BIN1 knockdown rescues systolic dysfunction in aging male mouse hearts.

Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac CaV1.2 and type 2 ryanodine receptors. These deficiencies affect channel function at rest and their upregulation during acute stress. In vivo echocardiography reveals reduced systolic function in old mice. BIN1 knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restores the nanoscale distribution and clustering plasticity of ryanodine receptors and recovers Ca2+ transient amplitudes and cardiac systolic function toward youthful levels. Enhanced systolic function correlates with increased phosphorylation of the myofilament protein cardiac myosin binding protein-C. These results reveal BIN1 knockdown as a novel therapeutic strategy to rejuvenate the aging myocardium.

Randomized Phase II Study of Gemcitabine With or Without ATR Inhibitor Berzosertib in Platinum-Resistant Ovarian Cancer: Final Overall Survival and Biomarker Analyses.

PURPOSE: The multicenter, open-label, randomized phase 2 NCI-9944 study (NCT02595892) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (hazard ratio [HR]=0.57, one-sided log-rank P = .044, which met the one-sided significance level of 0.1 used for sample size calculation). METHODS: We report here the final overall survival (OS) analysis and biomarker correlations (ATM expression by immunohistochemistry, mutational signature 3 and a genomic biomarker of replication stress) along with post-hoc exploratory analyses to adjust for crossover from gemcitabine to gemcitabine/berzosertib. RESULTS: At the data cutoff of January 27, 2023 (>30 months of additional follow-up from the primary analysis), median OS was 59.4 weeks with gemcitabine/berzosertib versus 43.0 weeks with gemcitabine alone (HR 0.79, 90% CI 0.52 to 1.2, one-sided log-rank P = .18). An OS benefit with addition of berzosertib to gemcitabine was suggested in patients stratified into the platinum-free interval ≤3 months (N = 26) subgroup (HR, 0.48, 90% CI 0.22 to 1.01, one-sided log-rank P =.04) and in patients with ATM-negative/low (N = 24) tumors (HR, 0.50, 90% CI 0.23 to 1.08, one-sided log-rank P = .06). CONCLUSION: The results of this follow-up analysis continue to support the promise of combined gemcitabine/ATRi therapy in platinum resistant ovarian cancer, an active area of investigation with several ongoing clinical trials.

Alterações oculares decorrentes de picada de abelha na córnea / Ocular changes due to corneal bee sting

RESUMO O propósito deste estudo foi reportar as alterações oculares observadas após picada de abelha com ferrão retido na córnea. Destacamos o tratamento e o desfecho de uma lesão de córnea incomum e sua patogênese. Trata-se de relato de caso e revisão da literatura de lesões oculares por picada de abelha. Paciente do sexo feminino, 63 anos, procurou atendimento oftalmológico de urgência devido à picada de abelha na córnea do olho direito há 6 dias. Queixava-se de embaçamento visual, dor e hiperemia ocular. Apresentou acuidade visual de vultos no olho afetado. Ao exame, notaram-se hiperemia moderada de conjuntiva bulbar, edema corneano com dobras de Descemet e presença do ferrão alojado na região temporal, no estroma profundo da córnea. A paciente foi internada para ser abordada no centro cirúrgico sob anestesia geral. Durante a cirurgia, o ferrão teve que ser retirado via câmara anterior, mediante a realização de uma paracentese e uma lavagem da câmara anterior, com dupla via e solução salina balanceada. Ainda não existe na literatura um tratamento padrão na abordagem de pacientes com lesões oculares por picada de abelha, sendo importantes a identificação e o reconhecimento precoce de possíveis complicações que ameacem a visão.

ABSTRACT The purpose of this study was to report the ocular changes observed after a bee sting with a stinger retained in the cornea. We show the treatment and outcome of an unusual corneal injury and its pathogenesis. This is a case report and literature review of ocular injuries caused by bee stings. A 63-year-old female patient sought emergency ophthalmic care because of a bee sting on the cornea of her right eye six days before. She complained of blurred vision, pain, and ocular hyperemia. She had glare sensitivity on visual acuity in the affected eye. Examination revealed moderate hyperemia of the bulbar conjunctiva, corneal edema with Descemet's folds and a stinger lodged in the temporal region, in the deep stroma of the cornea. The patient was admitted to the operating room under general anesthesia. During surgery, the stinger had to be removed via the anterior chamber, by performing a paracentesis and washing the anterior chamber with a double flushing and balanced saline solution. There is still no standard treatment in the literature for patients with eye injuries caused by bee stings, and early identification and recognition of possible sight-threatening complications is important.

Integration of serial self-testing for COVID-19 as part of contact tracing in the Brazilian public health system: A pragmatic trial protocol.

The coronavirus disease (COVID-19) pandemic has led to an unprecedented public health crisis. Insufficient testing continues to limit the effectiveness of the global response to the COVID-19 pandemic. Molecular testing methods such as reverse transcriptase polymerase chain reaction (RT-PCR) continue to be highly centralized and are a sub-optimal option for population surveillance. Rapid antigen tests (Ag-RDTs) offer multiple benefits including low costs, high flexibility to conduct tests in a wide variety of settings, and faster return of results. Self-test Ag-RDTs (STs) have gained approval in several markets and offer the possibility to expand testing, reaching at-risk populations. While STs have the potential to assist the COVID-19 response, test result integrity, reporting, and appropriate linkage to care continue to hinder the widespread implementation of self-testing programs. This protocol presents a mixed-methods pragmatic trial (ISRCTN91602092) to better understand the feasibility of self-testing as part of a contact tracing strategy within the Brazilian public health system. Approximately 604 close contacts of 150 index cases testing positive for COVID-19 will be enrolled. Index cases will be randomized for their close contacts to participate in either serial (daily) self-testing over a 10-day follow-up period or a more traditional approach to contact tracing with a professional Ag-RDT at one time point post-exposure. Usability workshops and focus group discussions will also be conducted. This study protocol presents a comprehensive plan to assess the effectiveness, operational feasibility, and stakeholder preferences of a serial self-testing strategy for contact tracing within the Brazilian public health system. Our results will contribute to better understanding of the feasibility of a self-testing strategy within the public sector. Potential risks and limitations are discussed. Our findings will have important implications as governments continue working to mitigate the impact of COVID-19, particularly in the context of where to direct limited resources for testing and healthcare infrastructure. Registration: This trial is registered at ISCTRN (ISRCTN91602092).

d-Limonene complexed with cyclodextrin attenuates cardiac arrhythmias in an experimental model of doxorubicin-induced cardiotoxicity: Possible involvement of calcium/calmodulin-dependent protein kinase type II.

BACKGROUND: Arrhythmias are one manifestation of the cardiotoxicity that results from doxorubicin (Doxo) administration. Although cardiotoxicity is an anticipated outcome in anticancer therapies, there is still a lack of treatment options available for its effective management. This study sought to evaluate the possible cardioprotective effect of complex d-limonene (DL) plus hydroxypropyl-ß-cyclodextrin (HßDL) during treatment with Doxo, focusing on the arrhythmic feature. METHODS: Cardiotoxicity was induced in Swiss mice with Doxo 20 mg/kg, with 10 mg/kg of HßDL being administered 30 min before the Doxo. Plasma CK-MB and LDH levels were analyzed. Cellular excitability and susceptibility to cardiac and cardiomyocyte arrhythmias were evaluated using in vivo (pharmacological cardiac stress) and in vitro (burst pacing) ECG protocols. Ca2+ dynamics were also investigated. The expression of CaMKII and its activation by phosphorylation and oxidation were evaluated by western blot, and molecular docking was used to analyze the possible interaction between DL and CaMKII. RESULTS: Electrocardiograms showed that administration of 10 mg/kg of HßDL prevented Doxo-induced widening of the QRS complex and QT interval. HßDL also prevented cardiomyocyte electrophysiological changes that trigger cellular arrhythmias, such as increases in action potential duration and variability; decreased the occurrence of delayed afterdepolarizations (DADs) and triggered activities (TAs), and reduced the incidence of arrhythmia in vivo. Ca2+ waves and CaMKII overactivation caused by phosphorylation and oxidation were also decreased. In the in silico study, DL showed potential inhibitory interaction with CaMKII. CONCLUSION: Our results show that 10 mg/kg of ßDL protects the heart against Doxo-induced cardiotoxicity arrhythmias, and that this is probably due to its inhibitory effect on CaMKII hyperactivation.

Genomic landscapes of ovarian clear cell carcinoma from latin countries reveal aberrations linked to survival and progression.

BACKGROUND: Ovarian clear cell carcinomas (OCCCs) are rare, aggressive and chemoresistant tumors. Geographical and ethnic differences in the incidence of OCCC have been reported with a higher incidence in Asiatic countries. There is a paucity of information regarding OCCC in Latin America (LA) and other countries. METHODS: Here, we characterized two cohorts of 33 patients with OCCC from LA (24 from Brazil and 9 from Costa Rica) and a cohort of 27 patients from Spain. Genomic analysis was performed for 26 OCCC using the OncoScan platform. Tumors were classified according to their genomic landscapes into subgroups. Clinical parameters were related to the frequency of genomic aberrations. RESULTS: The median overall survival (OS) was not significantly different between the cohorts. Genomic landscapes were characterized by different homologous recombination deficiency (HRD) levels. No difference in the distribution of genomic landscapes profiles was detected between patients from the different cohorts. OCCCs with MYC-amplified tumors harboring a concomitant loss of a region in chromosome 13q12-q13 that includes the BRCA2 gene had the longest OS. In contrast, patients carrying a high number (> 30) of total copy number (CN) aberrations with no concomitant alterations in MYC and BRCA2 genes presented the shortest OS. Furthermore, amplification of the ASH1L gene was also associated with a shorter OS. Initial-stage OCCCs with early progression were characterized by gains in the JNK1 and MKL1 genes. CONCLUSIONS: Our results provide new data from understudied OCCC populations and reveal new potential markers for OCCCs.

Antigen concentration, viral load, and test performance for SARS-CoV-2 in multiple specimen types.

The relationship between N-antigen concentration and viral load within and across different specimens guides the clinical performance of rapid diagnostic tests (RDT) in different uses. A prospective study was conducted in Porto Velho, Brazil, to investigate RDT performance in different specimen types as a function of the correlation between antigen concentration and viral load. The study included 214 close contacts with recent exposures to confirmed cases, aged 12 years and older and with various levels of vaccination. Antigen concentration was measured in nasopharyngeal swab (NPS), anterior nares swab (ANS), and saliva specimens. Reverse transcriptase (RT)-PCR was conducted on the NPS and saliva specimens, and two RDTs were conducted on ANS and one RDT on saliva. Antigen concentration correlated well with viral load when measured in the same specimen type but not across specimen types. Antigen levels were higher in symptomatic cases compared to asymptomatic/oligosymptomatic cases and lower in saliva compared to NPS and ANS samples. Discordant results between the RDTs conducted on ANS and the RT-PCR on NPS were resolved by antigen concentration values. The analytical limit-of-detection of RDTs can be used to predict the performance of the tests in populations for which the antigen concentration is known. The antigen dynamics across different sample types observed in SARS-CoV-2 disease progression support use of RDTs with nasal samples. Given lower antigen concentrations in saliva, rapid testing using saliva is expected to require improved RDT analytical sensitivity to achieve clinical sensitivity similar to rapid testing of nasal samples.

Validation of the NAT Chagas IVD Kit for the Detection and Quantification of Trypanosoma cruzi in Blood Samples of Patients with Chagas Disease.

In the absence of validated biomarkers to control the cure of Chagas disease, PCR-based diagnosis is being used as the main tool for an early indication of therapeutic failure. However, since it is considered a technique of complex reproducibility, mainly due to difficulties in establishing accurate controls to guarantee the quality of the reaction, the use of PCR for Chagas disease diagnosis is restricted to specialized centers. In an effort to disseminate the molecular diagnosis of Chagas disease and its applications, new diagnostic kits based on qPCR have been made available in the market in recent years. Here, we show the results of the validation of the NAT Chagas kit (Nucleic Acid Test for Chagas Disease) for the detection and quantification of T. cruzi in blood samples of patients suspected of Chagas disease infection. The kit, composed of a TaqMan duplex reaction targeting the T. cruzi satellite nuclear DNA and an exogenous internal amplification control, presented a reportable range from 104 to 0.5 parasite equivalents/mL and a limit of detection (LOD) of 0.16 parasite equivalents/mL of blood. In addition, the NAT Chagas kit detected T. cruzi belonging to all six discrete typing units (DTUs-TcI to TcVI), similarly to the in-house real-time PCR performed with commercial reagents, which has been selected as the best performance assay in the international consensus for the validation of qPCR for Chagas disease. In the clinical validation presented here, the kit showed 100% sensitivity and 100% specificity when compared to the consensus in-house real-time PCR assay. Thus, the NAT Chagas kit, which is produced entirely in Brazil under the international standards of good manufacturing practices (GMP), appears as an excellent alternative to enable the molecular diagnosis of Chagas disease in public and private diagnostic centers, as well as to facilitate the monitoring of patients under etiological treatment participating in clinical trials.

Optimization of a medium composition for the heterologous production of Alcaligenes faecalis penicillin G acylase in Bacillus megaterium.

Penicillin G acylase (PGA) is a strategic enzyme in the production processes of beta-lactam antibiotics. High demand for ß-lactam semisynthetic antibiotics explain the genetic and biochemical engineering strategies devoted towards novel ways for PGA production and application. This work presents a fermentation process for the heterologous production of PGA from Alcaligenes faecalis in Bacillus megaterium with optimization. The thermal stability from A. faecalis PGA is considerably higher than other described PGA and the recombinant enzyme is secreted to the culture medium by B. megaterium, which facilitates the separation and purification steps. Media optimization using fractional factorial design experiments was used to identify factors related to PGA activity detection in supernatant and cell lysates. The optimized medium resulted in almost 6-fold increased activity in the supernatant samples when compared with the basal medium. Maximum enzyme activity in optimized medium composition achieves values between 135 and 140 IU/ml. The results suggest a promising model for recombinant production of PGA in B. megaterium with possible extracellular expression of the active enzyme.

Effects of rainfall and land use on nutrient responses in rivers in the Brazilian semiarid region.

This paper investigated whether rainfall promotes dilution or increase in nutrient concentrations and which land use indicators are the main predictors of nutrients in intermittent rivers in a large Brazilian semiarid region. The total phosphorus (TP) and total inorganic nitrogen (TIN) were monitored between 2013 and 2018 at 92 river water quality monitoring sites. The monthly rainfall (Rn) was obtained from 575 rain gauges. Pearson's correlation (R) between Rn and nutrient concentration was performed. The correlation patterns were also analysed based on land use data: urban area (%), agricultural field area (%), demographic density (inhabitants/km2), sewer system coverage (%), and reservoir density (reservoir/km2). Backward stepwise regression was performed to identify predictors of nutrient concentrations. The results revealed a marginal effect of rainfall on nutrients when the effects of urbanisation outweigh all other aspects. However, in regions with greater accumulated rainfall and lower reservoir density, the rainfall was related to a linear increase in nutrient concentrations (R > 0.8). Contrastingly, in the basins with less accumulated rainfall and greater inter-basin hydrological disconnection, there was a linear reduction in nutrient concentration (R < - 0.5). In the backward stepwise regression, sewer system coverage and Rn had the greatest influence for TP, and the urban area was the strongest predictor for TIN. Importantly, our results demonstrated that in semiarid rivers in densely populated regions, there is no single pattern of variability in nutrient concentration, on a wide scale of assessment. Therefore, adaptative and decentralised management can be more effective in improving water quality in these regions.

Expanding the universe of Piroplasmids: morphological detection and phylogenetic positioning of putative novel piroplasmids in black-eared opossums (Didelphis aurita) from southeastern Brazil, with description of "South American Marsupialia Group" of Piroplasmida.

The growing proximity of wildlife to large urban niches arouses greater interest in understanding wild reservoirs in the epidemiology of diseases of importance to animal and human health. The aim of the present study was to investigate the presence of piroplasmids in opossums rescued from the metropolitan region of Rio de Janeiro state, Brazil. Blood and bone marrow samples were collected from 15 Didelphis aurita and subjected to DNA extraction and PCR using primers for the 18S rRNA, cox1, cox3, and hsp70 genes of piroplasmids. Clinical and hematological evaluation of the animals was also performed. Five (33.3%) of the 15 opossums tested positive for piroplasms in the nested PCR based on the 18S rRNA, and in two animals, it was possible to observe intra-erythrocytic structures compatible with merozoites. One of the positive animals showed clinical signs of infection such as jaundice, fever, and apathy. Anemia, low level of plasma protein, leukocytosis, and regenerative erythrocyte signs were observed in positive animals. Phylogenetic analysis based on both 18S rRNA and cox-3 genes demonstrated that the piroplasmids detected in D. aurita formed a unique sub-clade, albeit related to piroplasmids previously detected in Didelphis albiventris and associated ticks from Brazil. This study proposes the novel Piroplasmida Clade, namely "South American Marsupialia Group," and reinforces the need for new clinical-epidemiological surveys to understand the dynamics of these infections in didelphids in Brazil.

Assessment of Health Risk and Presence of Metals in Water and Fish Samples from Doce River, Brazil, After Fundão Dam Collapse.

The rupture of the Fundão dam released about 50 million m3 of mining tailings in the Doce river basin. To assess the potential for environmental contamination and the risks of residual exposure of the human population generated by these tailings, water and fish samples from the Doce river were collected 25 days after the accident and analyzed the physicochemical parameters of the water and levels of metals by ICP-MS, in addition to the temporal variability of the concentration of these elements through other studies. This was the first study to carry out an assessment of the health risk associated with the consumption of fish contaminated by metals from the areas affected by the disaster. The values of turbidity (5460 NTU), electrical conductivity (74.8 µS cm-1), total dissolved solids (892 mg L-1) and total suspended solids (772 mg L-1) were above the maximum limit allowed by Brazilian legislation, due to the presence of large amounts of solid materials released after the dam rupture. The analysis of metals in water samples indicated high concentrations of Al (1,906.71 µg L-1), Mn (370.32 µg L-1), Fe (8,503.50 µg L-1) and Hg (34.25 µg L-1), while for the fish samples, only As (1,033.98 µg kg-1) and Hg (herbivorous: 505.32 µg kg-1; predatory: 1,184.09 µg kg-1) presented levels above those established by Brazilian legislation. The health risk assessment showed that the estimated daily intake for Hg was higher than the reference dose, reinforcing the need for monitoring the area affected by the disaster.

TFOS Lifestyle: Impact of cosmetics on the ocular surface.

In this report the use of eye cosmetic products and procedures and how this represents a lifestyle challenge that may exacerbate or promote the development of ocular surface and adnexal disease is discussed. Multiple aspects of eye cosmetics are addressed, including their history and market value, psychological and social impacts, possible problems associated with cosmetic ingredients, products, and procedures, and regulations for eye cosmetic use. In addition, a systematic review that critically appraises randomized controlled trial evidence concerning the ocular effects of eyelash growth products is included. The findings of this systematic review highlight the evidence gaps and indicate future directions for research to focus on ocular surface outcomes associated with eyelash growth products.

Molecular detection of hemoplasmas in rescued black-eared opossums (Didelphis aurita Wied-Neuwied, 1826) from southeastern Brazil, with evidence of a novel genotype infecting marsupials.

There is a growing concern about the participation of wild hosts and reservoirs in the epidemiology of several pathogens, particularly within the context of environmental changes and the expansion of the One Health concept. The aim of this study was to investigate the presence of hemoplasmas in opossums rescued from the metropolitan region of Rio de Janeiro state, Brazil. Blood samples were collected from 15 Didelphis aurita and subjected to DNA extraction and PCR using primers for the 16S rRNA and 23S rRNA genes. Physical examination and hematological analysis were also performed. Three out of 15 opossums tested positive for hemotropic Mycoplasma spp. by PCR and showed hematological alterations such as anemia and leukocytosis. Clinical signs were non-specific and associated to traumatic lesions. The phylogenetic analysis indicated that the hemoplasma detected was positioned between 'Ca. Mycoplasma haemodidelphis' detected in D. virginiana from North American and hemoplasmas recently detected in D. aurita from the state of Minas Gerais, Brazil. This study indicates the existence of hemoplasma infections in D. aurita from the metropolitan region of Rio de Janeiro, and reinforce the need for new epidemiological inquiries to clarify the participation of these in the dynamics of circulation of tick-borne pathogens.

Acute phosphatidylinositol 4,5 bisphosphate depletion destabilizes sarcolemmal expression of cardiac L-type Ca2+ channel CaV1.2.

CaV1.2 channels are critical players in cardiac excitation-contraction coupling, yet we do not understand how they are affected by an important therapeutic target of heart failure drugs and regulator of blood pressure, angiotensin II. Signaling through Gq-coupled AT1 receptors, angiotensin II triggers a decrease in PIP2, a phosphoinositide component of the plasma membrane (PM) and known regulator of many ion channels. PIP2 depletion suppresses CaV1.2 currents in heterologous expression systems but the mechanism of this regulation and whether a similar phenomenon occurs in cardiomyocytes is unknown. Previous studies have shown that CaV1.2 currents are also suppressed by angiotensin II. We hypothesized that these two observations are linked and that PIP2 stabilizes CaV1.2 expression at the PM and angiotensin II depresses cardiac excitability by stimulating PIP2 depletion and destabilization of CaV1.2 expression. We tested this hypothesis and report that CaV1.2 channels in tsA201 cells are destabilized after AT1 receptor-triggered PIP2 depletion, leading to their dynamin-dependent endocytosis. Likewise, in cardiomyocytes, angiotensin II decreased t-tubular CaV1.2 expression and cluster size by inducing their dynamic removal from the sarcolemma. These effects were abrogated by PIP2 supplementation. Functional data revealed acute angiotensin II reduced CaV1.2 currents and Ca2+ transient amplitudes thus diminishing excitation-contraction coupling. Finally, mass spectrometry results indicated whole-heart levels of PIP2 are decreased by acute angiotensin II treatment. Based on these observations, we propose a model wherein PIP2 stabilizes CaV1.2 membrane lifetimes, and angiotensin II-induced PIP2 depletion destabilizes sarcolemmal CaV1.2, triggering their removal, and the acute reduction of CaV1.2 currents and contractility.

The value of PET/CT for cytoreductive surgery selection in recurrent ovarian carcinoma.

OBJECTIVE: To evaluate the value of positron emission tomography/computed tomography (PET/CT) in predicting no residual disease (NRD) after secondary cytoreductive surgery (SCS) compared with MSK criteria, the iMODEL, and the AGO score. METHODS: We analyzed 112 patients with platinum-sensitive ovarian carcinoma who underwent SCS. We excluded patients for whom PET/CT was not performed, those without sufficient data, and who received chemotherapy before SCS. Ultimately, 69 patients were included. RESULTS: Variables that correlated with NRD were peritoneal carcinomatosis index (odds ratio [OR]=0.91; 95% confidence interval [CI]=0.83-0.99; p=0.044), European Cooperative Oncology Group Performance Status (ECOG) 0 (OR=8.0; 95% CI=1.34-47.5; p=0.022), and ≤2 lesions by PET/CT (OR=4.36; 95% CI=1.07-17.7; p=0.039). Of the patients with ≤2 lesions by PET/CT, 48 (92.3%) underwent complete SCS. The sensitivity, positive predictive value, negative predictive value, and accuracy of PET/CT for NRD were 85.7%, 92.3%, 33.3%, and 81.2%, respectively. NRD was achieved after fulfilling the MSK criteria, iMODEL and AGO Score in 89.1%, 88.1% and 85.9%, respectively. The accuracy of the MSK criteria, iMODEL, and AGO score in predicting NRD was 87%, 83.3%, and 77.3%, respectively. The PET/CT findings agreed well with the AGO score and iMODEL. The addition of PET/CT to these models increased the NRD rates (92.2%, 91.8%, and 89.4% for MSK+PET/CT, iMODEL+PET/CT, and AGO+PET/CT, respectively), but lowered their accuracy. CONCLUSION: We observed NRD in 92.3% of patients with ≤2 lesions by PET/CT, with an accuracy of 81.2%. PET/CT did not increase the accuracy of the MSK criteria, iMODEL, or AGO score models.

Targeting replication stress in cancer therapy.

Replication stress is a major cause of genomic instability and a crucial vulnerability of cancer cells. This vulnerability can be therapeutically targeted by inhibiting kinases that coordinate the DNA damage response with cell cycle control, including ATR, CHK1, WEE1 and MYT1 checkpoint kinases. In addition, inhibiting the DNA damage response releases DNA fragments into the cytoplasm, eliciting an innate immune response. Therefore, several ATR, CHK1, WEE1 and MYT1 inhibitors are undergoing clinical evaluation as monotherapies or in combination with chemotherapy, poly[ADP-ribose]polymerase (PARP) inhibitors, or immune checkpoint inhibitors to capitalize on high replication stress, overcome therapeutic resistance and promote effective antitumour immunity. Here, we review current and emerging approaches for targeting replication stress in cancer, from preclinical and biomarker development to clinical trial evaluation.

Despigmentação precoce em caso de ceratopigmentação / Early depigmentation in case of keratopigmentation

RESUMO A ceratopigmentação teve seu primeiro registro pelo filósofo Galeno há muitos séculos como uma estratégia utilizada para o tratamento estético de pacientes com leucomas. As córneas com leucoma são patológicas e, muitas vezes, intolerantes a lentes de contato cosméticas ou próteses oculares, sendo comum a queixa de desconforto excessivo, proporcionado pela superfície corneana irregular. Assim, a ceratopigmentação é uma alternativa para a melhora estética de pacientes com opacidades corneanas. Descrevemos o caso de um paciente do sexo masculino, 39 anos, que apresentou despigmentação precoce em caso de ceratopigmentação associado a quadro de ceratite herpética necrotizante. O paciente foi submetido ao tratamento com aciclovir 2g ao dia e doxiciclina 200mg ao dia, evoluindo com melhora do quadro clínico, apesar da má adesão medicamentosa.

ABSTRACT Keratopigmentation was first recorded many centuries ago by the philosopher Galeno, as a strategy used for the aesthetic treatment of patients with leukomas. Corneas with leucoma are pathological and often intolerant of cosmetic contact lenses or ocular prostheses, with complaints of excessive discomfort provided by the irregular corneal surface being common. Therefore, keratopigmentation is an alternative for the aesthetic improvement of patients with corneal opacities. We describe the case of a 39-year old male patient, who presented early depigmentation in a case of keratopigmentation associated with necrotizing herpetic keratitis. The patient was treated with Acyclovir 2g/day and Doxycycline 200mg/day, evolving with clinical improvement, despite poor medication adherence.