10.5, interquartile range [IQR]: 5-30) was significantly higher than previously (4, IQR: 3-34). The coinfection rate of IAV and RSV in this winter epidemic (0.695%) was significantly higher than that of the last cocirculation period (0.027%) (p < 0.001). Similar trend was also found in the coinfection of IAV and SARS-CoV-2. The present study observed the cocirculation of multiple respiratory pathogens, changing age range of susceptible population, and increasing coinfection rates during the autumn and winter of 2023, in Beijing, China.

T Cell Receptor-Directed Bispecific T Cell Engager Targeting MHC-Linked NY-ESO-1 for Tumor Immunotherapy.

Antibody-based bispecific T cell engagers (TCEs) that redirect T cells to kill tumor cells have shown a promising therapeutic effect on hematologic malignancies. However, tumor-specific targeting is still a challenge for TCEs, impeding the development of TCEs for solid tumor therapy. The major histocompatibility complex (MHC) presents almost all intracellular peptides (including tumor-specific peptides) on the cell surface to be scanned by the TCR on T cells. With the premise of choosing optimal peptides, the final complex peptide-MHC could be the tumor-specific target for TCEs. Here, a novel TCR-directed format of a TCE targeting peptide-MHC was designed named IgG-T-TCE, which was modified from the IgG backbone and prepared in a mammalian cell expression system. The recombinant IgG-T-TCE-NY targeting NY-ESO-1157-165/HLA-A*02:01 could be generated in HEK293 cells with a glycosylated TCR and showed potency in T cell activation and redirecting T cells to specifically kill target tumor cells. We also found that the in vitro activity of IgG-T-TCE-NY could be leveraged by various anti-CD3 antibodies and Fc silencing. The IgG-T-TCE-NY efficiently inhibited tumor growth in a tumor-PBMC co-engrafted mouse model without any obvious toxicities.

Emergence and clonal expansion of Aeromonas hydrophila ST1172 that simultaneously produces MOX-13 and OXA-724.

BACKGROUND: Aeromonas hydrophila infections can cause gastrointestinal symptoms such as diarrhea; however, deep infections are rarely reported. Outbreaks of A. hydrophila are reported more frequently in fish, poultry, and snakes than in humans. This study aimed to track clonal relatedness of deep infections caused by A. hydrophila using whole genome sequencing (WGS). METHODS: We collected three isolates of A. hydrophila in July 19 to August 29, 2019, from patients that underwent spine surgery. Accurate species identification was performed using whole-genome average nucleotide identity (ANI). Antimicrobial susceptibility testing was performed using a VITEK 2 automated AST-N334 Gram-negative susceptibility card system. Antimicrobial resistance and virulence genes were identified using the Comprehensive Antibiotic Resistance Database and Virulence Factor Database VFanalyzer. RESULTS: All three isolates were identified as A. hydrophila based on ANI and multilocus sequence typing analysis revealed that A. hydrophila belonged to a novel sequence type (ST1172). All three isolates were susceptible to amikacin and levofloxacin; however, they were resistant to piperacillin/tazobactam, ceftriaxone, cefuroxime, cefoxitin, and imipenem. Isolate 19W05620 (patient 3) showed increased ceftazidime resistance (minimum inhibitory concentration ≥ 64 µg/mL). All three isolates possessed the same chromosomally encoded ß-lactamases, including blaOXA-724 (ß-lactamase), imiH (metallo-ß-lactamase), and blaMOX-13 (AmpC) in plasmids. CONCLUSIONS: Our study validated the transmission of a novel carbapenem-resistant A. hydrophila sequence type (ST1172) in patients that underwent spine surgery. Control measures should be developed to prevent dissemination of A. hydrophila in the hospital setting.

Efficacy of chemo-immunotherapy in metastatic BRAF-mutated lung cancer: a single-center retrospective data.

Background: The effectiveness of combining immune checkpoint inhibitors (ICIs) with chemotherapy in treating non-small cell lung cancers (NSCLCs) with BRAF mutations has not been sufficiently explored. Methods: We compiled data from 306 NSCLC patients with identified BRAF mutations. We looked at efficacy by assessing the objective response rate (ORR) and disease control rate (DCR), as well as survival through measuring progression-free survival (PFS) and overall survival (OS). Results: Out of the patient pool, 44 were treated with a regimen of immune-chemotherapy. Patients undergoing ICI in combination with chemotherapy had a median PFS of 4 months, and the median OS was recorded at 29 months. There was a notable increase in OS in patients receiving first-line treatment versus subsequent lines (29 vs 9.75 months, p=0.01); however, this was not the case with PFS (9 vs 4 months, p=0.46). The ORR for patients on ICIs was 36.3%. PFS and OS rates did not significantly differ between patients with the BRAF-V600E mutation and those with non-V600E mutations (p=0.75 and p=0.97, respectively). Additionally, we found a significant variation in PD-L1 expression between those who responded to treatment and those who didn't (p=0.04). Conclusion: Our findings indicate that chemo-immunotherapy as an initial treatment may lead to improved OS in patients with BRAF-mutated NSCLC when compared to its use in subsequent lines of therapy. Further studies are needed to validate these results and to delve deeper into how specific types of BRAF mutations and PD-L1 expression levels might predict a patient's response to treatments in NSCLC.

TLR2 regulates Moraxella catarrhalis adhesion to and invasion into alveolar epithelial cells and mediates inflammatory responses.

Moraxella catarrhalis is a major cause of chronic obstructive pulmonary disease. Toll-like receptor 2 (TLR2) plays an important role in the inflammatory response in host respiratory epithelial cells. M. catarrhalis induces an inflammatory immune response in respiratory epithelial cells that is mostly dependent on TLR2. However, the mechanisms by which this pathogen adheres to and invades the respiratory epithelium are not well understood. The present study aimed to reveal the role of TLR2 in M. catarrhalis adhesion to and invasion into alveolar epithelial cells, using molecular techniques. Pretreatment with the TLR2 inhibitor TLR2-IN-C29 enhanced M. catarrhalis adhesion to A549 cells but reduced its invasion, whereas the agonist Pam3CSK4 reduced both M. catarrhalis adhesion and invasion into A549 cells. Similarly, M. catarrhalis 73-OR strain adhesion and invasion were significantly reduced in TLR2-/- A549 cells. Moreover, the lung clearance rate of the 73-OR strain was significantly higher in TLR2-/- C57/BL6J mice than in wild-type (WT) mice. Histological analysis showed that inflammatory responses were milder in TLR2-/- C57/BL6J mice than in WT mice, which was confirmed by a decrease in cytokine levels in TLR2-/- C57/BL6J mice. Overall, these results indicate that TLR2 promoted M. catarrhalis adhesion and invasion of A549 cells and lung tissues and mediated inflammatory responses in infected lungs. This study provides important insights into the development of potential therapeutic strategies against M. catarrhalis and TLR2-induced inflammatory responses.

The metabolic slowdown caused by the deletion of pspA accelerates protein aggregation during stationary phase facilitating antibiotic persistence.

Entering a dormant state is a prevailing mechanism used by bacterial cells to transiently evade antibiotic attacks and become persisters. The dynamic progression of bacterial dormancy depths driven by protein aggregation has been found to be critical for antibiotic persistence in recent years. However, our current understanding of the endogenous genes that affects dormancy depth remains limited. Here, we discovered a novel role of phage shock protein A (pspA) gene in modulating bacterial dormancy depth. Deletion of pspA of Escherichia coli resulted in increased bacterial dormancy depths and prolonged lag times for resuscitation during the stationary phase. ∆pspA exhibited a higher persister ratio compared to the wild type when challenged with various antibiotics. Microscopic images revealed that ∆pspA showed accelerated formation of protein aggresomes, which were collections of endogenous protein aggregates. Time-lapse imaging established the positive correlation between protein aggregation and antibiotic persistence of ∆pspA at the single-cell level. To investigate the molecular mechanism underlying accelerated protein aggregation, we performed transcriptome profiling and found the increased abundance of chaperons and a general metabolic slowdown in the absence of pspA. Consistent with the transcriptomic results, the ∆pspA strain showed a decreased cellular ATP level, which could be rescued by glucose supplementation. Then, we verified that replenishment of cellular ATP levels by adding glucose could inhibit protein aggregation and reduce persister formation in ∆pspA. This study highlights the novel role of pspA in maintaining proteostasis, regulating dormancy depth, and affecting antibiotic persistence during stationary phase.

Superantigen-fused T cell engagers for tumor antigen-mediated robust T cell activation and tumor cell killing.

Inadequate T cell activation has severely limited the success of T cell engager (TCE) therapy, especially in solid tumors. Enhancing T cell activity while maintaining the tumor specificity of TCEs is the key to improving their clinical efficacy. However, currently, there needs to be more effective strategies in clinical practice. Here, we design novel superantigen-fused TCEs that display robust tumor antigen-mediated T cell activation effects. These innovative drugs are not only armed with the powerful T cell activation ability of superantigens but also retain the dependence of TCEs on tumor antigens, realizing the ingenious combination of the advantages of two existing drugs. Superantigen-fused TCEs have been preliminarily proven to have good (>30-fold more potent) and specific (>25-fold more potent) antitumor activity in vitro and in vivo. Surprisingly, they can also induce the activation of T cell chemotaxis signals, which may promote T cell infiltration and further provide an additional guarantee for improving TCE efficacy in solid tumors. Overall, this proof-of-concept provides a potential strategy for improving the clinical efficacy of TCEs.

The impact of the COVID-19 pandemic on the prevalence and genotype distribution of HPV infection in Beijing, China.

Human papillomavirus (HPV) is one of the most common sexually transmitted infections nationwide. The COVID-19 pandemic has greatly influenced on the HPV prevention project. The objective of this study was to examine the influence of the pandemic on HPV prevalence and genotype distribution in Beijing, China. A total of 44 401 genital swabs were obtained from outpatients at Peking Union Medical College Hospital during two distinct periods: the prepandemic stage from January 2017 to December 2019 and the pandemic stage from January 2020 to December 2022. During the prepandemic and pandemic stages, a total of 33 531 and 10 870 swabs were respectively collected. Fifteen high-risk HPV (HR-HPV) DNA type and a combination of two low-risk (LR-HPV) types (6/11) of genital swabs were detected to compare the HPV infection rates and genotype distributions in two stages. The results showed that the pandemic period witnessed a decrease in the overall HPV infection rate from 33.43% (11 245/33 531) to 29.43% (5527/18 780) compared to the prepandemic. There were statistically significant differences in infection rates between females and males (p < 0.05). Single infection was the predominant type while multiple infection was more prevalent in males than females in both prepandemic and pandemic periods. HR-HPV infection constituted the majority of infections and cannot be disregarded. The distribution of HR-HPV genotypes exhibited little variation before and after the outbreak, but there were some differences between females and males. HPV 16, 52, 58, 56, and 66 were the most commonly detected genotypes in females, whereas HPV 16, 52, 51, 58, and 18 were frequently detected in males. Additionally, HPV 6/11 exhibited a higher prevalence in males than in females. Notably, the age group of 31-40 years old exhibited the highest prevalence of HPV and the lowest infection rate was detected among individuals aged ≤20 years (p < 0.05), which remained relatively consistent before and during the pandemic. These findings underscore the importance of monitoring the trend of HPV epidemic and offer valuable insights for the prevention, treatment, and scientific investigation of HPV in the post-COVID-19 era.

Performance evaluation of QuantStudio 1 plus real-time PCR instrument for clinical laboratory analysis: A proof-of-concept study.

Objective: The real-time PCR system is one of the most powerful research tools available in the life sciences field. The aim of this study was to preliminarily evaluate the analytical performance of QuantStudio 1 Plus real-time PCR system (QS 1 plus) for clinical procedures. Methods: The consistency of QS 1 plus with the reference system in terms of various clinical procedures was evaluated. For qualitative data, the Kappa test was used to analyze the agreement of the results. For the quantitative data, Passing-Bablok regression analysis and Bland-Altman plot analysis were used to assess the concordance between QS 1 plus and the reference instrument. Results: Passing-Bablok regression showed an excellent agreement between the QS 1 plus and LC 480 systems for HBV DNA quantification (y = 0.928 + 0.970x), whereas Bland-Altman plot analysis showed very small mean deviations between the two systems. The QS 1 plus yielded perfectly consistent results with the reference instrument for methylenetetrahydrofolate reductase (MTHFR) C677T melting curve genotyping analysis, MTHFR C677T genotyping analysis, Norovirus RNA negative/positive analysis, influenza B virus (Flu B) RNA negative/positive analysis, Mycobacterium tuberculosis (MTB) DNA negative/positive analysis, Human Papillomavirus (HPV) genotyping analysis, epidermal growth factor receptor (EGFR) gene mutation analysis. Both the relative quantitative analysis and the relative quantitative analysis (standard curve) confirmed the satisfactory concordance between the QS 1 plus instrument and the ABI 7500 instrument by Passing-Bablok regression analysis (y = 0.180 + 0.817x and y = 0.012 + 1.000x, respectively) and Bland-Altman plot analysis. Conclusions: Our research has proven that QS 1 plus is adaptable to most test procedures in the clinical laboratory. This may provide the basis for its further application.

Improving the tumor selectivity of T cell engagers by logic-gated dual tumor-targeting.

Targeting single tumor antigens makes it difficult to provide sufficient tumor selectivity for T cell engagers (TCEs), leading to undesirable toxicity and even treatment failure, which is particularly serious in solid tumors. Here, we designed novel trispecific TCEs (TriTCEs) to improve the tumor selectivity of TCEs by logic-gated dual tumor-targeting. TriTCE can effectively redirect and activate T cells to kill tumor cells (∼18 pM EC50) by inducing the aggregation of dual tumor antigens, which was ∼70- or 750- fold more effective than the single tumor-targeted isotype controls, respectively. Further in vivo experiments indicated that TriTCE has the ability to accumulate in tumor tissue and can induce circulating T cells to infiltrate into tumor sites. Hence, TriTCE showed a stronger tumor growth inhibition ability and significantly prolonged the survival time of the mice. Finally, we revealed that this concept of logic-gated dual tumor-targeted TriTCE can be applied to target different tumor antigens. Cumulatively, we reported novel dual tumor-targeted TriTCEs that can mediate a robust T cell response by simultaneous recognition of dual tumor antigens at the same cell surface. TriTCEs allow better selective T cell activity on tumor cells, resulting in safer TCE treatment.

Cryptococcus neoformans, a global threat to human health.

BACKGROUND: Emerging fungal pathogens pose important threats to global public health. The World Health Organization has responded to the rising threat of traditionally neglected fungal infections by developing a Fungal Priority Pathogens List (FPPL). Taking the highest-ranked fungal pathogen in the FPPL, Cryptococcus neoformans, as a paradigm, we review progress made over the past two decades on its global burden, its clinical manifestation and management of cryptococcal infection, and its antifungal resistance. The purpose of this review is to drive research efforts to improve future diagnoses, therapies, and interventions associated with fungal infections. METHODS: We first reviewed trends in the global burden of HIV-associated cryptococcal infection, mainly based on a series of systematic studies. We next conducted scoping reviews in accordance with the guidelines described in the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews using PubMed and ScienceDirect with the keyword Cryptococcus neoformans to identify case reports of cryptococcal infections published since 2000. We then reviewed recent updates on the diagnosis and antifungal treatment of cryptococcal infections. Finally, we summarized knowledge regarding the resistance and tolerance of C. neoformans to approved antifungal drugs. RESULTS: There has been a general reduction in the estimated global burden of HIV-associated cryptococcal meningitis since 2009, probably due to improvements in highly active antiretroviral therapies. However, cryptococcal meningitis still accounts for 19% of AIDS-related deaths annually. The incidences of CM in Europe and North America and the Latin America region have increased by approximately two-fold since 2009, while other regions showed either reduced or stable numbers of cases. Unfortunately, diagnostic and treatment options for cryptococcal infections are limited, and emerging antifungal resistance exacerbates the public health burden. CONCLUSION: The rising threat of C. neoformans is compounded by accumulating evidence for its ability to infect immunocompetent individuals and the emergence of antifungal-resistant variants. Emphasis should be placed on further understanding the mechanisms of pathogenicity and of antifungal resistance and tolerance. The development of novel management strategies through the identification of new drug targets and the discovery and optimization of new and existing diagnostics and therapeutics are key to reducing the health burden.

Association of Gut Microbiota Composition in Pregnant Women Colonized with Group B Streptococcus with Maternal Blood Routine and Neonatal Blood-Gas Analysis.

Group B Streptococcus (GBS) colonizes the vaginal and rectal mucosa in a substantial proportion of healthy women, and GBS is a risk factor for GBS-associated adverse birth outcomes, such as bacterial infection, in neonates. Whether changes in the gut microbiota of GBS-infected pregnant women are associated with maternal complete blood cell count (CBC) and neonatal blood-gas analysis is unknown. To explore the relationship between the intestinal microecological composition of pregnant women and maternal blood routine and neonatal blood-gas analysis, we collected intestinal microecology samples of 26 pregnant women in clinic. They were divided into a positive group(GBS positive,GBS +) and a negative group (GBS negative, GBS-), with 12 in the positive group and 14 in the negative group. 16S rRNA gene sequencing was used to examine the gut microbiota profile from a fecal sample of pregnant women. CBC was carried out in enrolled pregnant women and umbilical arterial blood-gas analysis (UABGA)was conducted for analysis of intestinal microbiota composition, maternal blood routine and neonatal blood gas. Our results showed significant differences in the total number of organisms and microbial diversity of intestinal microbiota between healthy pregnant women and GBS-positive pregnant women. Particularly, abundances of Lentisphaerae, Chlorobi, Parcubacteria, Chloroflexi, Gemmatimonadetes, Acidobacteria, Fusobacteria and Fibrobacteres were only detected in participants with GBS colonization. Blood-gas analysis revealed that neonates born to mothers with GBS colonization had significantly higher fractions of carboxyhemoglobin (FCOHb) and lower methemoglobin (FMetHb), and abundances of OTU80, OTU122, OTU518 and OTU375 were associated with blood-gas indicators, such as carboxyhemoglobin, methemoglobin, PCO2, PH and ABE. Interestingly, there were significant correlations between OTU levels and inflammatory indexes in pregnant women with GBS infection. Together, this study revealed for the first time that altered gut microbiota compositions are related to the inflammatory state in GBS-positive pregnant women and neonatal blood-gas indicators. GBS colonization may lead to significant changes in the gut microbiome, which might be involved in the pathogenesis of the maternal inflammatory state and neonatal blood gas abnormalities.

Metastatic ovarian tumor from pancreatic cancer treated with combined immunotherapy: A case report.

Pancreatic cancer (PC) is a fatal disease with a high mortality rate due to difficulties in early diagnosis and metastasis. Common sites of metastasis from PC include the liver, lung, stomach and kidney. Patients diagnosed at already the metastatic stages on presentation constitute 50-55% of the cases, with a 5-year survival rate of 3%. By contrast, secondary ovarian metastases account for 10-25% of all ovarian malignancies, though an accurate diagnosis remain challenging. The present study reports the rare case of a 42-year-old woman with primary hepatic metastasis and secondary ovarian metastasis from PC treated with two lines of immunotherapy, who is also experiencing severe treatment-associated toxicity. The patient first received combined immunotherapy consisting of camrelizumab (200 mg; day 1; every 3 weeks) and chemotherapy with nab-paclitaxel (125 mg/m2; days 1 and 8; every 3 weeks) and gemcitabine (1,000 mg/m2; days 1 and 8; every 3 weeks). She then exhibited a partial response following 4 months of treatment. However, 9 months after the initial treatment, the disease progressed with ovarian involvement, which was confirmed by surgery. Second-line treatment included immunotherapy, targeted therapy and oral chemotherapy (200 mg sintilimab on day 1; 50 mg tegafur from days 1-14, twice daily; and 8 mg anlotinib from days 1-14, every 3 weeks). The progression-free survival time from this second-line treatment was 6 months. Immunotherapy was permanently aborted due to severe intestinal inflammation, where four lines of combined treatments were recommended. The patient remains on treatment with a good quality of life in July 2022, and a current overall survival time of >24 months. In conclusion, the diagnosis of metastatic PC leads to a poor prognosis, but ovarian metastasis from PC is rare. Furthermore, the combination of immunotherapy with chemotherapy or antiangiogenic inhibitors shows promise as a treatment strategy for advanced stages of PC.

Long-term remission under Disitamab Vedotin (RC48) in HR-positive/HER2-positive metastatic breast cancer with brain meningeal, and bone marrow involvement: A case report.

Breast cancer (BC) with overexpression of human epidermal growth factor receptor 2 (HER2) is closely associated with an elevated risk of multiple distant metastases and unfavorable prognosis. Disitamab Vedotin (RC48) is a newly developed antibody-drug conjugate targeting HER2, which is comprised of hertuzumab coupled to monomethyl auristatin E via a cleavable linker. Pre-clinical studies indicated its strong anti-tumor activity in HER2-positive and low HER2 expression models of BC. The present study reported on the case of a 60-year-old postmenopausal female who suffered from fatigue and was diagnosed with a right-sided BC tumor. The diagnosis was stage IV (cT4N3M1) hormone receptor (HR)-positive and HER2-positive invasive ductal carcinoma with systemic metastases (brain included). The patient initially responded well to 26 cycles of the first-line anti-HER2 targeted therapy plus chemotherapy (trastuzumab+pertuzumab+nab-paclitaxel) combined with whole-brain radiotherapy. However, both extracranial and intracranial lesions achieved progressive disease (PD), which eventually occurred during 5 sequential cycles of maintenance therapy. Subsequently, 4 cycles of second-line treatment (trastuzumab + pyrotinib + capecitabin) were continued until the levels of blood tumor markers CEA, CA15-3 and CA125 were elevated, and systemic PD was able to be attained (the brain metastases were rated as stable disease). Finally, the patient received RC48 as the third-line therapy and achieved a durable and effective clinical response. To date, the patient has benefited from 12 cycles of RC48 without any severe adverse effects. The overall survival was >3 years. The present study showcased that RC48 was effective and tolerable for a patient with HR- and HER2-positive BMBC.

Structure-guided and phage-assisted evolution of a therapeutic anti-EGFR antibody to reverse acquired resistance.

Acquired resistance to cetuximab in colorectal cancers is partially mediated by the acquisition of mutations located in the cetuximab epitope in the epidermal growth factor receptor (EGFR) ectodomain and hinders the clinical application of cetuximab. We develop a structure-guided and phage-assisted evolution approach for cetuximab evolution to reverse EGFRS492R- or EGFRG465R-driven resistance without altering the binding epitope or undermining antibody efficacy. Two evolved cetuximab variants, Ctx-VY and Ctx-Y104D, exhibit a restored binding ability with EGFRS492R, which harbors the most common resistance substitution, S492R. Ctx-W52D exhibits restored binding with EGFR harboring another common cetuximab resistance substitution, G465R (EGFRG465R). All the evolved cetuximab variants effectively inhibit EGFR activation and downstream signaling and induce the internalization and degradation of EGFRS492R and EGFRG465R as well as EGFRWT. The evolved cetuximab variants (Ctx-VY, Ctx-Y104D and Ctx-W52D) with one or two amino acid substitutions in the complementarity-determining region inherit the optimized physical and chemical properties of cetuximab to a great extent, thus ensuring their druggability. Our data collectively show that structure-guided and phage-assisted evolution is an efficient and general approach for reversing receptor mutation-mediated resistance to therapeutic antibody drugs.

Correlation of Moraxella catarrhalis macrolide susceptibility with the ability to adhere and invade human respiratory epithelial cells.

Recently, the prevalence of macrolide-resistant Moraxella catarrhalis has been reported, especially among Chinese children. The fitness cost of resistance is reported to render the resistant bacteria less virulent. To investigate the correlation between macrolide susceptibility of M. catarrhalis and pathogenicity, the whole genome of 70 M. catarrhalis isolates belonging to four clonal complexes with different macrolide susceptibilities was sequenced. The gene products were annotated with the Gene Ontology terms. Based on 46 extracted essential virulence genes, 19 representative isolates were selected to infect type II alveolar cells (A549 cells). The ability of these isolates to adhere and invade human epithelial cells and to produce cytokines was comparatively analysed. Furthermore, mice were infected with a pair of M. catarrhalis isolates with different pathogenic behaviours and macrolide susceptibilities to examine pulmonary clearance, histological findings, and the production of cytokines. The percentages of annotations for binding, metabolic process, cellular process, and cell were non-significantly different between the macrolide-resistant and macrolide-susceptible groups. The presence of uspA2, uspA2H, pilO, lbpB, lex1, modM, mboIA, and mboIB significantly differed among the four clonal complexes and macrolide susceptibility groups. Furthermore, compared with those in macrolide-susceptible isolates, the adhesion ability was stronger (P = 0.0019) and the invasion ability was weaker (P < 0.0001) in the macrolide-resistant isolates. Mouse experiments revealed that pulmonary macrophages elicit immune responses against M. catarrhalis infection by significantly upregulating the Csf2, Il4, Il13, Il1b, Il6, Tnf, and Il18. Therefore, M. catarrhalis populations exhibited diverse pathogenicity in vitro and in vivo.

Emerging nanobiotechnology-encoded relaxation tuning establishes new MRI modes to localize, monitor and predict diseases.

Magnetic resonance imaging (MRI) is one of the most important techniques in the diagnosis of many diseases including cancers, where contrast agents (CAs) are usually necessary to improve its precision and sensitivity. Previous MRI CAs are confined to the signal-to-noise ratio (SNR) elevation of lesions for precisely localizing lesions. As nanobiotechnology advances, some new MRI CAs or nanobiotechnology-enabled MRI modes have been established to vary the longitudinal or transverse relaxation of CAs, which are harnessed to detect lesion targets, monitor disease evolution, predict or evaluate curative effect, etc. These distinct cases provide unexpected insights into the correlation of the design principles of these nanobiotechnologies and corresponding MRI CAs with their potential applications. In this review, first, we briefly present the principles, classifications and applications of conventional MRI CAs, and then elucidate the recent advances in relaxation tuning via the development of various nanobiotechnologies with emphasis on the design strategies of nanobiotechnology and the corresponding MRI CAs to target the tumor microenvironment (TME) and biological targets or activities in tumors or other diseases. In addition, we exemplified the advantages of these strategies in disease theranostics and explored their potential application fields. Finally, we analyzed the present limitations, potential solutions and future development direction of MRI after its combination with nanobiotechnology.

Evaluation of Anti-Helicobacter pylori IgG Antibodies for the Detection of Helicobacter pylori Infection in Different Populations.

Serological testing (immunoassay) for Helicobacter pylori (H. pylori) is widely available and inexpensive, and does not require medication modifications before testing. It can also determine the type of infection, which helps with clinical diagnosis and treatment, and guides the use of medication. However, the performance of immunoblotting for the detection of H. pylori infections in different populations has still not been fully evaluated. We performed a retrospective analysis of patients in the Health Examination Center and Outpatient Department, from November 2017 to September 2020, at Peking Union Medical College Hospital. All the subjects were tested with the 13C-urea breath test (13C-UBT) and for IgG antibodies. A total of 1678 participants, including 1377 individuals who had undergone physical examinations, were recruited. The results of the immunoassay were significantly different from those of the 13C-UBT for all the subjects and outpatients (p < 0.001). For the physical examinations of individuals, the agreement between the immunoassay and the 13C-UBT was 0.64 (95%CI: 0.59−0.68; p < 0.001), and the H. pylori immunoassay demonstrated a sensitivity and specificity of 74.24% and 90.45%, respectively, with a positive predictive value of 71.01% and negative predictive value of 91.76%. In addition, in patients with gastric mucosal atrophy or early gastric cancer, antibody typing tests can also detect infected patients with missed UBT. The prevalence of H. pylori in Beijing was 26.8%, and the serological positivity rate for H. pylori in the population of Beijing was about 31.7% (25.1% in the physical examination population). The rate of H. pylori antibody positivity among patients with allergic diseases was 73.5%, which is significantly higher than that of the non-allergic disease population (29.3%, p < 0.001). In conclusion, H. pylori antibody typing testing can be applied as a specific test in the healthy physical examination population, and the test can be performed with the remaining serum during the physical examination.

Comparing single or dual tracing modality on sentinel lymph node biopsy from patients who plan to omitting axillary lymph node dissection referring to the criteria of Z0011 trial: a retrospective study.

Axillary lymph node dissection (ALND) can be omitted in the part of the breast-conserving patients with positive sentinel lymph nodes (SLNs) since Z0011 trial has presented. Nevertheless, to date, no studies revealed the influence of different tracing modalities (single tracer versus dual tracers) for sentinel lymph node biopsy (SLNB) on axillary management referring to Z0011 trial criteria. This study aimed to assess whether different tracing modalities of SLNB have impact on axillary management referring to Z0011 trial criteria. The clinical data of breast-conserving patients who underwent SLNB guided by combination of methylene blue (MB) and indocyanine green(ICG) were retrospectively analyzed in our center. The numbers of metastatic (positive) SLNs guided by the single tracer and the dual tracer were compared by self-control study. 127 patients with 1-2 metastatic SLNs dyed by MB [(recorded as MB(+))]were retrieved from our database between 2016 and 2020. In these cases, 53 patients contained 86 SLNs, which were ICG staining but MB negative staining (recorded as ICG(+)/MB(-)). In addition, 16 patients contained 20 metastatic SLNs with ICG(+)/MB(-). There were six patients finally excluded patients (6/127, 4.7%) who initially met the criteria of Z0011 trial, because the further detection of ICG(+)/MB(-) SLNs led the total numbers of positive SLNs over two. The difference was statistically significant. Single tracing modality may underestimate the positive SLN numbers compared to dual tracing modality. Different tracing modalities of SLNB will significantly affect Axillary management referring to Z0011 trial criteria.

Emerging new therapeutic antibody derivatives for cancer treatment.

Monoclonal antibodies constitute a promising class of targeted anticancer agents that enhance natural immune system functions to suppress cancer cell activity and eliminate cancer cells. The successful application of IgG monoclonal antibodies has inspired the development of various types of therapeutic antibodies, such as antibody fragments, bispecific antibodies, and antibody derivatives (e.g., antibody-drug conjugates and immunocytokines). The miniaturization and multifunctionalization of antibodies are flexible and viable strategies for diagnosing or treating malignant tumors in a complex tumor environment. In this review, we summarize antibodies of various molecular types, antibody applications in cancer therapy, and details of clinical study advances. We also discuss the rationale and mechanism of action of various antibody formats, including antibody-drug conjugates, antibody-oligonucleotide conjugates, bispecific/multispecific antibodies, immunocytokines, antibody fragments, and scaffold proteins. With advances in modern biotechnology, well-designed novel antibodies are finally paving the way for successful treatments of various cancers, including precise tumor immunotherapy, in the clinic.