Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis.

Histone acetylation plays critical roles in chromatin remodeling, DNA repair, and epigenetic regulation of gene expression, but the underlying mechanisms are unclear. Proteasomes usually catalyze ATP- and polyubiquitin-dependent proteolysis. Here, we show that the proteasomes containing the activator PA200 catalyze the polyubiquitin-independent degradation of histones. Most proteasomes in mammalian testes ("spermatoproteasomes") contain a spermatid/sperm-specific α subunit α4 s/PSMA8 and/or the catalytic ß subunits of immunoproteasomes in addition to PA200. Deletion of PA200 in mice abolishes acetylation-dependent degradation of somatic core histones during DNA double-strand breaks and delays core histone disappearance in elongated spermatids. Purified PA200 greatly promotes ATP-independent proteasomal degradation of the acetylated core histones, but not polyubiquitinated proteins. Furthermore, acetylation on histones is required for their binding to the bromodomain-like regions in PA200 and its yeast ortholog, Blm10. Thus, PA200/Blm10 specifically targets the core histones for acetylation-mediated degradation by proteasomes, providing mechanisms by which acetylation regulates histone degradation, DNA repair, and spermatogenesis.

Scbean: a python library for single-cell multi-omics data analysis.

SUMMARY: Single-cell multi-omics technologies provide a unique platform for characterizing cell states and reconstructing developmental process by simultaneously quantifying and integrating molecular signatures across various modalities, including genome, transcriptome, epigenome, and other omics layers. However, there is still an urgent unmet need for novel computational tools in this nascent field, which are critical for both effective and efficient interrogation of functionality across different omics modalities. Scbean represents a user-friendly Python library, designed to seamlessly incorporate a diverse array of models for the examination of single-cell data, encompassing both paired and unpaired multi-omics data. The library offers uniform and straightforward interfaces for tasks, such as dimensionality reduction, batch effect elimination, cell label transfer from well-annotated scRNA-seq data to scATAC-seq data, and the identification of spatially variable genes. Moreover, Scbean's models are engineered to harness the computational power of GPU acceleration through Tensorflow, rendering them capable of effortlessly handling datasets comprising millions of cells. AVAILABILITY AND IMPLEMENTATION: Scbean is released on the Python Package Index (PyPI) (https://pypi.org/project/scbean/) and GitHub (https://github.com/jhu99/scbean) under the MIT license. The documentation and example code can be found at https://scbean.readthedocs.io/en/latest/.

Predominance of hyperprogression in mucosal melanoma during anti-PD-1 monotherapy treatment.

BACKGROUND: A minority subset of immunotherapy patients manifests hyperprogressive disease (HPD), with the disparity in melanoma subtypes yet to be reported. This study aimed to delineate the proportion and prognosis of HPD in patients receiving anti-PD-1 monotherapy and to identify patient with HPD clinical characteristics across melanoma subtypes to inform clinical decision making. METHODS: Utilizing 4 established HPD definitions, the incidence of HPD in patients with advanced melanoma on anti-PD-1 monotherapy was determined. The incidence rates and prognostic abilities of various HPD definitions were compared to elect the most effective one. This facilitated a comparative analysis of subtypes and clinical features between patients with HPD and traditional progression. RESULTS: A total of 262 patients with advanced melanoma treated with anti-PD-1 monotherapy from 5 prospectively registered clinical trials were included in the study. The objective response rate (ORR) and disease control rate (DCR) was 21% and 58%, respectively, with 42% showcasing progression disease. The HPD incidences by 4 definitions were 13.2%, 16.8%, 10.8%, and 28.2%. All definitions effectively segregated HPD patients, with significantly poorer outcome than other progressive patients. The Delta TGR > 100 definition was the most indicative of a reduced overall survival, corroborated by the highest hazard ratio and statistical significance. The number of metastatic organs over 2 is a risk factor for HPD (OR = 4.18, P = .0103). Mucosal melanoma was the HPD prevalent subtype (OR = 3.13, P = .0489) in multivariable analysis, which is also indicated by RECIST criteria (P = .005). CONCLUSION: A delta TGR exceeding 100 best identified HPD patients in the advanced melanoma population treated with anti-PD-1 monotherapy. Hyperprogression was notably prevalent in mucosal melanoma patients with multiple metastatic organs. Caution against HPD is warranted when applying anti-PD-1 monotherapy in mucosal subtype.

A multi-view latent variable model reveals cellular heterogeneity in complex tissues for paired multimodal single-cell data.

MOTIVATION: Single-cell multimodal assays allow us to simultaneously measure two different molecular features of the same cell, enabling new insights into cellular heterogeneity, cell development and diseases. However, most existing methods suffer from inaccurate dimensionality reduction for the joint-modality data, hindering their discovery of novel or rare cell subpopulations. RESULTS: Here, we present VIMCCA, a computational framework based on variational-assisted multi-view canonical correlation analysis to integrate paired multimodal single-cell data. Our statistical model uses a common latent variable to interpret the common source of variances in two different data modalities. Our approach jointly learns an inference model and two modality-specific non-linear models by leveraging variational inference and deep learning. We perform VIMCCA and compare it with 10 existing state-of-the-art algorithms on four paired multi-modal datasets sequenced by different protocols. Results demonstrate that VIMCCA facilitates integrating various types of joint-modality data, thus leading to more reliable and accurate downstream analysis. VIMCCA improves our ability to identify novel or rare cell subtypes compared to existing widely used methods. Besides, it can also facilitate inferring cell lineage based on joint-modality profiles. AVAILABILITY AND IMPLEMENTATION: The VIMCCA algorithm has been implemented in our toolkit package scbean (≥0.5.0), and its code has been archived at https://github.com/jhu99/scbean under MIT license. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A novel entity of HIPK2::YAP1 pulmonary fibromatosis.

BACKGROUND: Pulmonary fibromatosis (PF) is a specific variant of fibromatosis, which is rarely reported occurring in the lung. PF with HIPK2-YAP1 fusion was a novel entity. CASE PRESENTATION: In this report, a 66-year-old male with PF had been smoking over 40 years. Multiple cords and small nodules in both lungs had been detected in a health examination two years earlier at our hospital. But approximately twofold enlarged in the lingual segment of the upper lobe in the left lung were disclosed in this year. Immunohistochemical analysis demonstrated that the vimentin and ß-Catenin were positive in the largest nodule. After underwent a DNA/RNA panel next-generation sequencing (NGS), missense mutations and HIPK2-YAP1 fusion were found in this sample. Ultimately, the case diagnosis as PF with HIPK2-YAP1 fusion after multidisciplinary treatment. Currently, the patient is doing well and recurrence-free at 14 months post-surgery. CONCLUSIONS: It's difficult for patients with complex morphology to make accurate diagnosis solely based on morphology and immunohistochemistry. But molecular detection is an effective method for further determining pathological subtypes.

Phase Ib study of anlotinib in combination with anti-PD-L1 antibody (TQB2450) in patients with advanced acral melanoma.

BACKGROUND: Acral melanoma, the most common subtype of melanoma in Asians, is often diagnosed at an advanced stage and responds poorly to current programmed cell death protein 1 (PD-1) inhibitors. OBJECTIVES: To evaluate the safety and efficacy of TQB2450 and anlotinib in patients with advanced acral melanoma in a phase Ib study (NCT03991975). METHODS: Patients received TQB2450 (1200 mg every 3 weeks) and anlotinib (10 mg or 12 mg once daily, 2-week on/1-week off) in the dose-escalation and dose-expansion phases. The primary endpoints were dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and objective response rate (ORR). RESULTS: Nineteen patients were enrolled between June 2019 and June 2022. The majority of patients (16 of 19 patients) received anlotinib and TQB2450 as first-line treatment. No DLTs were observed, and MTD was not reached. Eighteen (94.7%) out of 19 patients experienced treatment-related adverse events (TRAEs), but most were grade 1 or 2. Grade 3 or greater TRAEs occurred in seven patients (36.8%). The ORR was 26.3% (two complete responses and three partial responses). The disease control rate was 73.7%. The median duration of response was 30.3 months [95% confidence interval (CI): 5.8-NA]. The median progression-free survival (PFS) was 5.5 months (95% CI: 2.8-NA), and median overall survival was 20.3 months (95% CI: 14.8-NA). Whole-exome sequencing suggested that acquired drug resistance might be attributed to activation of the MAPK signalling pathway and transformation to an immunosuppressive tumour environment. CONCLUSIONS: TQB2450 combined with anlotinib showed favourable tolerance and promising anti-tumour activity with a prolonged PFS compared with anti-PD1 monotherapy in patients with advanced acral melanoma.

HNRNPC promotes collagen fiber alignment and immune evasion in breast cancer via activation of the VIRMA-mediated TFAP2A/DDR1 axis.

BACKGROUND: Cancers aggressively reorganize collagen in their microenvironment, leading to the evasion of tumor cells from immune surveillance. However, the biological significance and molecular mechanism of collagen alignment in breast cancer (BC) have not been well established. METHODS: In this study, BC-related RNA-Seq data were obtained from the TCGA database to analyze the correlation between DDR1 and immune cells. Mouse BC cells EO771 were selected for in vitro validation, and dual-luciferase experiments were conducted to examine the effect of TFAP2A on DDR1 promoter transcription activity. ChIP experiments were performed to assess TFAP2A enrichment on the DDR1 promoter, while Me-RIP experiments were conducted to detect TFAP2A mRNA m6A modification levels, and PAR-CLIP experiments were conducted to determine VIRMA's binding to TFAP2A mRNA and RIP experiments to investigate HNRNPC's recognition of m6A modification on TFAP2A mRNA. Additionally, an in vivo mouse BC transplant model and the micro-physiological system was constructed for validation, and Masson staining was used to assess collagen fiber arrangement. Immunohistochemistry was conducted to identify the number of CD8-positive cells in mouse BC tumors and Collagen IV content in ECM, while CD8 + T cell migration experiments were performed to measure CD8 + T cell migration. RESULTS: Bioinformatics analysis showed that DDR1 was highly expressed in BC and negatively correlated with the proportion of anti-tumor immune cell infiltration. In vitro cell experiments indicated that VIRMA, HNRNPC, TFAP2A, and DDR1 were highly expressed in BC cells. In addition, HNRNPC promoted TFAP2A expression and, therefore, DDR1 transcription by recognizing the m6A modification of TFAP2A mRNA by VIRMA. In vivo animal experiments further confirmed that VIRMA and HNRNPC enhanced the TFAP2A/DDR1 axis, promoting collagen fiber alignment, reducing anti-tumor immune cell infiltration, and promoting immune escape in BC. CONCLUSION: This study demonstrated that HNRNPC promoted DDR1 transcription by recognizing VIRMA-unveiled m6A modification of TFAP2A mRNA, which enhanced collagen fiber alignment and ultimately resulted in the reduction of anti-tumor immune cell infiltration and promotion of immune escape in BC.

HER2 Expression Associated with Clinical Characteristics and Prognosis of Urothelial Carcinoma in a Chinese Population.

BACKGROUND: The frequency of HER2 overexpression in bladder cancer is reported as 9%-61%. HER2 alteration correlates with aggressive disease in bladder cancer. Traditional anti-HER2 targeted therapy has failed to show clinical benefits in patients with advanced urothelial carcinoma . METHODS: The information on pathologically proven patients with urothelial carcinoma with detected HER2 status was collected from the database of Peking University Cancer Hospital. The HER2 expression, as well as its association with clinical characteristics and prognosis, was analyzed. RESULTS: A total of 284 consecutive patients with urothelial carcinoma were enrolled. HER2 was positive (IHC 2+/3+) in 44% of urothelial carcinoma. HER2 positivity was found more frequent in UCB than in UTUC (51% vs. 38%). Stage, radical surgery, and histological variant were associated with survival (P < .05). For metastatic patients, multivariate analysis shows that 3 indicators, including liver metastasis, the number of involved organs, and anemia, are independent risk factors of prognosis. Receiving immunotherapy or disitamab vedotin (DV) treatment is an independent protecting factor. The survival of patients with low HER2 expression was also significantly improved by the treatment of DV (P < .001). HER2 expression (IHC 1+, 2+, 3+) was associated with a better prognosis in this population. CONCLUSION: DV has improved the survival of patients with urothelial carcinoma in the real world. With the new-generation anti-HER2 ADC treatment, HER2 expression is no longer a poor prognostic factor.

Impact of response patterns for patients with advanced acral melanoma treated with anti-programmed death-1 monotherapy.

BACKGROUND: Acral melanoma (AM) is less responsive to immunotherapy than nonacral cutaneous melanoma. Variable responses are seen during immunotherapy, including pseudoprogression, hyperprogressive disease (HPD) and heterogeneous responses. There are currently no studies on the response patterns of patients with AM treated with immunotherapy and the impact on the outcome. OBJECTIVES: To evaluate the response patterns and prognosis of patients with AM treated with anti-programmed death (PD)-1 antibodies. METHODS: Patients with advanced AM treated prospectively in five clinical trials of anti-PD-1 monotherapy at Peking University Cancer Hospital were included. Responses of individual metastases and heterogeneous responses were evaluated during immunotherapy. Cox proportional hazards regression analysis was conducted to identify the possible predictive factors and generate a nomogram to predict the risk of 1-year and 2-year mortality. RESULTS: The overall response rate was 18·0%, the disease control rate was 36·1%, median progression-free survival was 3·5 months [95% confidence interval (CI) 1·7-5·3] and median overall survival was 17·5 months (95% CI 15·1-19·9) for anti-PD-1 monotherapy. Overall, 9·8% of patients met the criteria of HPD, and displayed a dramatically worse outcome than patients without HPD. In total, 369 metastatic lesions were assessed, with the highest response rate in lymph nodes (20·4%) and the lowest in the liver (5·6%). Homogeneous response, heterogeneous response and heterogeneous or homogeneous progression had different prognoses from the best to the worst. A predictive model was constructed and achieved good accuracy with a C-index of 0·73 (95% CI 0·63-0·84) in the training set and 0·74 (95% CI 0·61-0·86) in the validation set. CONCLUSIONS: HPD during immunotherapy serves as an essential biomarker of poor prognosis in advanced AM. Metastases in different sites respond distinctively to immunotherapy. Clinically heterogeneous responses to immunotherapy affect the outcome of patients. A predictive model was built to distinguish the prognosis of acral melanoma under immunotherapy.

microRNA-128-3p inhibits proliferation and accelerates apoptosis of gastric cancer cells via inhibition of TUFT1.

OBJECTIVE: Gastric cancer (GC) is a malignant tumor rooting in the gastric mucosal epithelium, ranking the first among various malignant tumors. Therefore, the influence of microRNA-128-3p (miR-128-3p) by regulation of Tuftelin1 (TUFT1) on GC cells was investigated. METHODS: The expression levels of miR-128-3p and TUFT1 in GC tissues and cells were detected. The correlation between miR-128-3p expression and overall survival of GC patients was analyzed. Human GC cells MGC803 were transfected with miR-128-3p or TUFT1-related oligonucleotides to figure their roles in viability, apoptosis, invasion, as well as epithelial-mesenchymal transition (EMT). The relationship between miR-128-3p and TUFT1 was validated. RESULTS: miR-128-3p expression was low and TUFT1 expression was high in GC tissues. miR-128-3p expression was positively correlated with the overall survival of patients with GC. miR-128-3p targeted TUFT1. Up-regulated miR-128-3p or suppressed TUFT1 repressed viability, invasion, and EMT, and accelerated apoptosis of GC cells. Overexpressed TUFT1 reduced miR-128-3p-mediated growth inhibition of GC cells. CONCLUSION: The study stresses that miR-128-3p can inhibit TUFT1 expression, thereby repressing GC cell activities.

Proteasome subunit α4s is essential for formation of spermatoproteasomes and histone degradation during meiotic DNA repair in spermatocytes.

Meiosis, which produces haploid progeny, is critical to ensuring both faithful genome transmission and genetic diversity. Proteasomes play critical roles at various stages of spermatogenesis, including meiosis, but the underlying mechanisms remain unclear. The atypical proteasomes, which contain the activator PA200, catalyze the acetylation-dependent degradation of the core histones in elongated spermatids and DNA repair in somatic cells. We show here that the testis-specific proteasome subunit α4s/PSMA8 is essential for male fertility by promoting proper formation of spermatoproteasomes, which harbor both PA200 and constitutive catalytic subunits. Immunostaining of a spermatocyte marker, SYCP3, indicated that meiosis was halted at the stage of spermatocytes in the α4s-deficient testes. α4s stimulated the in vitro degradation of the acetylated core histones, instead of nonacetylated histones, by the PA200-proteasome. Deletion of α4s blocked degradation of the core histones at DNA damage loci in spermatocytes, leading to meiotic arrest at metaphase I. Thus, α4s is required for histone degradation at meiotic DNA damage loci, proper progression of meiosis, and fertility in males by promoting proper formation of spermatoproteasomes. These results are important for understanding male infertility and might provide potential targets for male contraception or treatment of male infertility.

Predictive and prognostic effect of HO-1 expression in breast cancer patients undergoing neoadjuvant chemotherapy.

PURPOSE: Heme oxygenase-1 (HO-1) has complex biological function, and is a candidate oncogene with a wide variety of deleterious functions in breast cancer. Here, we evaluated the relationship between expression of HO-1 protein with clinical response to neoadjuvant chemotherapy (NAC) in breast cancer patients. METHODS: We used immunohistochemistry (IHC) to determine expression of HO-1 protein from core needle biopsy before NAC, then applied univariate and multivariate analyses to understand the relationship between HO-1 with pathological complete response (pCR) outcomes. Next, Kaplan-Meier and Log-rank tests were used to compare disease-free survival (DFS) and overall survival (OS), between groups, and Cox proportional hazards regression analysis applied for prognostic evaluation. RESULTS: A total of 575 patients with locally advanced invasive breast cancer were included in the study, of which 111 (19.3%) achieved pCR after NAC. Results from multivariate analysis showed that high HO-1 expression was an independent predictor of low pCR rate (OR 0.254, 95% CI 0.026-0.643, p = 0.002). Moreover, results from survival analysis showed that high HO-1 expression was significantly associated with shorter DFS (HR 4.843, 95% CI 1.205-32.572, p = 0.026), but not with OS (HR 3.219, 95% CI 0.928-32.124, p = 0.071). Furthermore, HO-1 expression was significantly associated with lower pCR rate (OR 0.102, 95% CI 0.013-0.352), p = 0.001), poor DFS (HR 8.562, 95% CI 1.592-34.950, p = 0.009), and OS (HR 7.835, 95% CI 1.220-56.213, p = 0.023) of patients with triple-negative breast cancer (TNBC) patients. CONCLUSION: Our results indicated that HO-1 expression is not only a biomarker for predicting pCR, but also a prognostic factor in breast cancer patients in a neoadjuvant setting, especially in TNBC subgroups.

An Evidence-Based Staging System for Mucosal Melanoma: A Proposal.

BACKGROUND: There is no widely employed staging system for mucosal melanoma (MuM) that incorporates all anatomic sites. We hypothesized that MuM patients arising from different anatomical sites could be staged using a common approach. METHODS: A prospective database contained 1814 MuM patients with a median follow-up of 5.14 years was employed. Overall survival (OS) was calculated from the time of pathological diagnosis to the date of death from any cause. Multivariate analyses of prognostic variables and OS were performed using the Cox proportional hazard model. RESULTS: For localized MuM, the most significant median OS differences were primary tumors invading submucosa (i.e., T1) versus deeper (i.e., T2/T3/T4): 4.3 versus 3.4, 3.1, and 2.9 years, respectively (p < 0.001). For patients only with regional node metastasis at presentation, the most significant were: 1 versus ≥ 2 regional nodes (N1 vs. N2, 2.5 vs. 2.1 years, p < 0.001). For patients with distant metastasis at presentation, the median OS was 1.5, 1.2, 0.8, and 0.6 years respectively for skin/subcutaneous tissue/distant lymph nodes (M1a), lung metastasis (M1b), all other visceral sites except brain (M1c), and brain (M1d) (p < 0.001). Based on these results, the staging system for MuM is proposed: (1) Stage I: T1N0M0 (median OS, 4.3 years); (2) Stage II: T2-4N0M0 (3.1 years); (3) Stage IIIA: T1-4N1M0 (2.5 years), Stage IIIB: T1-4N2M0 (2.1 years); (4) Stage IV: TanyNanyM1 (0.9 years) (p < 0.001). CONCLUSIONS: A single, unified, staging system for mucosal melanoma inclusive of all anatomical primary tumor sites can harmonize staging of MuM and the design of clinical trials.

Safety, activity, and pharmacokinetics of camrelizumab in advanced Asian melanoma patients: a phase I study.

BACKGROUND: Anti-programmed cell death receptor-1 (PD-1) monotherapy is the standard treatment for metastatic melanoma in current. Camrelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody whose safety and efficacy have not been reported in advanced Asian melanoma patients. METHODS: This phase I study investigated the safety, activity, and pharmacokinetics of camrelizumab in Chinese patients with advanced melanoma. The study included two phases, the dose-escalation phase ("3 + 3" design at 60 mg, 200 mg, and 400 mg) and the dose-expansion phase. RESULTS: No dose-limiting toxicities were recorded over the dose-escalation phase, and the maximum tolerated dose was not reached. The most common treatment-related adverse events (TRAEs) in 36 patients were reactive cutaneous capillary endothelial proliferation, followed by rash, fever, hypothyroidism, hyperthyroidism, vitiligo, and fatigue. Five grade 3 or above TRAEs were reported (13.9%), including two cases of elevated γ-glutamyltransferase and blood triglycerides without clinical symptoms, and one liver injury recovered after symptomatic treatment. The confirmed overall response rate was 13.9% (95%CI: 4.7, 29.5%) and disease control rate was 38.9% (95%CI: 23.1, 56.5%). The median progression-free survival was 1.8 months (95%CI: 1.1, 2.4) and the median overall survival was 11.1 months (95%CI: 6.8, 15.4). CONCLUSIONS: Camrelizumab had acceptable tolerability and similar anti-tumor activity compared with other anti-PD-1 antibodies in advanced Asian melanoma patients. TRIAL REGISTRATION: ClinicalTrials.gov identification: NCT02738489. Registered on 14/04/2016, prospectively registered.

Prognostic value of ulceration varies across Breslow thicknesses and clinical stages in acral melanoma: a retrospective study.

BACKGROUND: Ulceration is regarded as an adverse prognostic factor and is used together with tumour thickness to subcategorize patients with cutaneous melanoma. However, the prognostic impact of ulceration in acral melanoma (AM) is controversial. OBJECTIVES: To assess the prognostic impact of ulceration in AM and the variability across different Breslow thicknesses and clinical stages. METHODS: A multicentre retrospective study of patients diagnosed with AM between January 2000 and December 2017. Differences in melanoma-specific survival (MSS) between patients with and without ulceration were assessed using the multivariable Cox proportional hazards model and log-rank test. RESULTS: Among 1053 enrolled patients, 62.6% had ulceration. After a median follow-up of 61 months, patients with ulceration had a lower median MSS than those without: 66.1 months, 95% confidence interval (CI) 60.0-86.0 vs. not reached; hazard ratio 1.41, 95% CI 1.09-1.82; P = 0.012. Among patients with thin (≤ 1 mm) melanoma, the survival curves of patients with vs. without ulceration clearly separated over time (P < 0.001). No association between ulceration and MSS was observed for melanomas of thickness > 1 mm (subgroups of T2, T3 and T4; all P-values > 0.05) or patients with stage III disease (hazard ratio 1.09, 95% CI 0.71-1.68, P = 0.39). CONCLUSIONS: Ulceration is an independent negative prognostic factor for patients with AM, but the impact varies across Breslow thicknesses and clinical stages. Ulceration has a significant effect on prognosis for patients with thin (≤ 1 mm) melanoma, but there was no association between ulceration and survival in intermediate/thick AM or stage III AM. What is already known about this topic? Ulceration status is used together with Breslow tumour thickness to subcategorize patients into different stages according to the America Joint Committee on Cancer melanoma staging system. As one distinctive subtype of cutaneous melanoma, acral melanoma (AM) is characterized by poor survival outcomes due to delayed diagnosis and a high prevalence of negative prognostic and genetic features. The prognostic impact of ulceration in AM is still controversial. What does this study add? This was the first large-scale study to assess the prognostic and staging values of ulceration in patients with AM. Ulceration has a significant effect on prognosis for patients with thin (≤1 mm) melanoma, but no association between ulceration and survival was found in intermediate/thick or stage III AM. These findings should be considered when using ulceration-based staging systems.

Prognostic impact of Breslow thickness in acral melanoma: A retrospective analysis.

BACKGROUND: Evidence for the prognostic importance of tumor thickness in acral melanoma (AM) patients is limited. OBJECTIVE: The objective of the study was to determine the prognostic impact of Breslow thickness in AM. METHODS: This multicenter study enrolled patients diagnosed with localized AM between January 1, 2000 and December 31, 2017. Melanoma-specific survival (MSS) in different tumor thickness strata (T1-T4: ≤1, >1-2, >2-4, >4 mm, respectively) was estimated by the Kaplan-Meier method. Comparisons were performed by the log-rank test and multivariable Cox regression. RESULTS: A total of 853 patients with clinical N0 (cN0) AM were included in the analysis. The median follow-up time was 60.1 months. The median MSS in patients with T1-T4 disease was not reached, 111.0, 92.8, and 67.1 months, respectively. MSS differed significantly among cN0 patients with T1-T3 AM (log-rank P = .004, .012, <0.001 for T1 vs T2, T2 vs T3, and T1 vs T3, respectively); however, there was no significant difference between T3 and T4 AM (hazard ratio = 0.82, 95% CI, 0.62-1.09). Six-subgroup analyses confirmed that survival outcomes were similar between different subgroups with tumor thickness >2 mm. LIMITATIONS: The limitations were retrospective design and some missing variables. CONCLUSIONS: There was no association between tumor thickness and survival in AM patients with a Breslow thickness >2 mm.

Widespread bacterial responses and their mechanism of bacterial metallogenic detoxification under high concentrations of heavy metals.

Microbial mineralization is increasingly used in bioremediation of heavy metal pollution, but better mechanistic understanding of the processes involved and how they are regulated are required to improve the practical application of microorganisms in bioremediation. We used a combination of morphological (TEM) and analytical (XRD, XPS, FTIR) methods, together with novel proteomic analyses, to investigate the detoxification mechanisms, used by a range of bacteria, including the strains Bacillus velezensis LB002, Escherichia coli DH5α, B. subtilis 168, Pseudomonas putida KT2440, and B. licheniformis MT-1, exposed to elevated concentrations of Cd2+ and combinations of Cd2+, Pb2+, Cu2+, and Zn2+, in the presence and absence of added CaCl2. Common features of detoxification included biomineralization, including the production of biological vaterite, up-regulation of proteins involved in flagellar movement and chemotaxis, biofilm synthesis, transmembrane transport of small molecules and organic matter decomposition. The putative roles of differentially expressed proteins in detoxification are discussed in relation to chemical and morphological data and together provide important tools to improve screening, selection, and practical application of bacterial isolates in bioremediation of polluted environments.

A Review on Rainfall Measurement Based on Commercial Microwave Links in Wireless Cellular Networks.

As one of the most critical elements in the hydrological cycle, real-time and accurate rainfall measurement is of great significance to flood and drought disaster risk assessment and early warning. Using commercial microwave links (CMLs) to conduct rainfall measure is a promising solution due to the advantages of high spatial resolution, low implementation cost, near-surface measurement, and so on. However, because of the temporal and spatial dynamics of rainfall and the atmospheric influence, it is necessary to go through complicated signal processing steps from signal attenuation analysis of a CML to rainfall map. This article first introduces the basic principle and the revolution of CML-based rainfall measurement. Then, the article illustrates different steps of signal process in CML-based rainfall measurement, reviewing the state of the art solutions in each step. In addition, uncertainties and errors involved in each step of signal process as well as their impacts on the accuracy of rainfall measurement are analyzed. Moreover, the article also discusses how machine learning technologies facilitate CML-based rainfall measurement. Additionally, the applications of CML in monitoring phenomena other than rain and the hydrological simulation are summarized. Finally, the challenges and future directions are discussed.

Genetic substructure analysis of three isolated populations in southwest China.

Southwest China is home to numerous ethnic minorities, as well as many geographically and genetically isolated groups. However, the genetic substructure of these ethnic groups, especially the paternal genetic structure between groups, has not been comprehensively analyzed. In this study, we used Y chromosome capture and Illumina sequencing technologies to investigate the paternal genetic structure of three isolated groups of male unrelated individuals, including Baima in Pingwu, Sichuan Province, Muya in Shimian, Sichuan Province, and Kongge in Jinghong, Yunnan Province. We calculated the frequencies of related haplogroups by the fixed-point compound amplification method and direct counting method, and used the Past3.0 software to perform principal component analysis to draw a population clustering tree. we observed that Kongge had 3 Y chromosome haplogroups, Baima had 4 Y chromosome haplogroups, and Muya had 5 Y chromosome haplogroups. The results showed that Kongge was most closely related to the Wa, and the Y chromosome types of the Baima and Muya were mainly concentrated in the D haplogroup and its lower reaches. It has the closest relationship with the Tibetans in Qamdo and Nyingchi. The study on the genetic structure of different ethnic groups has enriched the genetic relationship of isolated populations and provided a new perspective for understanding Chinese ethnic groups.

Collaborative relationships in translational medical research among Chinese clinicians: an internet-based cross-sectional survey.

BACKGROUND: This study aimed to explore the collaborative relationship in translational medical research from the perspective of clinicians in China. The findings are expected to help practitioners optimize and experience the greatest advantages of collaboration. METHODS: We conducted a national internet-based survey from July 29 to October 12, 2020. Of the 806 responses, 804 were completed with valid responses (valid response rate = 99.8%). The collected data were presented as descriptive statistics and analyzed using nonparametric tests (including the Wilcoxon rank test and Kruskal-Wallis H test) and stepwise logistic regression. RESULTS: Of the 804 participants, 733 were either willing or very willing to collaborate in translational medical research. Clinicians' willingness was influenced by their current research type, role in current translational medical research, burdens of their present research, preferred partners for collaboration at the institutional or individual level, and preferences for independent or dependent relationships. CONCLUSIONS: Clinicians should evaluate their time, role, burdens, personal preferences for research relationships, and appropriate partners based on their current translational medical research and its goals, before deciding to collaborate.