Multi-trait index: selection and recommendation of superior black bean genotypes as new improved varieties.

Common bean provides diet rich in vitamins, fiber, minerals, and protein, which could contribute into food security of needy populations in many countries. Developing genotypes that associate favorable agronomic and grain quality traits in the common bean crop could increase the chances of adopting new cultivars black bean. In this context, the present study aimed at selection of superior black bean lines using multi-variate indexes, Smith-Hazel-index, and genotype by yield*trait biplot analysis. These trials were conducted in Campos dos Goytacazes - RJ, in 2020 and 2021. The experimental design used was randomized blocks, with 28 treatments and three replications. The experimental unit consisted of four rows 4.0 m long, spaced at 0.50 m apart, with a sowing density of 15 seeds per meter. The two central rows were used for the evaluations. The selection of superior genotypes was conducted using the multiple trait stability index (MTSI), multi-trait genotype-ideotype distance index (MGIDI), multi-trait index based on factor analysis and genotype-ideotype distance (FAI-BLUP), Smith-Hazel index, and Genotype by Yield*Trait Biplot (GYT). The multivariate indexes efficiently selected the best black bean genotypes, presenting desirable selection gains for most traits. The use of multivariate indexes and GYT enable the selection of early genotypes with higher grain yields. These lines G9, G13, G17, G23, and G27 were selected based on their performance for multiple traits closest to the ideotype and could be recommended as new varieties.

The Screening of microRNAs in Chronic Myeloid Leukemia: A Clinical Evaluation.

Chronic myeloid leukemia (CML) is a type of leukemia whose main genetic marker is the reciprocal translocation that leads to the production of the BCR::ABL1 oncoprotein. The expression of some genes may interfere with the progression and development of leukemias. MicroRNAs are small non-coding RNAs that have the potential to alter the expression of some genes and may be correlated with some types of leukemia and could be used as biomarkers in the diagnosis and prognosis of patients. Therefore, this project carried out an analysis of microRNA-type plasma biomarkers in patients with chronic myeloid leukemia at unique points, including follow-up analysis of patients from the Erasto Gaertner Hospital. 35 microRNAs were analyzed in different cohorts. Inside those groups, 70 samples were analyzed at unique points and 11 patients in a follow-up analysis. Statistically different results were found for microRNA-7-5p, which was found to be upregulated in patients with high expression of the BCR::ABL1 transcript when compared to healthy controls. This microRNA also had evidence of behavior related to BCR::ABL1 when analyzed in follow-up, but strong evidence was not found. In this way, this work obtained results that may lead to manifestations of a relationship between miR-7-5p and chronic myeloid leukemia, and evaluations of possible microRNAs that are not related to this pathology.

Targeting KRAS in Pancreatic Ductal Adenocarcinoma: The Long Road to Cure.

Pancreatic ductal adenocarcinoma (PDAC) remains an important cause of cancer-related mortality, and it is expected to play an even bigger part in cancer burden in the years to come. Despite concerted efforts from scientists and physicians, patients have experienced little improvement in survival over the past decades, possibly because of the non-specific nature of the tested treatment modalities. Recently, the discovery of potentially targetable molecular alterations has paved the way for the personalized treatment of PDAC. Indeed, the central piece in the molecular framework of PDAC is starting to be unveiled. KRAS mutations are seen in 90% of PDACs, and multiple studies have demonstrated their pivotal role in pancreatic carcinogenesis. Recent investigations have shed light on the differences in prognosis as well as therapeutic implications of the different KRAS mutations and disentangled the relationship between KRAS and effectors of downstream and parallel signaling pathways. Additionally, the recognition of other mechanisms involving KRAS-mediated pathogenesis, such as KRAS dosing and allelic imbalance, has contributed to broadening the current knowledge regarding this molecular alteration. Finally, KRAS G12C inhibitors have been recently tested in patients with pancreatic cancer with relative success, and inhibitors of KRAS harboring other mutations are under clinical development. These drugs currently represent a true hope for a meaningful leap forward in this dreadful disease.

Molecular BCR::ABL1 Quantification and ABL1 Mutation Detection as Essential Tools for the Clinical Management of Chronic Myeloid Leukemia Patients: Results from a Brazilian Single-Center Study.

Chronic myeloid leukemia (CML) is a well-characterized oncological disease in which virtually all patients possess a translocation (9;22) that generates the tyrosine kinase BCR::ABL1 protein. This translocation represents one of the milestones in molecular oncology in terms of both diagnostic and prognostic evaluations. The molecular detection of the BCR::ABL1 transcription is a required factor for CML diagnosis, and its molecular quantification is essential for assessing treatment options and clinical approaches. In the CML molecular context, point mutations on the ABL1 gene are also a challenge for clinical guidelines because several mutations are responsible for tyrosine kinase inhibitor resistance, indicating that a change may be necessary in the treatment protocol. So far, the European LeukemiaNet and the National Comprehensive Cancer Network (NCCN) have presented international guidelines on CML molecular approaches, especially those related to BCR::ABL1 expression. In this study, we show almost three years' worth of data regarding the clinical treatment of CML patients at the Erasto Gaertner Hospital, Curitiba, Brazil. These data primarily comprise 155 patients and 532 clinical samples. BCR::ABL1 quantification by a duplex-one-step RT-qPCR and ABL1 mutations detection were conducted. Furthermore, digital PCR for both BCR::ABL1 expression and ABL1 mutations were conducted in a sub-cohort. This manuscript describes and discusses the clinical importance and relevance of molecular biology testing in Brazilian CML patients, demonstrating its cost-effectiveness.

Hilab System Device in an Oncological Hospital: A New Clinical Approach for Point of Care CBC Test, Supported by the Internet of Things and Machine Learning.

The complete blood count (CBC) is a highly requested test that is generally restricted to centralized laboratories, which are limited by high cost, being maintenance-demanding, and requiring costly equipment. The Hilab System (HS) is a small, handheld hematological platform that uses microscopy and chromatography techniques, combined with machine learning (ML) and artificial intelligence (AI), to perform a CBC test. This platform uses ML and AI techniques to add higher accuracy and reliability to the results besides allowing for faster reporting. For clinical and flagging capability evaluation of the handheld device, the study analyzed 550 blood samples of patients from a reference institution for oncological diseases. The clinical analysis encompassed the data comparison between the Hilab System and a conventional hematological analyzer (Sysmex XE-2100) for all CBC analytes. The flagging capability study compared the microscopic findings from the Hilab System and the standard blood smear evaluation method. The study also assessed the sample collection source (venous or capillary) influences. The Pearson correlation, Student t-test, Bland-Altman, and Passing-Bablok plot of analytes were calculated and are shown. Data from both methodologies were similar (p > 0.05; r ≥ 0.9 for most parameters) for all CBC analytes and flagging parameters. Venous and capillary samples did not differ statistically (p > 0.05). The study indicates that the Hilab System provides humanized blood collection associated with fast and accurate data, essential features for patient wellbeing and quick physician decision making.

Genomic analysis of two phlebotomine sand fly vectors of Leishmania from the New and Old World.

Phlebotomine sand flies are of global significance as important vectors of human disease, transmitting bacterial, viral, and protozoan pathogens, including the kinetoplastid parasites of the genus Leishmania, the causative agents of devastating diseases collectively termed leishmaniasis. More than 40 pathogenic Leishmania species are transmitted to humans by approximately 35 sand fly species in 98 countries with hundreds of millions of people at risk around the world. No approved efficacious vaccine exists for leishmaniasis and available therapeutic drugs are either toxic and/or expensive, or the parasites are becoming resistant to the more recently developed drugs. Therefore, sand fly and/or reservoir control are currently the most effective strategies to break transmission. To better understand the biology of sand flies, including the mechanisms involved in their vectorial capacity, insecticide resistance, and population structures we sequenced the genomes of two geographically widespread and important sand fly vector species: Phlebotomus papatasi, a vector of Leishmania parasites that cause cutaneous leishmaniasis, (distributed in Europe, the Middle East and North Africa) and Lutzomyia longipalpis, a vector of Leishmania parasites that cause visceral leishmaniasis (distributed across Central and South America). We categorized and curated genes involved in processes important to their roles as disease vectors, including chemosensation, blood feeding, circadian rhythm, immunity, and detoxification, as well as mobile genetic elements. We also defined gene orthology and observed micro-synteny among the genomes. Finally, we present the genetic diversity and population structure of these species in their respective geographical areas. These genomes will be a foundation on which to base future efforts to prevent vector-borne transmission of Leishmania parasites.

Brazilian experience with caplacizumab in acquired thrombotic thrombocytopenic purpura: outcomes of the expanded access program.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare disease with an acute and severe clinical presentation. The anti-von Willebrand factor caplacizumab was licensed for adults with aTTP based on prospective controlled trials. However, until now, there was no Brazilian experience with this new treatment modality. This retrospective, multicenter, single-arm, expanded access program (EAP) with caplacizumab, plasma exchange (PEX), and immunosuppression was conducted between 02/24/21 and 04/14/21, and enrolled 5 Brazilian patients with aTTP. EAP allowed access to caplacizumab in Brazil and real-world data was collected, at a time when the medication was not commercially available in Brazil. The median age was 31 years old, most patients were women (80%), and neurological manifestation was observed in 80% of cases. The median of laboratory tests was hemoglobin (Hb) of 11 g/dL, platelets (16.1 × 109/L), lactic dehydrogenase (LDH) of 1471 U/L, creatinine (0.7 mg/dL), ADAMTS13 activity lower than 0.71%, and PLASMIC score of 6. All patients received immunosuppression, PEX, and caplacizumab. Until clinical response was achieved, the median was 3 sessions of PEX and 3 days of treatment. The median time of caplacizumab use was 35 days, with platelet normalization in 2 days after starting the drug. The median total length of stay was 8 days. All patients achieved clinical response and clinical remission, with a good safety profile. There was rapid clinical response, few PEX sessions were necessary, and there were short hospital stay, absence of refractoriness, little exacerbation, no death, and resolution of signs and symptoms at diagnosis.

Impact of baseline abnormal liver enzymes in the outcome of COVID-19 infection.

Background: Little is known about the significance of liver function tests (LFT) abnormalities in COVID-19 and their impact on disease outcomes. The aims of the study were to evaluate abnormalities of LFT in patients with COVID-19 and their impact on disease severity, mortality, and correlation with leukocyte markers of inflammation. Methods: All patients with COVID-19 admitted to the emergency department (ED) of a single reference center were retrospectively evaluated. Data were collected using an electronic medical database covering the following variables: demographics, baseline complete blood count (CBC) and ratios, neutrophil-lymphocyte (NLR) and monocyte-lymphocyte ratios (MLR), systemic immune-inflammation index (SII), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Disease severity was defined by the presence of organ failure (OF) or requirement for intensive care unit (ICU) support. Mortality was considered as patient death during hospitalization. Results: A total of 1,539 subjects (799 women, mean age 57±18 years) with COVID-19 were evaluated. Abnormal AST and/or ALT were seen in 50% of them, with a frequency and magnitude that significantly correlated with leukocyte count and ratios. Both LFT were significantly associated with requirement for hospital and ICU admission and mortality. High AST levels were significantly associated with the presence, number, and types of OFs and in-hospital length of stay (LOS). Elevated ALT was also significantly associated with the aforementioned variables, with the exception of OFs presence, circulatory failure and LOS. Conclusions: LFT abnormalities are frequently seen in COVID-19 patients, reflect SARS-CoV-2 associated inflammation and may predict adverse outcomes. LFT may be useful to aid decision-making in the ED for hospital admission or scheduled outpatient reevaluation.

Intelligent Control with Artificial Neural Networks for Automated Insulin Delivery Systems.

Type 1 diabetes mellitus is a disease that affects millions of people around the world. Recent progress in embedded devices has allowed the development of artificial pancreas that can pump insulin subcutaneously to automatically regulate blood glucose levels in diabetic patients. In this work, a Lyapunov-based intelligent controller using artificial neural networks is proposed for application in automated insulin delivery systems. The adoption of an adaptive radial basis function network within the control scheme allows regulation of blood glucose levels without the need for a dynamic model of the system. The proposed model-free approach does not require the patient to inform when they are going to have a meal and is able to deal with inter- and intrapatient variability. To ensure safe operating conditions, the stability of the control law is rigorously addressed through a Lyapunov-like analysis. In silico analysis using virtual patients are provided to demonstrate the effectiveness of the proposed control scheme, showing its ability to maintain normoglycemia in patients with type 1 diabetes mellitus. Three different scenarios were considered: one long- and two short-term simulation studies. In the short-term analyses, 20 virtual patients were simulated for a period of 7 days, with and without prior basal therapy, while in the long-term simulation, 1 virtual patient was assessed over 63 days. The results show that the proposed approach was able to guarantee a time in the range above 95% for the target glycemia in all scenarios studied, which is in fact well above the desirable 70%. Even in the long-term analysis, the intelligent control scheme was able to keep blood glucose metrics within clinical care standards: mean blood glucose of 119.59 mg/dL with standard deviation of 32.02 mg/dL and coefficient of variation of 26.78%, all below the respective reference values.

Leukocyte ratios are useful early predictors for adverse outcomes of COVID-19 infection.

Leukocyte biomarkers, including the neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte-(MLR), platelet-to-lymphocyte (PLR) ratios and systemic immune-inflammation index (SII) have been associated with severity and mortality of patients with COVID-19. The purpose of this study was to evaluate the association of baseline leukocyte biomarkers calculated in the emergency department (ED) with the disease severity and mortality. This was a retrospective cohort study that evaluated 1,535 (mean age 57+18 years) patients with SARS-CoV-2 infection in the ED of a single reference center. Outcomes were severity, defined as intensive care unit (ICU) admission requirement, and in-hospital mortality. All leukocyte biomarkers were calculated in the ED before the hospital admission. Their ability to predict the severity and mortality was measured using receiver operating characteristic (ROC) curves. Severity and mortality were observed in 30.9% and 12.6% of the patients, respectively, and were significantly correlated with NLR, MLR, PLR and SII, but only NLR was independently associated with both outcomes on multivariate analysis. Analysis of ROC curves revealed that NLR (0.78 for severity and 0.80 for mortality) and SII (0.77 for severity and 0.75 for mortality) had the best ability to predict mortality, when compared to other ratios. The highest AUC was observed for NLR, employing cut-off points of 5.4 for severity and 5.5 for mortality. Leukocyte biomarkers, particularly NLR, are capable of predicting the severity and mortality of patients with SARS-CoV-2 infection and could be important adjunct tools to identify patients in the ED that are more prone to develop adverse outcomes.

A Pilot Randomized Controlled Clinical Trial Comparing Piezo Versus Conventional Rotary Surgery for Removal of Impacted Mandibular Third Molars.

BACKGROUND: The extraction of impacted mandibular third molars is a frequent dental surgery, interfering with patients' quality of life. Ultrasonic surgery is an alternative to osteotomy with conventional rotary instruments. This study compares postoperative signals and symptoms after extracting impacted mandibular third molars using ultrasonic surgery or conventional rotary osteotomy. METHODS: A pilot randomized controlled clinical trial was conducted. Thirty patients were randomly divided into the test group (ultrasonic technique) and a control group (conventional rotatory technique). All surgeries were timed. Swelling parameters, trismus and paraesthesia were evaluated on the day of surgery and the third, fifth and seventh postoperative days. Intraoperative bleeding was evaluated during surgery. Postoperative pain was evaluated daily by the patient through a visual analogue scale and the number of ingested analgesics. RESULTS: Pain, swelling and trismus present beneficial results with the ultrasonic technique but without statistical significance. Intraoperative bleeding was significantly lower with ultrasonic surgery (t(28) = 3.258; p = 0.003). Operating time was significantly higher in extractions involving osteotomy and cutting crown and roots either with the conventional technique (p = 0.020) or ultrasonic technique (p = 0.039). Regardless of the surgical difficulty, no statistically significant results were detected between techniques regarding the procedure duration. CONCLUSIONS: The beneficial postoperative signs and symptoms make ultrasonic surgery a favourable therapeutic option, especially when the integrity of noble anatomical structures is the most important risk factor. Further studies with larger samples are needed to support the use of piezosurgery as a valid option for impacted mandibular third molar extraction.

Hilab system, a new point-of-care hematology analyzer supported by the Internet of Things and Artificial Intelligence.

The complete blood count (CBC) is one of the most requested tests by physicians. CBC tests, most realized in conventional hematological analyzers, are restricted to centralized laboratories due to frequent maintenance, large devices, and expensive costs required. On the other hand, most handheld CBC devices commercially available show high prices and are not liable to calibration or control procedures, which results in poor quality compared to standard hematology instruments. The Hilab system is a small-handed hematological platform that uses microscopy and chromatography techniques for blood cells and hematimetric parameters analysis through artificial intelligence, machine learning, and deep learning techniques. For clinical evaluation of the handheld CBC device, 450 blood samples were analyzed. The samples encompassed normal (82%) and pathological conditions (18%), such as thalassemias (2.2%), anemias (6.6%), and infections (9.2%). For all analytes, accuracy, precision, method comparison, and flagging capabilities of the Hilab System, were compared with the Sysmex XE-2100 (Sysmex, Japan) results. The sample source (venous and capillary) influences were also evaluated. Pearson correlation, Student t test, bias, and the Bland-Altman plot of each blood count analyte were calculated and shown. The significance level was set at p ≤ 0.05. For clinical evaluation, Hilab System and the Sysmex XE-2100 showed a strong correlation (r ≥ 0.9) for most evaluated parameters. In the precision study, analytes showed CV inside the limits established according to European Federation of Clinical Chemistry and Laboratory Medicine guidelines. The flagging capabilities of the Hilab system, compared to the manual microscopy technique, presented high sensibility, specificity, and accuracy. Venous and capillary samples (p > 0.05) do not differ statistically. Considering the need for point-of-care CBCs, the study indicated that the Hilab system provides fast, accurate, low cost, and robust analysis for reliable clinical use.

Complete mitochondrial genome of the greater round-eared bat, Tonatia bidens (Chiroptera: Phyllostomidae) from Brazil and phylogenetic relationships within the family.

The greater round-eared bat, Tonatia bidens, is a locally rare species belonging to the highly diverse family Phyllostomidae. In this study, the complete mitogenome of T. bidens was sequenced using optimized protocols of DNA extraction from fixed cells originally prepared for cytogenetic studies. Here we present the complete mitogenome and place our results in a phylogenetic context with other data generated for the family Phyllostomidae. The circular genome had 16,717 bp in size, comprising 37 genes and GC content of 42.24%. Furthermore, the phylogenetic tree indicated a well-supported relationship between the representatives of Tonatia into the subfamily Phyllostominae.

Leukocyte ratios are useful early predictors for adverse outcomes of COVID-19 infection

ABSTRACT Leukocyte biomarkers, including the neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte-(MLR), platelet-to-lymphocyte (PLR) ratios and systemic immune-inflammation index (SII) have been associated with severity and mortality of patients with COVID-19. The purpose of this study was to evaluate the association of baseline leukocyte biomarkers calculated in the emergency department (ED) with the disease severity and mortality. This was a retrospective cohort study that evaluated 1,535 (mean age 57+18 years) patients with SARS-CoV-2 infection in the ED of a single reference center. Outcomes were severity, defined as intensive care unit (ICU) admission requirement, and in-hospital mortality. All leukocyte biomarkers were calculated in the ED before the hospital admission. Their ability to predict the severity and mortality was measured using receiver operating characteristic (ROC) curves. Severity and mortality were observed in 30.9% and 12.6% of the patients, respectively, and were significantly correlated with NLR, MLR, PLR and SII, but only NLR was independently associated with both outcomes on multivariate analysis. Analysis of ROC curves revealed that NLR (0.78 for severity and 0.80 for mortality) and SII (0.77 for severity and 0.75 for mortality) had the best ability to predict mortality, when compared to other ratios. The highest AUC was observed for NLR, employing cut-off points of 5.4 for severity and 5.5 for mortality. Leukocyte biomarkers, particularly NLR, are capable of predicting the severity and mortality of patients with SARS-CoV-2 infection and could be important adjunct tools to identify patients in the ED that are more prone to develop adverse outcomes.

Avaliação audiológica em pacientes com hepatite C crônica tratados por antivirais de ação direta / Audiological evaluation in patients with chronic hepatitis C treated by direct-action antivirals

RESUMO Objetivo Verificar se o tratamento com os antivirais de ação direta para a hepatite C provocam efeitos adversos na audição. Métodos A casuística foi composta por 16 indivíduos portadores do vírus da hepatite C, de ambos os gêneros, com média de idade de 51 anos. Foram excluídos do grupo indivíduos com perda auditiva do tipo condutiva ou mista e que apresentassem fatores de risco para perda auditiva. A avaliação foi realizada em dois momentos: antes do uso dos antivirais de ação direta e após o término do tratamento de três meses. Incluiu os seguintes procedimentos: anamnese, inspeção do meato acústico externo, audiometria tonal liminar, limiar de recepção de fala, índice de reconhecimento de fala, medidas de imitância acústica e emissões otoacústicas evocadas por estímulo transiente e produto de distorção. Resultados: Houve baixa ocorrência de zumbido e vertigem. Não houve diferença estatisticamente significativa entre os resultados da avaliação pré-tratamento e pós-tratamento. Conclusão O tratamento com antivirais de ação direta contra o vírus da hepatite C não provocou efeitos adversos na função auditiva.

ABSTRACT Purpose To verify whether treatment with hepatitis C direct-acting antivirals has adverse effects on hearing. Methods The sample consisted of 16 individuals with hepatitis C virus, of both sexes, with an average age of 51 years. Individuals with conductive or mixed hearing loss who presented risk factors for hearing loss were excluded from the group. The evaluation was carried out in two moments: before the use of direct-acting antivirals and after the three-month treatment. It included the following procedures: anamnesis, external auditory canal inspection, pure tone audiometry, speech reception threshold, speech recognition index, acoustic immittance measures and transient and distortion product otoacoustic emissions. Results There was a low incidence of tinnitus and vertigo. There was no statistically significant difference between the results of the pre- and post-treatment assessment. Conclusion The treatment with direct-acting antivirals against the hepatitis C virus did not cause any adverse effects on hearing function.

Efficacy and Safety Associated With Immune Checkpoint Inhibitors in Unresectable Hepatocellular Carcinoma: A Meta-analysis.

Importance: Immune checkpoint inhibitors (ICIs) have yielded conflicting results in hepatocellular carcinoma (HCC). The overall effect of ICIs compared with standard therapies in unresectable HCC requires more research. Objective: To estimate the efficacy and safety associated with ICIs compared with standard therapies in patients with unresectable HCC. Data Sources: PubMed, Cochrane Library, Web of Science, Latin American and Caribbean Health Sciences Literature, and American Society of Clinical Oncology and European Society of Medical Oncology meeting proceedings were systematically searched. Reference lists from studies selected by electronic searching were manually searched to identify additional relevant studies. The search included literature published or presented from February 2010 to February 2020. Study Selection: From December 2019 to February 2020, independent reviewers evaluated each database, scanning the title, abstract, and keywords of every record retrieved. Full articles were further assessed if the information given suggested that the study was a randomized clinical trial (RCT) comparing ICIs vs standard therapies in the treatment of unresectable HCC. Data Extraction and Synthesis: The full text of the resulting studies and extracted data were reviewed independently according to PRISMA guidelines. Summary hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were calculated by a random-effects model. The likelihood of ICIs being associated with overall response rate (ORR) and treatment-related adverse events (TRAEs) was expressed by odds ratios (ORs) using a random-effects model. Main Outcomes and Measures: The main outcomes were OS, PFS, ORR, and TRAEs. Results: Of 1836 studies yielded by the search, 3 were retained, totaling 1657 patients (985 treated with ICIs vs 672 receiving standard treatment). Two studies evaluated ICIs as monotherapy, and 1 study investigated the combination of ICIs with bevacizumab. Compared with standard therapies (sorafenib in first-line therapy or placebo in second-line therapy), ICIs were associated with significantly improved OS (HR, 0.75; 95% CI, 0.62-0.92; P = .006), PFS (HR, 0.74; 95% CI, 0.56-0.97; P = .03), and ORR (OR, 2.82; 95% CI 2.02-3.93; P < .001). The probability of grade 3 or 4 TRAEs was lower with ICIs than with sorafenib (OR, 0.44; 95% CI, 0.20-0.96; P = .04). Conclusions and Relevance: This meta-analysis found superior efficacy and safety associated with ICIs compared with standard therapies and highlights the survival benefit associated with the combination of antiangiogenic therapy with ICIs in first-line systemic therapy of unresectable HCC.

Emerging and Experimental Agents for Anal Cancer: What is New?

Squamous cell carcinoma of the anal canal (SCCA) is an HPV-related malignancy with rising incidence in the past few decades in the US, characterized by high rates of complete response to chemoradiotherapy with curative intent. However, in a long-term follow-up, a meaningful subgroup of patients with locally advanced disease presents disease recurrence, which demands treatments with high morbidity and important impact in the quality of life. In metastatic or unresectable disease, palliative chemotherapy is the standard of care, but it is still associated with a dismal prognosis. Novel agents are urgently needed in the systemic therapy of SCCA. From a translational standpoint, there are many hurdles to overcome, since PI3KCA mutation is the most frequent genetic abnormality and actionable mutations are rarely found in SCCA, as well as it is characterized by low tumor mutational burden and low rates of high-frequency microsatellite instability. But the latest studies of immunotherapeutic approaches have produced promising findings and this therapeutic strategy is the major path being followed in the ongoing clinical trials. The latest advances in the systemic therapy of SCCA have provided the framework for the conception of new clinical trials. Therefore, carboplatin plus paclitaxel have become the backbone for novel agents. Immune checkpoint inhibitors (ICIs), mainly anti-PD-1 monoclonal antibodies, such as retifanlimab, nivolumab, and atezolizumab have been studied in Phase III trials with chemotherapy in first-line therapy. Likewise, ICIs have been evaluated in locally advanced and refractory disease. Novel technologies, such as bispecific antibodies, and immunotherapeutic approaches, such as vaccines and adoptive T-cell therapies, have also been tested in ongoing clinical trials. Immunotherapy may bring practice-changing advances in the systemic therapy of SCCA in the next few years and it might play a larger role in the therapeutic management of this challenging disease.

Chromosome Painting in Lonchorhina aurita Sheds Light onto the Controversial Phylogenetic Position of Sword-Nosed Bats (Chiroptera, Phyllostomidae).

The subfamily Lonchorhininae encompasses 6 species of sword-nosed bats (Lonchorhina) and is one of the most problematic lineages in the Neotropical leaf-nosed bats (Phyllostomidae) phylogeny. There are at least 5 different hypotheses to explain when the subfamily diverged from the remaining phyllostomids, but none with robust statistical support. Here, we generated a chromosome painting homology map of Lonchorhina aurita karyotype (2n = 32 and FN = 60) using whole-chromosome probes of Macrotus californicus (MCA; 2n = 40 and FN = 60). We placed the karyotype changes of L. aurita in a phylogenetic context to discuss the most likely branching position of Lonchorhininae based on karyotypic evolution. We show that L. aurita has a derived karyotype with 24 segments homologous to the 20 MCA chromosomes used as probes. Comparative analyses between 7 published painted bats species across 4 phyllostomid subfamilies (Macrotinae, Phyllostominae, Glossophaginae, and Lonchophyllinae) revealed that one inversion (MCA 4inv) and one fusion (MCA 17 + 18) are shared derived features between the karyotypes of L. aurita and species of Phyllostominae not yet observed in other bats. Our data show that chromosomal homology maps may contribute with new insights into a long-standing phylogenetic debate that has endured for decades.

PERIPHERAL BLOOD ENDOTOXIN LEVELS ARE NOT ASSOCIATED WITH SMALL INTESTINAL BACTERIAL OVERGROWTH IN NONALCOHOLIC FATTY LIVER DISEASE WITHOUT CIRRHOSIS.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease worldwide. Approximately 20% of individuals with NAFLD develop nonalcoholic steatohepatitis (NASH), which is associated with increased risk of cirrhosis, portal hypertension, and hepatocellular carcinoma. Intestinal microflora, including small intestinal bacterial overgrowth (SIBO), appear to play an important role in the pathogenesis of the disease, as demonstrated in several clinical and experimental studies, by altering intestinal permeability and allowing bacterial endotoxins to enter the circulation. OBJECTIVE: To determine the relationship between SIBO and endotoxin serum levels with clinical, laboratory, and histopathological aspects of NAFLD and the relationship between SIBO and endotoxin serum levels before and after antibiotic therapy. METHODS: Adult patients with a histological diagnosis of NAFLD, without cirrhosis were included. A comprehensive biochemistry panel, lactulose breath test (for diagnosis of SIBO), and serum endotoxin measurement (chromogenic LAL assay) were performed. SIBO was treated with metronidazole 250 mg q8h for 10 days and refractory cases were given ciprofloxacin 500 mg q12h for 10 days. RESULTS: Overall, 42 patients with a histopathological diagnosis of NAFLD were examined. The prevalence of SIBO was 26.2%. Comparison of demographic and biochemical parameters between patients with SIBO and those without SIBO revealed no statistically significant differences, except for use of proton pump inhibitors, which was significantly more frequent in patients with positive breath testing. The presence of SIBO was also associated with greater severity of hepatocellular ballooning on liver biopsy. Although the sample, as a whole, have elevated circulating endotoxin levels, we found no significant differences in this parameter between the groups with and without SIBO. Endotoxin values before and after antibiotic treatment did not differ, even on paired analysis, suggesting absence of any relationship between these factors. Serum endotoxin levels were inversely correlated with HDL levels, and directly correlated with triglyceride levels. CONCLUSION: Serum endotoxin levels did not differ between patients with and without SIBO, nor did these levels change after antibacterial therapy, virtually ruling out the possibility that elevated endotoxinemia in non-cirrhotic patients with NAFLD is associated with SIBO. Presence of SIBO was associated with greater severity of ballooning degeneration on liver biopsy, but not with a significantly higher prevalence of NASH. Additional studies are needed to evaluate the reproducibility and importance of this finding in patients with NAFLD and SIBO.