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Background The receptor-binding domain (RBD) variants of SARS-CoV-2 could impair antibody-mediated neutralization of the virus by host immunity; thus, prospective surveillance of antibody escape mutants and understanding the evolution of RBD are urgently needed. Methods Using the single B cell cloning technology, we isolated and characterized 93 RBD-specific antibodies from the memory B cells of four COVID-19 convalescent individuals in the early stage of the pandemic. Then, global RBD alanine scanning with a panel of 19 selected neutralizing antibodies (NAbs), including several broadly reactive NAbs, was performed. Furthermore, we assessed the impact of single natural mutation or co-mutations of concern at key positions of RBD on the neutralization escape and ACE2 binding function by recombinant proteins and pseudoviruses. Results Thirty-three amino acid positions within four independent antigenic sites (1 to 4) of RBD were identified as valuable indicators of antigenic changes in the RBD. The comprehensive escape mutation map not only confirms the widely circulating strains carrying important immune escape RBD mutations such as K417N, E484K, and L452R, but also facilitates the discovery of new immune escape-enabling mutations such as F486L, N450K, F490S, and R346S. Of note, these escape mutations could not affect the ACE2 binding affinity of RBD, among which L452R even enhanced binding. Furthermore, we showed that RBD co-mutations K417N, E484K, and N501Y present in B.1.351 appear more resistant to NAbs and human convalescent plasma from the early stage of the pandemic, possibly due to an additive effect. Conversely, double mutations E484Q and L452R present in B.1.617.1 variant show partial antibody evasion with no evidence for an additive effect. Conclusions Our study provides a global view of the determinants for neutralizing antibody recognition, antigenic conservation, and RBD conformation. The in-depth escape maps may have value for prospective surveillance of SARS-CoV-2 immune escape variants. Special attention should be paid to the accumulation of co-mutations at distinct major antigenic sites. Finally, the new broadly reactive NAbs described here represent new potential opportunities for the prevention and treatment of COVID-19.

Background Talaromyces marneffei (TM) bloodstream infection is common in Acquired Immunodeficiency Syndrome (AIDS) patients with extreme immunodeficiency in Southeast Asia and South China, however, clinical case study on TM bloodstream infection is scarce. We retrospectively analyzed the clinical characteristics of TM bloodstream infection in hospitalized AIDS patients and determined the outcomes of hospitalization after diagnosis in our hospital over the past 5 years. Methods From January 2015 to July 2020, 87 cases of TM detected by blood culture in patients admitted to our center were collected. The admission complaints, blood cells, biochemistry, CD4 and CD8 cell counts and 1,3-β-D-glucan (BDG), procalcitonin (PCT), CRP level on the day of blood culture test, and outcomes during hospitalization were analyzed. Logistic regression analysis was performed for the risk factors for poor prognosis (60 cases). Spearman correlation analysis was used to analyze the correlation between peripheral blood cells, albumin and the time required for TM turnaround in blood culture. The difference was statistically significant when the P value was < 0.05. Results A total of 87 patients were collected, with a median age of 34 years, a median hemoglobin of 94 g/L and CD4 count of 7/μl. The rate of TM bloodstream infection among all in-hospital patients increased from 0.99% in 2015 to 2.09% in 2020(half year). Patients with TM bloodstream infection with CD8 count < 200/μl had a 12.6-fold higher risk of poor prognosis than those with CD8 count > 200/μl ( p  = 0.04), and those with BDG < 100 pg/mL had a 34.9-fold higher risk of poor prognosis than those with BDG > 100 pg/mL ( p  = 0.01). Conclusions TM bloodstream infection is becoming more common in advanced AIDS patients in endemic areas. For those patients with extremely low CD4 and CD8 cell counts below 200/μl is with an increased risk of poor prognosis.

We investigated the clinical characteristics and outcomes of acquired immunodeficiency syndrome-related Burkitt lymphoma (AIDS-BL). A single-center retrospective study was performed of 78 cases over a 10-year period. The baseline characteristics of enrolled patients included the following: median age, 46 years; median CD4+ T lymphocyte count, 156 cells/μL; advanced stage, 74.3%; > 1 extranodal site, 55.1%; international prognostic index (IPI) > 1, 85.9%; and elevated serum lactate dehydrogenase, 82.1%. The 1-year and 2-year overall survival (OS) rates were 52.2 ± 5.9% and 42.7 ± 6.2%, respectively. A prognostic analysis of 65 patients who had undergone chemotherapy showed that B symptoms (with vs. without fever, night sweat or weight loss), number of extranodal sites (0, 1 vs. > 1), level of serum albumin (≥ 35 g/L vs. < 35 g/L), hemoglobin (≥ 110 g/L vs. < 110 g/L), and IPI score (≤ 2 vs. > 1) were all associated with OS. However, only B symptoms (HR = 4.036, 95% CI 1.821–8.948, p = 0.001), serum albumin level < 35 g/L (HR = 2.131, 95% CI 1.013–4.483, p = 0.046), and chemotherapy without rituximab (HR = 2.286, 95% CI 1.108–4.714, p = 0.025) were independent predictors of OS after multivariate adjustment. Patients with AIDS-BL were likely to present with high-risk features, and their clinical outcomes were relatively poor, especially those with B symptoms and lower serum albumin levels.

The heterogeneity in the pathological and clinical manifestations of ovarian cancer is a major hurdle impeding early and accurate diagnosis. A host of imaging modalities, including Doppler ultrasound, MRI, and CT, have been investigated to improve the assessment of ovarian lesions. We hypothesized that pathologic conditions might affect the ovarian vasculature and that these changes might be detectable by optical-resolution photoacoustic microscopy (OR-PAM). In our previous work, we developed a benchtop OR-PAM and demonstrated it on a limited set of ovarian and fallopian tube specimens. In this study, we collected data from over 50 patients, supporting a more robust statistical analysis. We then developed an efficient custom analysis pipeline for characterizing the vascular features of the samples, including the mean vessel diameter, vascular density, global vascular directionality, local vascular definition, and local vascular tortuosity/branchedness. Phantom studies using carbon fibers showed that our algorithm was accurate within an acceptable error range. Between normal ovaries and normal fallopian tubes, we observed significant differences in five of six extracted vascular features. Further, we showed that distinct subsets of vascular features could distinguish normal ovaries from cystic, fibrous, and malignant ovarian lesions. In addition, a statistically significant difference was found in the mean vascular tortuosity/branchedness values of normal and abnormal tubes. The findings support the proposition that OR-PAM can help distinguish the severity of tubal and ovarian pathologies.

Objectives This study aimed to explore the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐specific humoral responses and T‐cell responses in patients who have recovered from coronavirus disease 2019 (COVID‐19) to understand the natural protective immune responses and to facilitate the development of vaccines. Methods We conducted a combined assessment of the changes in neutralising antibody levels and SARS‐CoV‐2‐specific T‐cell responses over time in 27 patients up to 7 months after infection. Results The neutralising antibody remained detectable in 96.3% of the patients at their second visit at about 7 months post‐onset of symptoms. However, their humoral responses, including titres of the spike receptor‐binding domain IgG and neutralising antibody, decreased significantly compared with those at first clinic visit. By contrast, the proportions of spike‐specific CD4+ T cells, but not CD8+ T cells, in COVID‐19 patients after recovery were persistently higher than those in healthy controls. No significant change was observed in the proportion of spike‐specific CD4+ T cells in patients who had recovered from COVID‐19 within 7 months. Conclusion The SARS‐CoV‐2‐specific T‐cell immune responses persisted, while the neutralising antibodies decayed. Further studies are needed to extend the longevity of neutralising antibodies and to evaluate whether these T cells are sufficient to protect patients from reinfection. We followed up COVID‐19 patients discharged from the hospital up to 7 months post infection. We found that the neutralizing antibody responses are declining while T‐cell immunities are sustained in COVID‐19 patients during the follow‐up.

To investigate the sensitivity of SARS-CoV-2 testing in specimens collected from the anterior nasal vestibules of COVID-19 patients. A cross-sectional analysis was performed on 30 patients with a confirmed diagnosis of COVID-19 at the Shanghai Public Health Clinical Center from March 14, 2020 to March 21, 2020. Paired specimens were collected from both the anterior nasal vestibule and the oropharynx from all patients. All specimens were tested for SARS-CoV-2 using reverse transcription-polymerase chain reaction (RT-PCR) assays. Of the 30 patients with confirmed COVID-19, 17 patients (56.7%) tested positive for SARS-CoV-2 when oropharyngeal specimens were used, while 20 patients (66.7%) tested positive when nasal swab specimens were used. There was no statistically significant difference in sensitivity between the two methods. Respiratory swabs collected from the nasal vestibule offer a less invasive alternative to oropharyngeal swabs for specimen collection in the detection of SARS-CoV-2 infection, and have adequate sensitivity.

Cancer remains a leading cause of death worldwide, underscoring the need for imaging technologies that provide both structural and functional insights into cancer biology. Photoacoustic imaging (PAI), which detects ultrasonic signals generated by optical absorption, combines the strengths of both modalities, achieving optical contrast with ultrasonic resolution and depth. When co-registered with ultrasound (US), the hybrid US-PAI platform offers a unique combination of high-resolution anatomical and functional imaging that can improve cancer diagnosis, characterization, and treatment monitoring.This dissertation explores the clinical translation of US-PAI through innovations in imaging system design, computational analysis, and clinical validation across three major cancer types: ovarian, rectal, and breast cancer. In ovarian cancer, quantitative vascular biomarkers from photoacoustic tomography combined with multiparametric and radiomic analysis on coregistered ultrasound enabled improved differentiation between benign and malignant ovarian lesions. In rectal cancer, deep learning analysis of co-registered ultrasound-photoacoustic microscopy provided early indicators of response to neoadjuvant therapy by quantifying vascular remodeling that occurred prior to anatomical recovery. In breast cancer, diffuse optical tomography, photoacoustic tomography, and ultrasound were integrated to jointly reconstruct optical absorption and scattering maps, yielding more accurate quantitation of hemoglobin and oxygenation biomarkers while preserving vascular detail. In addition, this work extended to optical coherence tomography and photoacoustic microscopy for high-resolution microvascular and morphological imaging of endometrial cancer, exploring both conventional computer vision methods and deep learning based analysis to characterize endometrial tissue microarchitecture. Together, the studies presented in this dissertation establish a consistent imaging framework that correlates PAI-derived functional parameters with underlying cancer biology across different organ systems and cancer types. By combining structural and functional imaging within a single clinically translatable platform, the work demonstrates the potential of US-PAI to improve diagnostic accuracy, enable early treatment assessment, and support precision oncology.

Photoacoustic tomography (PAT) holds promise for non-invasive functional imaging in ovarian cancer diagnostics. However, accurate estimation of oxygen saturation ( ) and total hemoglobin concentration (THb) is hindered by wavelength- and depth-dependent fluence variations. We aim to improve the accuracy and clinical utility of and THb quantification in transvaginal ultrasound-guided PAT (US-PAT) by developing an integrated spectral and depth compensation (ISDC) method that corrects for both spectral distortion and depth-dependent attenuation. We introduce a spectral compensation strategy derived from Monte Carlo simulations and integrate it with depth-wise fluence correction to construct the proposed ISDC method. The approach has been validated using phantoms with known optical properties and applied to clinical PAT data from 82 ovarian lesions (67 benign and 15 malignant). Diagnostic performance was evaluated using logistic regression and receiver operating characteristic analysis. In phantom experiments, ISDC improved estimation accuracy compared with linear unmixing (LU) and enhanced uniformity of THb estimates across depth. In clinical data, ISDC has increased values by in both benign and malignant lesions, enhanced contrast of THb between malignant and benign lesion groups (mean THb ratio has increased from 1.4 to 1.9), and achieved higher classification performance (AUC = 0.93 versus 0.88 for LU) when combining and THb features. The ISDC approach significantly enhances the quantitative accuracy and diagnostic performance of PAT by compensating for both spectral and depth fluence variations within biological tissue. These improvements support the integration of ISDC into US-PAT systems for ovarian lesion characterization and future clinical applications.

Existing photoacoustic phantoms are unable to mimic complex microvascular structures with varying sizes and distributions. A suitable material with structures that mimic intricate microvascular networks is needed. Our aim is to introduce loofah as a natural phantom material with complex fiber networks ranging from 50 to , enabling the fabrication of phantoms with controlled optical properties comparable to those of human microvasculature. By introducing a controllable chromophore into the loofah material, we controlled its absorption properties. The loofah's vasculature-mimetic capabilities and stability in photoacoustic signal generation were evaluated using co-registered ultrasound, acoustic-resolution photoacoustic microscopy (ARPAM), and optical-resolution photoacoustic microscopy (ORPAM). ORPAM results confirmed the loofah's ability to control chromophore distribution, leading to consistent and regulated photoacoustic signals. ARPAM results demonstrated that the loofah phantom effectively replicates vascular structures, exhibiting superior performance in mimicking microvascular networks compared with commonly used tissue-mimetic phantoms. The dominant diameter range of the phantom's microvasculature was between 100 and , aligning well with the targeted range and facilitating meaningful comparisons with human vascular structures. The loofah material provides a low-cost and effective method for creating submillimeter microvascular phantoms for photoacoustic imaging. Its exceptional morphology and customizability allow it to be shaped into various vascular network configurations, enhancing the fidelity of phantom imaging and assisting in system calibration and validation. In addition, data obtained from this realistic microvascular phantom can offer greater opportunities for training machine learning models.

Ovarian cancer is the leading cause of death among gynecological cancers, but is poorly amenable to preoperative diagnosis. In this study, we investigate the feasibility of “optical biopsy,” using high-optical-resolution photoacoustic microscopy (OR-PAM) to quantify the microvasculature of ovarian and fallopian tube tissue. The technique is demonstrated using excised human ovary and fallopian tube specimens imaged immediately after surgery. Quantitative parameters are derived using Amira software. The parameters include three-dimensional vascular segment count, total volume and length, which are associated with tumor angiogenesis. Qualitative results of OR-PAM demonstrate that malignant ovarian tissue has larger and more tortuous blood vessels as well as smaller vessels of different sizes, while benign and normal ovarian tissue has smaller vessels of uniform size. Quantitative analysis shows that malignant ovaries have greater tumor vessel volume, length and number of segments, as compared with benign and normal ovaries. The vascular pattern of benign fallopian tube is different than that of benign ovarian tissue. Our initial results demonstrate the potential of OR-PAM as an imaging tool for fast assessment of ovarian tissue and fallopian tube and could avoid unnecessary surgery if the risk of the examined ovary is extremely low.