A transcriptome atlas of zygotic and somatic embryogenesis in Norway spruce.

Somatic embryogenesis (SE) is a powerful model system for studying embryo development and an important method for scaling up availability of elite and climate-adapted genetic material of Norway spruce (Picea abies L. Karst). However, there are several steps during the development of the somatic embryo (Sem) that are suboptimal compared to zygotic embryo (Zem) development. These differences are poorly understood and result in substantial yield losses during plant production, which limits cost-effective large-scale production of SE plants. This study presents a comprehensive data resource profiling gene expression during zygotic and somatic embryo development to support studies aiming to advance understanding of gene regulatory programmes controlling embryo development. Transcriptome expression patterns were analysed during zygotic embryogenesis (ZE) in Norway spruce, including separated samples of the female gametophytes and Zem, and at multiple stages during SE. Expression data from eight developmental stages of SE, starting with pro-embryogenic masses (PEMs) up until germination, revealed extensive modulation of the transcriptome between the early and mid-stage maturing embryos and at the transition of desiccated embryos to germination. Comparative analysis of gene expression changes during ZE and SE identified differences in the pattern of gene expression changes and functional enrichment of these provided insight into the associated biological processes. Orthologs of transcription factors known to regulate embryo development in angiosperms were differentially regulated during Zem and Sem development and in the different zygotic embryo tissues, providing clues to the differences in development observed between Zem and Sem. This resource represents the most comprehensive dataset available for exploring embryo development in conifers.

MoSBi: Automated signature mining for molecular stratification and subtyping.

The improving access to increasing amounts of biomedical data provides completely new chances for advanced patient stratification and disease subtyping strategies. This requires computational tools that produce uniformly robust results across highly heterogeneous molecular data. Unsupervised machine learning methodologies are able to discover de novo patterns in such data. Biclustering is especially suited by simultaneously identifying sample groups and corresponding feature sets across heterogeneous omics data. The performance of available biclustering algorithms heavily depends on individual parameterization and varies with their application. Here, we developed MoSBi (molecular signature identification using biclustering), an automated multialgorithm ensemble approach that integrates results utilizing an error model-supported similarity network. We systematically evaluated the performance of 11 available and established biclustering algorithms together with MoSBi. For this, we used transcriptomics, proteomics, and metabolomics data, as well as synthetic datasets covering various data properties. Profiting from multialgorithm integration, MoSBi identified robust group and disease-specific signatures across all scenarios, overcoming single algorithm specificities. Furthermore, we developed a scalable network-based visualization of bicluster communities that supports biological hypothesis generation. MoSBi is available as an R package and web service to make automated biclustering analysis accessible for application in molecular sample stratification.

RhoA rescues cardiac senescence by regulating Parkin-mediated mitophagy.

Heart failure is one of the leading causes of death worldwide. RhoA, a small GTPase, governs actin dynamics in various tissue and cell types, including cardiomyocytes; however, its involvement in cardiac function has not been fully elucidated. Here, we generated cardiomyocyte-specific RhoA conditional knockout (cKO) mice, which demonstrated a significantly shorter lifespan with left ventricular dilation and severely impaired ejection fraction. We found that the cardiac tissues of the cKO mice exhibited structural disorganization with fibrosis and also exhibited enhanced senescence compared with control mice. In addition, we show that cardiomyocyte mitochondria were structurally abnormal in the aged cKO hearts. Clearance of damaged mitochondria by mitophagy was remarkably inhibited in both cKO cardiomyocytes and RhoA-knockdown HL-1 cultured cardiomyocytes. In RhoA-depleted cardiomyocytes, we reveal that the expression of Parkin, an E3 ubiquitin ligase that plays a crucial role in mitophagy, was reduced, and expression of N-Myc, a negative regulator of Parkin, was increased. We further reveal that the RhoA-Rho kinase axis induced N-Myc phosphorylation, which led to N-Myc degradation and Parkin upregulation. Re-expression of Parkin in RhoA-depleted cardiomyocytes restored mitophagy, reduced mitochondrial damage, attenuated cardiomyocyte senescence, and rescued cardiac function both in vitro and in vivo. Finally, we found that patients with idiopathic dilated cardiomyopathy without causal mutations for dilated cardiomyopathy showed reduced cardiac expression of RhoA and Parkin. These results suggest that RhoA promotes Parkin-mediated mitophagy as an indispensable mechanism contributing to cardioprotection in the aging heart.

Characterization of Immune Cell Populations of Cutaneous Neurofibromas in Neurofibromatosis 1.

Cutaneous neurofibromas (cNFs) are characteristic of neurofibromatosis 1 (NF1), yet their immune microenvironment is incompletely known. A total of 61 cNFs from 10 patients with NF1 were immunolabeled for different types of T cells and macrophages, and the cell densities were correlated with clinical characteristics. Eight cNFs and their overlying skin were analyzed for T cell receptor CDR domain sequences, and mass spectrometry of 15 cNFs and the overlying skin was performed to study immune-related processes. Intratumoral T cells were detected in all cNFs. Tumors from individuals younger than the median age of the study participants (33 years), growing tumors, and tumors smaller than the data set median showed increased T cell density. Most samples displayed intratumoral or peritumoral aggregations of CD3-positive cells. T cell receptor sequencing demonstrated that the skin and cNFs host distinct T cell populations, whereas no dominant cNF-specific T cell clones were detected. Unique T cell clones were fewer in cNFs than in skin, and mass spectrometry suggested lower expression of proteins related to T cell-mediated immunity in cNFs than in skin. CD163-positive cells, suggestive of M2 macrophages, were abundant in cNFs. Human cNFs have substantial T cell and macrophage populations that may be tumor-specific.

Emerging Enterovirus A71 Subgenogroup B5 Causing Severe Hand, Foot, and Mouth Disease, Vietnam, 2023.

We report on a 2023 outbreak of severe hand, foot, and mouth disease in southern Vietnam caused by an emerging lineage of enterovirus A71 subgenogroup B5. Affected children were significantly older than those reported during previous outbreaks. The virus should be closely monitored to assess its potential for global dispersal.

Emerging Monkeypox Virus Sublineage C.1 Causing Community Transmission, Vietnam, 2023.

We studied a community cluster of 25 mpox cases in Vietnam caused by emerging monkeypox virus sublineage C.1 and imported into Vietnam through 2 independent events; 1 major cluster carried a novel APOBEC3-like mutation. Three patients died; all had advanced HIV co-infection. Viral evolution and its potential consequences should be closely monitored.

Protein Adequacy, Plant Protein Proportion, and Main Plant Protein Sources Consumed Across Vegan, Vegetarian, Pescovegetarian, and Semivegetarian Diets: A Systematic Review.

BACKGROUND: There are several types of plant-based diets, with unknown differences across diets on total/plant protein intake and variety of plant protein sources consumed. OBJECTIVES: This systematic review aimed to compare total protein intake, proportion of plant proteins, and main plant protein sources consumed across 4 primarily plant-based diets: vegan, vegetarian, pescovegetarian, and semivegetarian. METHODS: We included observational studies reporting on protein intake and/or protein sources in generally healthy adults that were published between 2002 and 2023. We determined the following: 1) % energy from total and plant protein; 2) the proportion of plant protein relative to total protein intake; and 3) main plant protein sources (median percentage contribution of each source to total plant protein intake; interquartile range) consumed across the 4 diets. The plant protein sources were broadly classified into the following United States Department of Agriculture food groups: grains; nuts and seeds; soy products; and beans, peas, and lentils. RESULTS: We included 13 studies reporting on protein intake/sources that were conducted in the United States, Europe, and South Korea. Of these, 7 reported on vegan, 11 on vegetarian, 7 on pescovegetarian, and 7 on semivegetarian diets with total protein intake ranging from 10% to 17.4%. Vegan diets had the highest plant protein proportion (range: 77%-98%) and semivegetarian diets the lowest (range: 37%-83%). Plant protein source contribution was the highest from grains (range: 60%-78%). Nuts and seeds were the most consumed in vegetarian diets (7.9%; 2.9%-10.3%) and least in semivegetarian diets (3.7%; 2%-14.8%). Soy products and beans, peas, and lentils were most consumed in vegan diets (17.3%; 16.3%-19.9, and 19.6%; 14.6%-21.3, respectively) and least in semivegetarian (3.7%; 1.3%-13.9%, and 8.5%; 5.2%-10.2%) diets. CONCLUSIONS: Vegan diets has the highest plant protein proportion and a variety of plant protein sources, while semivegetarian diets has the lowest plant protein proportion and mainly relied on grains as a plant protein source.

A Method to Estimate the Dietary α-Linolenic Acid Requirement Using Nonesterified DHA and Arachidonic Acid Oxylipins and Fatty Acids.

BACKGROUND: The dietary requirement for α-linolenic acid (ALA) remains unclear, as evidenced by the absence of an RDA for this essential fatty acid (FA). In previous studies, we observed that the amount of dietary ALA required to maximize nonesterified (NE) DHA oxylipins appears to be higher than the amount required to maximize tissue esterified DHA levels, which have classically been used to estimate the ALA requirement. Further, we observed that dietary ALA reduces esterified arachidonic acid (ARA) and its NE oxylipins. OBJECTIVES: Since NE oxylipins and FA mediate the biological activities of FA, we examined whether these DHA and ARA pools could be used to determine the dietary ALA requirement. METHODS: Nine groups of 4-wk-old male Sprague-Dawley rats (n = 5) and 10 groups of male and female CD1 mice (n = 6) were provided 0.1-2.5 g ALA and 2 g of linoleic acid per 100 g of AIN93G-based diets. NE DHA and ARA and their oxylipins in serum, liver, kidney, and brain homogenates underwent solid phase extraction and were quantified by HPLC-MS/MS. Breakpoint analysis of transitions from increase to plateau was conducted using piecewise regression. RESULTS: In response to increasing dietary ALA, NE DHA oxylipins, and DHA in serum, liver, and kidney (but not the brain) initially increased rapidly and then plateaued whereas ARA oxylipins and ARA tended to decrease and plateau. Thus, breakpoints were calculated for the ratios of DHA/ARA and hydroxy-DHA/hydroxy-ARA (DHAOH/ARAOH), which consisted of oxylipins synthesized via pathways common to both FA. In serum, liver, and kidney, the highest estimated breakpoint indicated an ALA requirement of ∼0.7 g/100 g diet (1.7% energy), approximately twice that of previous estimations. CONCLUSIONS: This study supports the use of NE DHAOH/ARAOH or DHA/ARA as biochemical indicators of the ALA requirement. Applying this method in rats and mice indicates that the requirement is higher than previously estimated using esterified DHA alone.

Clinical Significance Unveiled: Understanding the Meaning of FACE-Q Skin Cancer Scores for Improved Patient Care.

OBJECTIVE: The FACE-Q Skin Cancer Module is a Patient-Reported Outcome Measure (PROM) utilized to assess outcomes following facial skin cancer resection. However, the lack of Minimal Important Difference (MID) estimates hinders the interpretability of the PROM scores. This study established MID estimates for the four outcome scales from the FACE-Q Skin Cancer Module using distribution-based methods. METHODS: A prospective cohort study at four hospitals in the United States, enrolled participants who underwent Mohs Micrographic Surgery (MMS) for facial skin cancer between April 2020 and April 2022. Participants completed the Satisfaction with Facial Appearance, Appearance-related Psychosocial Distress, Cancer Worry, and Appraisal of Scars scales at four time points: pre-operatively, 2-week, 6-month, and 1-year post-surgery. RESULTS: A total of 990 patients participated in the study, with completion rates of 98.4% for the pre-operative assessment, 70.8% at 2 weeks, 59.3% at 6 months, and 60.4% at 1 year. MID estimates, calculated using 0.2 standard deviation and 0.2 standardized response mean, were determined for the four scales. The mean MID estimates, based on a Rasch transformed score ranging from 0 to 100, were 5 for the Appraisal of Scars scale and 4 for the remaining three scales. CONCLUSION: This multicenter study provides valuable MID estimates for the FACE-Q Skin Cancer Module, specifically for the MMS patient population, enabling clinicians and researchers to better interpret scores, determine appropriate sample sizes, and apply the findings in clinical care.

Cytopathic Effect Detection and Clonal Selection using Deep Learning.

PURPOSE: In biotechnology, microscopic cell imaging is often used to identify and analyze cell morphology and cell state for a variety of applications. For example, microscopy can be used to detect the presence of cytopathic effects (CPE) in cell culture samples to determine virus contamination. Another application of microscopy is to verify clonality during cell line development. Conventionally, inspection of these microscopy images is performed manually by human analysts. This is both tedious and time consuming. In this paper, we propose using supervised deep learning algorithms to automate the cell detection processes mentioned above. METHODS: The proposed algorithms utilize image processing techniques and convolutional neural networks (CNN) to detect the presence of CPE and to verify the clonality in cell line development. RESULTS: We train and test the algorithms on image data which have been collected and labeled by domain experts. Our experiments have shown promising results in terms of both accuracy and speed. CONCLUSION: Deep learning algorithms achieve high accuracy (more than 95%) on both CPE detection and clonal selection applications, resulting in a highly efficient and cost-effective automation process.

Late-onset sensory-motor axonal neuropathy, a novel SLC12A6-related phenotype.

We describe five families from different regions in Norway with a late-onset autosomal-dominant hereditary polyneuropathy sharing a heterozygous variant in the SLC12A6 gene. Mutations in the same gene have previously been described in infants with autosomal-recessive hereditary motor and sensory neuropathy with corpus callosum agenesis and mental retardation (Andermann syndrome), and in a few case reports describing dominantly acting de novo mutations, most of them with onset in childhood. The phenotypes in our families demonstrated heterogeneity. Some of our patients only had subtle to moderate symptoms and some individuals even no complaints. None had CNS manifestations. Clinical and neurophysiological evaluations revealed a predominant sensory axonal polyneuropathy with slight to moderate motor components. In all 10 patients the identical SLC12A6 missense variant, NM_001365088.1 c.1655G>A p.(Gly552Asp), was identified. For functional characterization, the mutant potassium chloride cotransporter 3 was modelled in Xenopus oocytes. This revealed a significant reduction in potassium influx for the p.(Gly552Asp) substitution. Our findings further expand the spectrum of SLC12A6 disease, from biallelic hereditary motor and sensory neuropathy with corpus callosum agenesis and mental retardation and monoallelic early-onset hereditary motor and sensory neuropathy caused by de novo mutations, to late-onset autosomal-dominant axonal neuropathy with predominant sensory deficits.

Impact of pharmacist managed oral epidermal growth factor receptor inhibitors.

BACKGROUND: Pharmacists are an integral part of medication management, with the positive impact of their clinical services in patient outcomes previously studied and reported in literature. The roles and responsibilities of pharmacists continue to expand, including optimizing patient medication and health outcomes related to complex oral anticancer drugs. OBJECTIVE: To evaluate the impact of a pharmacist-managed oral chemotherapy clinic in patients with non-small cell lung cancer (NSCLC) taking oral epidermal growth factor receptor inhibitor (EGFRi) regimens within an integrated healthcare delivery system. METHODS: This was an observational cohort study using data from Kaiser Permanente Northern and Southern California regions on adult patients who received oncology pharmacist-managed care compared to patients with usual care. Patients were newly initiated with EGFRi therapy to treat NSCLC between 2017 and 2019. The follow-up period was defined as the time from index date (first sold date of EGFRi) to December 2020 or end of membership or death, whichever occurred first. Primary outcome measures included adherence to EGFRi, frequency of imaging during drug exposure, and presence of imaging prior to treatment change. Outcomes were analyzed with Chi-square test for categorical variables, and Student's t-test or Wilcoxon rank-sum test for continuous variables. RESULTS: There were 613 patients in the pharmacist-managed group and 714 patients in the usual care group. Overall, the mean age was 68.2 ± 11.3 years, and 65.1% were female. In the pharmacist-managed group, there was a significantly higher mean proportion of days covered (PDC) during the first three months of therapy (0.86 ± 0.24 vs 0.82 ± 0.36, p = 0.01) and a higher percentage of patients who were adherent to EGFRi therapy (with PDC ≥0.80) during the drug exposure period (95.8% vs 92.4%, p = 0.01). The rate of computed tomography (CT) and magnetic resonance imaging (MRI) during drug exposure was higher in the pharmacist-managed group compared to the usual care group (31.8% vs 20.7%, p < 0.01) with a higher number of mean scans completed per patient (1.15 ± 2.42 vs 0.62 ± 1.63, p < 0.01) and per patient-year (2.60 ± 7.27 vs 1.58 ± 5.95, p < 0.01). Overall, 66.2% of patients had a treatment change, with a higher percentage of patients in the pharmacist-managed group who completed a CT or MRI scan prior to treatment change (36.3% vs 26.3%, p < 0.01). Additionally, the median time between the scan and treatment change was shorter for patients with pharmacist-managed care (1.8 vs 4 months, p = 0.04). CONCLUSION: Clinical pharmacy services contributed to improved adherence, higher rates of imaging, and shorter time between imaging and treatment changes in NSCLC patients who were taking EGFRi regimens.

Spatiotemporal Evolution of SARS-CoV-2 Alpha and Delta Variants during Large Nationwide Outbreak of COVID-19, Vietnam, 2021.

We analyzed 1,303 SARS-CoV-2 whole-genome sequences from Vietnam, and found the Alpha and Delta variants were responsible for a large nationwide outbreak of COVID-19 in 2021. The Delta variant was confined to the AY.57 lineage and caused >1.7 million infections and >32,000 deaths. Viral transmission was strongly affected by nonpharmaceutical interventions.

Characterization of Expanded Gamma Delta T Cells from Atypical X-SCID Patient Reveals Preserved Function and IL2RG-Mediated Signaling.

Abnormally high γδ T cell numbers among individuals with atypical SCID have been reported but detailed immunophenotyping and functional characterization of these expanded γδ T cells are limited. We have previously reported atypical SCID phenotype caused by hypomorphic IL2RG (NM_000206.3) c.172C > T;p.(Pro58Ser) variant. Here, we have further investigated the index patient's abnormally large γδ T cell population in terms of function and phenotype by studying IL2RG cell surface expression, STAT tyrosine phosphorylation and blast formation in response to interleukin stimulation, immunophenotyping, TCRvγ sequencing, and target cell killing. In contrast to his âºß T cells, the patient's γδ T cells showed normal IL2RG cell surface expression and normal or enhanced IL2RG-mediated signaling. Vδ2 + population was proportionally increased with a preponderance of memory phenotypes and high overall tendency towards perforin expression. The patient's γδ T cells showed enhanced cytotoxicity towards A549 cancer cells. His TCRvγ repertoire was versatile but sequencing of IL2RG revealed a novel c.534C > A; p.(Phe178Leu) somatic missense variant restricted to γδ T cells. Over time this variant became predominant in γδ T cells, though initially present only in part of them. IL2RG-Pro58Ser/Phe178Leu variant showed higher cell surface expression compared to IL2RG-Pro58Ser variant in stable HEK293 cell lines, suggesting that somatic p.(Phe178Leu) variant may at least partially rescue the pathogenic effect of germline p.(Pro58Ser) variant. In conclusion, our report indicates that expansion of γδ T cells associated with atypical SCID needs further studying and cannot exclusively be deemed as a homeostatic response to low numbers of conventional T cells.

New metrics of dietary carbohydrate quality.

PURPOSE OF REVIEW: The aim of this study was to introduce novel metrics of dietary carbohydrates quality relevant for products and diets. RECENT FINDINGS: Carbohydrate quality has long been associated with a low glycemic index. More recently, novel metrics of carbohydrate quality featuring variations of total carbohydrates-fibers-free sugars ratios have been applied to carbohydrate-rich foods, including grains, beans, vegetables, and fruit. High scoring products had higher levels of health-promoting nutrients (protein, dietary fiber, iron, magnesium, zinc, potassium, selenium, and various B-vitamins) and lower levels of nutrients of public health concern (total sugar, added/free sugars, and fat profile). Cross-sectional studies also found variants of carbohydrate quality metrics to be associated with better markers of cardiometabolic disease, including lower levels of blood triglycerides:high-density lipoprotein cholesterol ratio, homeostatic model assessment of insulin resistance, and SBP. SUMMARY: New ratio-based carbohydrate quality metrics are built around high fiber and whole grain content, combined with a low free sugar content. Such metrics allow the identification of food products of higher overall nutritional quality, and are associated with improved diet quality and certain health outcomes.

Single-Administration Long-Acting Microarray Patch with Ultrahigh Loading Capacity and Multiple Releases of Thermally Stable Antibodies.

Current antibody (Ab) therapies require development of stable formulations and an optimal delivery system. Here, we present a new strategy to create a single-administration long-lasting Ab-delivery microarray (MA) patch, which can carry high doses of thermally stabilized Abs. The MA fabricated by an additive three-dimensional manufacturing technology can be fully embedded into the skin via a single application to deliver doses of Abs at multiple programmable time points, thus sustaining Ab concentrations in systemic circulation. We developed an MA formulation that stabilized and delivered human immunoglobulins (hIg) in a time-controlled manner while maintaining their structure and functionality. As an example, the b12 Ab─a broadly neutralizing Ab against HIV-1─maintained antiviral activity in vitro after MA manufacturing and heat exposure. Pharmacokinetic studies of MA patch-delivered hIg in rats successfully provided a proof of concept for concurrent and time-delayed Ab delivery. These MA patches codeliver different Abs, providing a tool for expanded protection against viral infections or combination HIV therapy and prevention.

Deep learning for robust and flexible tracking in behavioral studies for C. elegans.

Robust and accurate behavioral tracking is essential for ethological studies. Common methods for tracking and extracting behavior rely on user adjusted heuristics that can significantly vary across different individuals, environments, and experimental conditions. As a result, they are difficult to implement in large-scale behavioral studies with complex, heterogenous environmental conditions. Recently developed deep-learning methods for object recognition such as Faster R-CNN have advantages in their speed, accuracy, and robustness. Here, we show that Faster R-CNN can be employed for identification and detection of Caenorhabditis elegans in a variety of life stages in complex environments. We applied the algorithm to track animal speeds during development, fecundity rates and spatial distribution in reproductive adults, and behavioral decline in aging populations. By doing so, we demonstrate the flexibility, speed, and scalability of Faster R-CNN across a variety of experimental conditions, illustrating its generalized use for future large-scale behavioral studies.

Measures of carbohydrate quality and their association with diet quality and cardiometabolic health outcomes in Singapore middle-aged and older adults.

BACKGROUND AND AIMS: Carbohydrate quality may play a key role in cardiometabolic health and disease risk. This study aimed to assess the dietary carbohydrate quality of the free-living middle-aged and older adults in Singapore, and its association with overall diet quality and cardiometabolic health. METHODS AND RESULTS: This cross-sectional study examined the diet and cardiometabolic disease risk indicators of middle-aged and older adults in Singapore (n = 104). Dietary carbohydrate quality was assessed as the pass and fail rate of the population to four measures of carbohydrate quality: (i) dietary fiber recommended daily allowance (RDA), (ii) whole-grain recommendation, (iii) free sugar recommendation, and (iv) carbohydrate metrics. The association between each carbohydrate quality measure and diet quality, as well as cardiometabolic health, was assessed. Except for free sugar recommendation, the carbohydrate quality of the population was found to be poor with a low adherence (20-36%) to three measures. Subjects meeting these measures had generally higher intakes of fiber, protein, and most micronutrients compared with subjects who failed. Meeting different variants of the carbohydrate metrics was associated with 60% lower odds of pre-hypertensive blood pressure (p = 0.037; p = 0.047), and meeting the dietary fiber RDA was associated with lower waist circumference (p = 0.021). CONCLUSION: An improvement in carbohydrate quality is warranted among free-living middle-aged and older adults in Singapore. Not all measures of carbohydrate quality were equally effective in preserving overall diet quality; the carbohydrate metrics and dietary fiber RDA can be identified as effective measures in relation to cardiometabolic disease risk. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ CLINICAL TRIAL REGISTRATION: NCT03554954, 13 Sept. 2018.

Outcomes of Squamous Cell Carcinoma of the Lip Treated With Mohs Micrographic Surgery: A Retrospective Cohort Study.

BACKGROUND: Cutaneous squamous cell carcinomas (cSCCs) of the lip have been reported to be at higher risk for poorer post-treatment outcomes. OBJECTIVE: To examine outcomes of patients with SCC of the lip treated with Mohs micrographic surgery (MMS) and identify factors for recurrence. MATERIALS AND METHODS: This retrospective review of a single tertiary referral center's Mohs case logs from 2010 to 2019 identified cases of lip SCC. Clinicopathologic characteristics and outcomes (local recurrence [LR], metastasis, and disease-specific death) were reviewed. RESULTS: One hundred ninety cases of SCC of the lip were identified and demonstrated that MMS offered a disease-free survival of 96.8% over an average follow-up period of 42 months. Younger age (61 vs 74 years p = .006), increased MMS stages ( p = .009), and higher American Joint Committee on Cancer and Brigham and Women's Hospital T stages were risk factors for LR. Immunosuppression, large tumor size, mucosal lip involvement, aggressive histology, and perineural invasion were not associated with LR. CONCLUSION: The results of this study show that SCC of the lip behaved similarly to cSCC outside the lip area, and that both primary and recurrent lesions can be treated effectively with MMS.

Cardio- and reno-protective effects of dipeptidyl peptidase III in diabetic mice.

Diabetes mellitus (DM) causes injury to tissues and organs, including to the heart and kidney, resulting in increased morbidity and mortality. Thus, novel potential therapeutics are continuously required to minimize DM-related organ damage. We have previously shown that dipeptidyl peptidase III (DPPIII) has beneficial roles in a hypertensive mouse model, but it is unknown whether DPPIII has any effects on DM. In this study, we found that intravenous administration of recombinant DPPIII in diabetic db/db mice for 8 weeks suppressed the DM-induced cardiac diastolic dysfunctions and renal injury without alteration of the blood glucose level. This treatment inhibited inflammatory cell infiltration and fibrosis in the heart and blocked the increase in albuminuria by attenuating the disruption of the glomerular microvasculature and inhibiting the effacement of podocyte foot processes in the kidney. The beneficial role of DPPIII was, at least in part, mediated by the cleavage of a cytotoxic peptide, named Peptide 2, which was increased in db/db mice compared with normal mice. This peptide consisted of nine amino acids, was a digested fragment of complement component 3 (C3), and had an anaphylatoxin-like effect determined by the Miles assay and chemoattractant analysis. The effect was dependent on its interaction with the C3a receptor and protein kinase C-mediated RhoA activation downstream of the receptor in endothelial cells. In conclusion, DPPIII plays a protective role in the heart and kidney in a DM animal model through cleavage of a peptide that is a part of C3.