The 6-4 photoproduct is the trigger of UV-induced replication blockage and ATR activation.

The most prevalent human carcinogen is sunlight-associated ultraviolet (UV), a physiologic dose of which generates thousands of DNA lesions per cell, mostly of two types: cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs). It has not been possible, in living cells, to precisely characterize the respective contributions of these two lesion types to the signals that regulate cell cycle progression, DNA replication, and cell survival. Here we coupled multiparameter flow cytometry with lesion-specific photolyases that eliminate either CPDs or 6-4PPs and determined their respective contributions to DNA damage responses. Strikingly, only 6-4PP lesions activated the ATR-Chk1 DNA damage response pathway. Mechanistically, 6-4PPs, but not CPDs, impeded DNA replication across the genome as revealed by microfluidic-assisted replication track analysis. Furthermore, single-stranded DNA accumulated preferentially at 6-4PPs during DNA replication, indicating selective and prolonged replication blockage at 6-4PPs. These findings suggest that 6-4PPs, although eightfold fewer in number than CPDs, are the trigger for UV-induced DNA damage responses.

The disposable bandage soft contact lenses therapy and anterior segment optical coherence tomography for management of ocular graft-versus-host disease.

PURPOSE: To identify the ocular surface changes of ocular graft-versus-host disease (GVHD) using anterior segment optical coherence tomography (AS-OCT) and examine the efficacy of disposable bandage soft contact lens (BSCL) treatment in ocular GVHD patients. METHODS: This study is a prospective, Phase II clinical trial. Nineteen patients diagnosed with chronic GVHD based on the NIH criteria and ocular symptoms of NIH eye score 2 or greater were enrolled. Disposable BSCL was applied to the GVHD-affected eyes with topical antibiotic coverage. Ocular exams, eye symptom surveys, and AS-OCT were performed with signed informed consent. Patients were followed for one to three months. RESULTS: Thirty-eight eyes of 19 patients with ocular GVHD underwent BSCL treatment in this study. AS-OCT scans were done in 14 out of 19 patients. The mean best-corrected visual acuity at enrollment, 2-week, and 4-week visits was 0.180, 0.128, and 0.163 logMAR, respectively. Twenty-four out of 25 eyes (96 %) that initially presented with conjunctival inflammation, twenty-three out of 30 eyes (76.7 %) that initially presented with punctate epithelial erosion, and 8 out of 15 (53.3 %) eyes that initially presented with filamentous keratopathy showed improvement after wearing BSCL for 2 to 4 weeks. AS-OCT revealed corneal epithelial irregularity, abnormal meibomian gland orifice, and conjunctival hyperemia, in patients with ocular GVHD. CONCLUSIONS: BSCL treatment provided significant subjective and objective improvements in ocular GVHD patients. Meanwhile, we found that AS-OCT can be a promising diagnostic tool to characterize the ocular surface changes associated with ocular GVHD.

Human antigen R protein modulates vascular endothelial growth factor expression in human corneal epithelial cells under hypoxia.

PURPOSE: Corneal avascularity is critical for corneal transparency; therefore, a tailored process has been presumed to minimize corneal neovascularization (NV). In most cell types, the transcription of vascular endothelial growth factor (VEGF) is up-regulated, and the stability of VEGF mRNA is sustained by human antigen R (HuR) during hypoxia; however, whether such response applies to corneal epithelial cells is unclear. METHODS: Human corneal epithelial cells (HCECs) and MCF-7 cells that serves as the control were incubated under 0.5% oxygen, and the levels of VEGF and HuR were examined time-dependently. The alteration of HuR was also examined in vivo using the closed-eye contact lens-induced corneal neovascularization rabbit model and immunohistochemistry. Additionally, the expression of HuR was modulated by transfection of plasmids encoding HuR or siRNA targeting HuR to validate the role of HuR in VEGF expression. RESULTS: We found that, unlike in control cells, the level of VEGF was not up-regulated, and the HuR expression was declined in HCECs following hypoxia. The HuR immunostaining intensities were decreased in corneal epithelial cells of rabbits wearing contact lenses. In addition, HuR overexpression restored the ability of HCECs to up-regulate VEGF under hypoxia; however, knockdown of HuR suppressed hypoxia-induced VEGF in control cells but did not further decrease VEGF in HCECs. These findings suggest that HCECs may modulate HuR to suppress hypoxia-mediated up-regulation of VEGF. CONCLUSION: Our study revealed a distinct regulation of VEGF via HuR in HCECs following hypoxia, which likely contributes to minimizing corneal NV and/or maintenance of corneal avascularity.

Adaptation to Endoplasmic Reticulum Stress Enhances Resistance of Oral Cancer Cells to Cisplatin by Up-Regulating Polymerase η and Increasing DNA Repair Efficiency.

Endoplasmic reticulum (ER) stress response is an adaptive program to cope with cellular stress that disturbs the function and homeostasis of ER, which commonly occurs during cancer progression to late stage. Late-stage cancers, mostly requiring chemotherapy, often develop treatment resistance. Chemoresistance has been linked to ER stress response; however, most of the evidence has come from studies that correlate the expression of stress markers with poor prognosis or demonstrate proapoptosis by the knockdown of stress-responsive genes. Since ER stress in cancers usually persists and is essentially not induced by genetic manipulations, we used low doses of ER stress inducers at levels that allowed cell adaptation to occur in order to investigate the effect of stress response on chemoresistance. We found that prolonged tolerable ER stress promotes mesenchymal-epithelial transition, slows cell-cycle progression, and delays the S-phase exit. Consequently, cisplatin-induced apoptosis was significantly decreased in stress-adapted cells, implying their acquisition of cisplatin resistance. Molecularly, we found that proliferating cell nuclear antigen (PCNA) ubiquitination and the expression of polymerase η, the main polymerase responsible for translesion synthesis across cisplatin-DNA damage, were up-regulated in ER stress-adaptive cells, and their enhanced cisplatin resistance was abrogated by the knockout of polymerase η. We also found that a fraction of p53 in stress-adapted cells was translocated to the nucleus, and that these cells exhibited a significant decline in the level of cisplatin-DNA damage. Consistently, we showed that the nuclear p53 coincided with strong positivity of glucose-related protein 78 (GRP78) on immunostaining of clinical biopsies, and the cisplatin-based chemotherapy was less effective for patients with high levels of ER stress. Taken together, this study uncovers that adaptation to ER stress enhances DNA repair and damage tolerance, with which stressed cells gain resistance to chemotherapeutics.

Therapeutic future of Fuchs endothelial corneal dystrophy: An ongoing way to explore.

Fuchs endothelial corneal dystrophy (FECD) is one of the most common corneal diseases that causes loss of visual acuity in the world. FECD is a genetically and pathogenetically heterogeneous disease that results in the failure of corneal endothelial cells to maintain fluid balance and functional homeostasis of the cornea. Corneal edema, central guttae formation, and bullae development are common corneal pathologies. Currently, the mainstay of FECD treatment is surgery. However, limited sources of corneal graft and postsurgical complications remain problematic. In recent years, with advances in medical science and technology, there have been a few promising trials of new treatment modalities for FECD. In addition to new surgical methods, novel modalities can be classified into pharmacological-associated treatment, cell therapy-associated treatment, and gene therapy-associated treatment. In this article, our primary focus is on the most recent clinical trials related to FECD, and we present a stepwise approach to enhance FECD management and ultimately improve patient outcomes. We thoroughly searched for FECD clinical trials and reviewed the study designs, methodologies, and outcomes of each trial conducted within the past decade. It is imperative for physicians to stay up-to-date with these cutting-edge treatment approaches.

Characterizing the Robustness of Distinct Clinical Assessments in Identifying Dry Eye Condition of Animal Models.

PURPOSE: The study aims to characterize the robustness of distinct clinical assessments in identifying the underlying conditions of dry eye disease (DED), with a specific emphasis on the involvement of conjunctival goblet cells. METHODS: Seven rabbits receiving surgical removal of the lacrimal and Harderian glands were divided into two groups, one with ablation of conjunctival goblet cells by topical soaking of trichloroacetic acid (TCA) to the bulbar conjunctiva (n = 3) and one without (n = 4), and the conditions of DED were assessed weekly using Schirmer test, tear breakup time (TBUT), tear osmolarity, and National Eye Institute (NEI) fluorescein staining grading. After 8 weeks, the rabbits were sacrificed, and the eyes were enucleated for histopathological examination. RESULTS: Histopathological analysis revealed corneal epithelial thinning in both groups. While TCA soaking significantly decreased the density of conjunctival goblet cells, DED rabbits without TCA also showed a partial reduction in goblet cell density, potentially attributable to dacryoadenectomy. Both groups showed significant decreases in Schirmer test and TBUT, as well as an increase in tear osmolarity. In DED rabbits with TCA soaking, tear osmolarity increased markedly, suggesting that tear osmolarity is highly sensitive to loss and/or dysfunction of conjunctival goblet cells. Fluorescein staining was gradually and similarly increased in both groups, suggesting that fluorescein staining may not reveal an early disruption of the tear film until the prolonged progression of DED. CONCLUSION: The Schirmer test, TBUT, tear osmolarity, and NEI fluorescein grading are distinct, yet complementary, clinical assessments for the evaluation of DED. By performing these assessments in definitive DED rabbit models, both with and without ablation of conjunctival goblet cells, the role of these cells in the homeostasis of tear osmolarity is highlighted. Characterizing the robustness of these assessments in identifying the underlying conditions of DED will guide a more appropriate management for patients with DED.

Structure-based approaches against COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has had a major impact on human life. This review highlights the versatile roles of both classical and modern structure-based approaches for COVID-19. X-ray crystallography, nuclear magnetic resonance spectroscopy, and cryogenic electron microscopy are the three cornerstones of classical structural biology. These technologies have helped provide fundamental and detailed knowledge regarding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the related human host proteins as well as enabled the identification of its target sites, facilitating the cessation of its transmission. Further progress into protein structure modeling was made using modern structure-based approaches derived from homology modeling and integrated with artificial intelligence (AI), facilitating advanced computational simulation tools to actively guide the design of new vaccines and the development of anti-SARS-CoV-2 drugs. This review presents the practical contributions and future directions of structure-based approaches for COVID-19.

Smart healthcare: A prospective future medical approach for COVID-19.

COVID-19 has greatly affected human life for over 3 years. In this review, we focus on smart healthcare solutions that address major requirements for coping with the COVID-19 pandemic, including (1) the continuous monitoring of severe acute respiratory syndrome coronavirus 2, (2) patient stratification with distinct short-term outcomes (eg, mild or severe diseases) and long-term outcomes (eg, long COVID), and (3) adherence to medication and treatments for patients with COVID-19. Smart healthcare often utilizes medical artificial intelligence (AI) and cloud computing and integrates cutting-edge biological and optoelectronic techniques. These are valuable technologies for addressing the unmet needs in the management of COVID. By leveraging deep learning/machine learning capabilities and big data, medical AI can perform precise prognosis predictions and provide reliable suggestions for physicians' decision-making. Through the assistance of the Internet of Medical Things, which encompasses wearable devices, smartphone apps, internet-based drug delivery systems, and telemedicine technologies, the status of mild cases can be continuously monitored and medications provided at home without the need for hospital care. In cases that develop into severe cases, emergency feedback can be provided through the hospital for rapid treatment. Smart healthcare can possibly prevent the development of severe COVID-19 cases and therefore lower the burden on intensive care units.

The Omicron variant wave: Where are we now and what are the prospects?

The Omicron variant BA.2 is the dominant form of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak in many countries, including those that have already implemented the strictest quarantine mandates that effectively contained the spread of the previous variants. Although many individuals were partially or fully vaccinated, confirmed Omicron infections have far surpassed all other variants combined in just a couple of months since the Omicron variant emerged. The ChAdOx1-S (AstraZeneca), BNT162b2 (Pfizer-BioNTech), and mRNA-1273 (Moderna) vaccines offer protection against the severe illness of SARS-CoV-2 infection; however, these currently available vaccines are less effective in terms of preventing Omicron infections. As a result, a booster dose of BNT162b2 or mRNA-1273 is recommended for individuals >12 years old who had received their second dose of the approved vaccines for >5 months. Herein, we review the studies that assessed the clinical benefits of the booster dose of vaccines against Omicron infections. We also analyzed public data to address whether early booster vaccination effectively prevented the surge of the Omicron infections. Finally, we discuss the consideration of a fourth dose of vaccine as a way to prevent possible upcoming infections.

Is N -acetylcysteine effective in treating patients with coronavirus disease 2019? A meta-analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). It has brought tremendous challenges to public health and medical systems around the world. The current strategy for drug repurposing has accumulated some evidence on the use of N -acetylcysteine (NAC) in treating patients with COVID-19. However, the evidence remains debated. METHODS: We performed the systematic review and meta-analysis that complies with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Five databases and reference lists were searched from inception to May 14, 2022. Studies evaluating the efficacy of NAC in treating patients with COVID-19 were regarded as eligible. The review was registered prospectively on PROSPERO (CRD42022332791). RESULTS: Of 778 records identified from the preliminary search, four studies were enrolled in the final qualitative review and quantitative meta-analysis. A total of 355 patients were allocated into the NAC group and the control group. The evaluated outcomes included intubation rate, improvement, duration of intensive unit stay and hospital stay and mortality. The pooled results showed nonsignificant differences in intubation rate (OR, 0.55; 95% CI, 0.16-1.89; p = 0.34; I2 = 75%), improvement of oxygenation ([MD], 80.84; 95% CI, -38.16 to 199.84; p = 0.18; I2 = 98%), ICU stay (MD, -0.74; 95% CI, -3.19 to 1.71; p = 0.55; I2 = 95%), hospital stay (MD, -1.05; 95% CI, -3.02 to 0.92; p = 0.30; I2 = 90%), and mortality (OR, 0.58; 95% CI, 0.23-1.45; p = 0.24; I2 = 54%). Subsequent trial sequential analysis (TSA) showed conclusive nonsignificant results for mortality, while the TSA for the other outcomes suggested that a larger sample size is essential. CONCLUSIONS: The current evidence reveals NAC is not beneficial for treating patients with COVID- 19 with regard to respiratory outcome, mortality, duration of ICU stay and hospital stay.

A modified SELEX approach to identify DNA aptamers with binding specificity to the major histocompatibility complex presenting ovalbumin model antigen.

Aptamers have sparked significant interest in cell recognition because of their superior binding specificity and biocompatibility. Cell recognition can be mediated by targeting the major histocompatibility complex (MHC) that presents short peptides derived from intracellular antigens. Although numerous antibodies have demonstrated a specific affinity for the peptide-MHC complex, the number of aptamers that exhibit comparable characteristics is limited. Aptamers are usually selected from large libraries via the Systemic Evolution of Ligands by Exponential Enrichment (SELEX), an iterative process of selection and PCR amplification to enrich a pool of aptamers with high affinity. However, the success rate of aptamer identification is low, possibly due to the presence of complementary sequences or sequences rich in guanine and cytosine that are less accessible for primers. Here, we modified SELEX by employing systemic consecutive selections with minimal PCR amplification. We also modified the analysis by selecting aptamers that were identified in multiple selection rounds rather than those that are highly enriched. Using this approach, we were able to identify two aptamers with binding specificity to cells expressing the ovalbumin alloantigen as a proof of concept. These two aptamers were also discovered among the top 150 abundant candidates, despite not being highly enriched, by performing conventional SELEX. Additionally, we found that highly enriched aptamers tend to contain fractions of the primer sequence and have minimal target affinity. Candidate aptamers are easily missed in the conventional SELEX process. Therefore, our modification for SELEX may facilitate the identification of aptamers for more application in diverse biomedical fields. Significance: we modify the conventional method to improve the efficiency in the identification of the aptamer, a single strand of nucleic acid with binding specificity to the target molecule, showing as a proof of concept that this approach is particularly useful to select aptamers that can selectively bind to cells presenting a particular peptide by the major histocompatibility complex (MHC) on the cell surface. Given that cancer cells may express mutant peptide-MHC complexes that are distinct from those expressed by normal cells, this study sheds light on the potential application of aptamers to cancer cell targeting.

Transmembrane Mucin 1 Blocks Fluorescein Ingress to Corneal Epithelium.

Purpose: To determine the role of transmembrane mucins in blocking fluorescein ingress to the corneal epithelium and its deficiency in contributing to corneal fluorescein punctate staining. Methods: A dry eye model was established by extirpating lacrimal and Harderian glands in rabbits to correlate the expression of mucins with fluorescein-stained areas on the corneal button using immunofluorescence. Expression of transmembrane mucins was promoted in human corneal epithelial cells (HCECs) by culturing with the mucin-promoting medium (MPM) or diquafosol treatment. Conversely, the expression of mucins was downregulated by knockdown with short hairpin RNA. The role of mucin1 extracellular domain in fluorescein ingress was further verified by overexpression of N-terminally truncated mucin1 in HCECs. Results: In the rabbit dry eye model, the expression level of mucin1 was significantly decreased in superficial corneal epithelial cells where fluorescein punctate staining was observed. Upregulation of mucin1 and mucin16 in HCECs promoted by MPM or by diquafosol treatment impeded intracellular fluorescein ingress. Downregulation of mucin1 and mucin16 enhanced fluorescence ingress in HCECs after fluorescein staining. Overexpression of truncated mucin1 did not alter the fluorescein intensity of fluorescein-stained HCECs, supporting the notion that the ability of mucin1 to block fluorescein ingress was primarily mediated by its extracellular domain. Minimal inherent expression of mucin16 in the rabbit cornea limited the validation of its role in blocking fluorescein ingress in vivo. Conclusion: Transmembrane mucin1 blocks fluorescein ingress in the corneal epithelium, explaining how fluorescein staining is positive when the level of transmembrane mucins is disturbed in dry eyes.

SARS-CoV-2 vaccines in children and adolescents: Can immunization prevent hospitalization?

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants of concern can infect people of all ages and can cause severe diseases in children, such as encephalitis, which require intensive care. Therefore, vaccines are urgently required to prevent severe disease in all age groups. We reviewed the safety and efficacy profiles of mRNA vaccines-BNT162b2 and mRNA-1273-demonstrated by clinical trials or observed in the real world. mRNA-1273 is effective in preventing SARS-CoV-2 infection in preschool children (6 months-6 years old). Both BNT162b2 and mRNA-1273 are effective in preventing SARS-CoV-2 infection in school-aged children and adolescents, thereby preventing post-coronavirus disease (COVID) conditions. The common side effects of vaccination are pain at the injection site, fatigue, and headache. Myocarditis and pericarditis are uncommon. Monitoring post-vaccination troponin levels may help prevent severe cardiac events. The SARS-CoV-2 coronavirus mutates its genome to overcome the herd immunity provided by mass vaccinations; therefore, we may need to develop new generations of vaccines, such as those using viral nucleocapsid proteins as antigens. In conclusion, the mRNA vaccines are generally safe and effective in preventing severe diseases and hospitalization among children and adolescents.

Identification of plasma hsa_circ_0000190 and 0001649 as biomarkers for predicting the recurrence and treatment response of patients with oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a type of malignancy characterized by high relapse and recurrence rates in the late stage despite optimal surgical intervention and postoperative chemoradiotherapy. Because the management of relapse following definitive treatment is challenging, accurate risk stratification is of clinical significance to improve treatment outcomes. Circular RNAs (circRNAs) are noncoding RNAs featured with cell-type specificity and high stability, owing to their circular structure, making these molecules excellent biomarkers for a variety of diseases. METHODS: The levels of hsa_circ_0000190 and 0001649 in plasma samples from 30 healthy controls and 66 OSCC patients were determined by droplet digital polymerase chain reaction. The same primer sets were used with PCR to examine the expression of these two circRNAs in cancerous and adjacent normal tissues. A receiver operating characteristics curve was generated to evaluate the diagnostic value. The Kaplan-Meier method with a log-rank test was used for survival analysis. RESULTS: We identified two circRNAs as potential biomarkers for OSCC, showing that the plasma level of hsa_circ_0000190 was significantly decreased in the late stage and marginally correlated with the development of second primary OSCC. We also found that the decreased plasma hsa_circ_0001649 was correlated with the recurrence and poor prognosis of patients. Additionally, we found that high plasma hsa_circ_0000190, but not hsa_circ_0001649, possibly predicted a better response of patients to induction chemotherapy. CONCLUSION: Our study demonstrated the potential of biomarkers in plasma to inform not just the tumor but the entire oral cavity, thereby offering a prediction for early recurrence and second primary OSCC. The plasma circRNAs remain valuable for OSCC, albeit the easy accessibility to the oral cavity.

Quantitative Spectrochip-Coupled Lateral Flow Immunoassay Demonstrates Clinical Potential for Overcoming Coronavirus Disease 2019 Pandemic Screening Challenges.

As coronavirus disease 2019 (COVID-19) continues to spread around the world, the establishment of decentralized severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) diagnostics and point-of-care testing is invaluable. While polymerase chain reaction (PCR) has been the gold standard for COVID-19 screening, serological assays detecting anti-SARS-CoV-2 antibodies in response to past and/or current infection remain vital tools. In particular, lateral flow immunoassay devices are easy to produce, scale, distribute, and use; however, they are unable to provide quantitative information. To enable quantitative analysis of lateral flow immunoassay device results, microgating technology was used to develop an innovative spectrochip that can be integrated into a portable, palm-sized device that was capable of capturing high-resolution reflectance spectrum data for quantitative immunoassay diagnostics. Using predefined spiked concentrations of recombinant anti-SARS-CoV-2 immunoglobulin G (IgG), this spectrochip-coupled immunoassay provided extraordinary sensitivity, with a detection limit as low as 186 pg/mL. Furthermore, this platform enabled the detection of anti-SARS-CoV-2 IgG in all PCR-confirmed patients as early as day 3 after symptom onset, including two patients whose spectrochip tests would be regarded as negative for COVID-19 using a direct visual read-out without spectral analysis. Therefore, the quantitative lateral flow immunoassay with an exceptionally low detection limit for SARS-CoV-2 is of value. An increase in the number of patients tested with this novel device may reveal its true clinical potential.

Animal models of dry eye: Their strengths and limitations for studying human dry eye disease.

Dry eye disease (DED), also called the keratoconjunctivitis sicca, is one of the most common diseases in the ophthalmology clinics. While DED is not a life-threatening disease, life quality may be substantially affected by the discomfort and the complications of poor vision. As such, a large number of studies have made contributions to the investigation of the DED pathogenesis and novel treatments. DED is a multifactorial disease featured with various phenotypic consequences; therefore, animal models are valuable tools suitable for the related studies. Accordingly, selection of the animal model to recapitulate the clinical presentation of interest is important for appropriately addressing the research objective. To this end, we systemically reviewed different murine and rabbit models of DED, which are categorized into the quantitative (aqueous-deficient) type and the qualitative (evaporative) type, based on the schemes to establish. The clinical manifestations of dry eye on animal models can be induced by mechanical or surgical approaches, iatrogenic immune response, topical eye drops, blockage of neural pathway, or others. Although these models have shown promising results, each has its own limitation and cannot fully reproduce the pathophysiological mechanisms that occur in patients. Nonetheless, the animal models remain the best approximation of human DED and represent the valuable tool for the DED studies.

Recent progress of biomarkers in oral cancers.

Oral cancers are the seventh most common cancer globally. While progresses in oral cancer treatment have been made, not all patients respond to these therapies in the same way. To overcome this difficulty, numerous studies have been devoted to identifying biomarkers, which enable early identification of patients who may benefit from a particular treatment modality or at risk for poor prognosis. Biomarkers are protein molecules, gene expression, DNA variants, or metabolites that are derived from tumors, adjacent normal tissue or bodily fluids, which can be acquired before treatment and during follow-up, thus extending their use to the evaluation of cancer progression and prediction of treatment outcome. In this review, we employed a basic significance level (<0.05) as the minimal requirement for candidate biomarkers. Effect sizes of the biomarkers in terms of odds ratio, hazard ratio, and area under the receiver operating characteristic curves were subsequently used to evaluate the potential of their clinical use. We identified the CCND1 from the tumor, human papillomavirus, HSP70, and IL-17 from the peripheral blood, and high density of CD45RO+ tumor-infiltrating lymphocytes as the clinically relevant biomarkers for oral cancers.

Deciphering UV-induced DNA Damage Responses to Prevent and Treat Skin Cancer.

Ultraviolet (UV) radiation is among the most prevalent environmental factors that influence human health and disease. Even 1 h of UV irradiation extensively damages the genome. To cope with resulting deleterious DNA lesions, cells activate a multitude of DNA damage response pathways, including DNA repair. Strikingly, UV-induced DNA damage formation and repair are affected by chromatin state. When cells enter S phase with these lesions, a distinct mutation signature is created via error-prone translesion synthesis. Chronic UV exposure leads to high mutation burden in skin and consequently the development of skin cancer, the most common cancer in the United States. Intriguingly, UV-induced oxidative stress has opposing effects on carcinogenesis. Elucidating the molecular mechanisms of UV-induced DNA damage responses will be useful for preventing and treating skin cancer with greater precision. Excitingly, recent studies have uncovered substantial depth of novel findings regarding the molecular and cellular consequences of UV irradiation. In this review, we will discuss updated mechanisms of UV-induced DNA damage responses including the ATR pathway, which maintains genome integrity following UV irradiation. We will also present current strategies for preventing and treating nonmelanoma skin cancer, including ATR pathway inhibition for prevention and photodynamic therapy for treatment.