Network-driven cancer cell avatars for combination discovery and biomarker identification for DNA damage response inhibitors.

Combination therapy is well established as a key intervention strategy for cancer treatment, with the potential to overcome monotherapy resistance and deliver a more durable efficacy. However, given the scale of unexplored potential target space and the resulting combinatorial explosion, identifying efficacious drug combinations is a critical unmet need that is still evolving. In this paper, we demonstrate a network biology-driven, simulation-based solution, the Simulated Cell™. Integration of omics data with a curated signaling network enables the accurate and interpretable prediction of 66,348 combination-cell line pairs obtained from a large-scale combinatorial drug sensitivity screen of 684 combinations across 97 cancer cell lines (BAC = 0.62, AUC = 0.7). We highlight drug combination pairs that interact with DNA Damage Response pathways and are predicted to be synergistic, and deep network insight to identify biomarkers driving combination synergy. We demonstrate that the cancer cell 'avatars' capture the biological complexity of their in vitro counterparts, enabling the identification of pathway-level mechanisms of combination benefit to guide clinical translatability.

Enhancement of novel Endo-polygalacturonase expression in Rhodotorula mucilaginosa PY18: insights from mutagenesis and molecular docking.

Pectinase is a particular type of enzyme that can break down pectin compounds and is extensively utilised in the agricultural field. In this study, twenty yeast isolates were isolated and assayed for pectinase activity. Molecular identification by PCR amplification and sequencing of internal transcribed spacer (ITS) regions of isolate no. 18 had the highest pectinase activity of 46.35 U/mg, was identified as Rhodotorula mucilaginosa PY18, and was submitted under accession no. (OM275426) in NCBI. Rhodotorula mucilaginosa PY18 was further enhanced through sequential mutagenesis, resulting in a mutant designated as Rhodotorula mucilaginosa E54 with a specific activity of 114.2 U/mg. Using Response Surface Methodology (RSM), the best culture conditions for the pectinase-producing yeast mutant Rhodotorula mucilaginosa E54 were pH 5, 72-h incubation, 2.5% xylose, and 2.5% malt extract, with a pectinase-specific activity of 156.55 U/mg. Then, the obtained sequences of the endo-polygalacturonase PGI gene from Rhodotorula mucilaginosa PY18 and mutant Rhodotorula mucilaginosa E54 were isolated for the first time, sequenced, and submitted to NCBI accession numbers OQ283005 and OQ283006, respectively. The modelled 3D structure of the endo-PGI enzyme (485 residues) was validated using Ramachandran's plot, which showed 87.71, 85.56, and 91.57% in the most favourable region for template Rhodotorula mucilaginosa KR, strain Rhodotorula mucilaginosa PY18, and mutant Rhodotorula mucilaginosa E54, respectively. In molecular docking studies, the results of template Rhodotorula mucilaginosa KR endo-PG1 showed an interaction with an affinity score of - 6.0, - 5.9, and - 5.6 kcal/mol for active sites 1, 2, and 3, respectively. Rhodotorula mucilaginosa PY18 endo-PG1 showed an interaction affinity with a score of - 5.8, - 6.0, and - 5.0 kcal/mol for active sites 1, 2, and 3, respectively. Mutant Rhodotorula mucilaginosa E54 endo-PG1 showed an interaction affinity of - 5.6, - 5.5, - 5.5 and - 5.4 kcal/mol for active sites 1, 2, and 3, respectively. The endo-PGI genes of both the yeast strain Rhodotorula mucilaginosa PY18 and mutant Rhodotorula mucilaginosa E54 were successfully cloned and expressed in E. coli DH5α, showing significantly higher endo-PG1 activity, which recorded 94.57 and 153.10 U/mg for recombinant Rhodotorula mucilaginosa pGEM-PGI-PY18 and recombinant mutant Rhotorula pGEM-PGI-E54, respectively.

The relationship between neural phase entrainment and statistical word-learning: A scoping review.

Statistical language-learning, the capacity to extract regularities from a continuous speech stream, arguably involves the ability to segment the stream before the discrete constituents can be stored in memory. According to recent accounts, the segmentation process is reflected in the alignment of neural activity to the statistical structure embedded in the input. However, the degree to which it can predict the subsequent leaning outcome is currently unclear. As this is a relatively new avenue of research on statistical learning, a scoping review approach was adopted to identify and explore the current body of evidence on the use of neural phase entrainment as a measure of online neural statistical language-learning and its relation to the learning outcome, as well as the design characteristics of these studies. All included studies (11) observed entrainment to the underlying statistical pattern with exposure to the structured speech stream. A significant association between entrainment and learning outcome was observed in six of the studies. We discuss these findings in light of what neural entrainment in statistical word-learning experiments might represent, and speculate that it might reflect a general auditory processing mechanism, rather than segmentation of the speech stream per se. Lastly, as we find the current selection of studies to provide inconclusive evidence for neural entrainment's role in statistical learning, future research avenues are proposed.

Structure prediction, docking studies and molecular cloning of novel Pichia kudriavzevii YK46 metalloprotease (MetPr) for improvement of feather waste biodegradation.

This study addresses the environmental risks associated with the accumulation of keratin waste from poultry, which is resistant to conventional protein degradation methods. To tackle this issue, microbial keratinases have emerged as promising tools for transforming resilient keratin materials into valuable products. We focus on the Metalloprotease (MetPr) gene isolated from novel Pichia kudriavzevii YK46, sequenced, and deposited in the NCBI GenBank database with the accession number OQ511281. The MetPr gene encodes a protein consisting of 557 amino acids and demonstrates a keratinase activity of 164.04 U/ml. The 3D structure of the protein was validated using Ramachandran's plot, revealing that 93% and 97.26% of the 557 residues were situated within the most favoured region for the MetPr proteins of template Pichia kudriavzevii strain 129 and Pichia kudriavzevii YK46, respectively. Computational analyses were employed to determine the binding affinities between the deduced protein and beta keratin. Molecular docking studies elucidated the optimal binding affinities between the metalloprotease (MetPr) and beta-keratin, yielding values of - 260.75 kcal/mol and - 257.02 kcal/mol for the template strains Pichia kudriavzevii strain 129 and Pichia kudriavzevii YK46, respectively. Subsequent molecular cloning and expression of the MetPr gene in E. coli DH5α led to a significantly higher keratinase activity of 281 ± 12.34 U/ml. These findings provide valuable insights into the potential of the MetPr gene and its encoded protein for keratin waste biotransformation, with implications for addressing environmental concerns related to keratinous waste accumulation.

Pilot study on the effect of supplementation with long-chain ω-3 polyunsaturated fatty acids on body composition in children with acute lymphoblastic leukemia: randomized clinical trial.

BACKGROUND: N-3 polyunsaturated fatty acids (LCPUFA-ω3), particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) might have beneficial effects on lean mass and fat mass synthesis. OBJECTIVE: To investigate the effect of LCPUFA-ω3 supplementation on body composition changes in children with acute lymphoblastic leukemia (ALL) at remission and three months (3 mo) after supplementation. METHODS: This randomized controlled trial enrolled 72 children (3-13 y) with newly diagnosed ALL (placebo group [500 mg sunflower oil]: 36 patients; LCPUFA-ω3 group [225 mg DHA, 45 mg EPA]: 36 patients). LCPUFA-ω3 was administered at 0.100 g/kg of body weight/day for 3 mo. Both groups were provided with an oral milkshake supplement. MAIN OUTCOMES AND MEASURES: Body composition was measured at diagnosis, remission, and 3 months after supplementation by dual-energy X-ray absorptiometry (DXA). Red blood cell fatty acid analyses were performed with gas chromatography. Student's t test compared the percentage changes in body weight, total body fat percentage (TBFP), and lean body mass (LBM) between the groups. The Mann-Whitney U test was used to compare the groups, and the Friedman range test and Wilcoxon signed rank test were used for intratreatment comparisons. Spearman correlation coefficients were calculated for LBM and erythrocyte LCPUFA-ω3 content. RESULTS: LBM decreased significantly in both groups. This loss was greater in the placebo group than in the LCPUFA-ω3 group at remission (p = 0.044) and at 3 months of supplementation (p = 0.039). There were significant and progressive increases in DHA and EPA concentrations in the LCPUFA-ω3 group (p < 0.001). LBM at remission was directly correlated with increased DHA (r = 0.487, p = 0.034) and EPA (r = 0.499, p = 0.030) erythrocytes in the LCPUFA-ω3 group. CONCLUSION: At ALL diagnosis and during the first three months of treatment, 100 mg/kg of body weight/d DHA and EPA decreased LBM loss and allowed the incorporation of fatty acids into cell membranes (clinicaltriasl.gov #: NCT01051154).

Leiomyoma of the Thumb Mimicking a Ganglion: A Case Report.

Our case report describes the presence of a leiomyoma in the left-hand thumb of a 69-year-old woman, an extremely uncommon location for such a tumor. Leiomyomas are typically benign tumors that arise from smooth muscle, but their occurrence in the hand is unusual. While leiomyomas are more commonly found in the uterus, they may occasionally develop in the extremities, though this is more frequently observed in the lower limbs. These tumors typically present in patients in their third to fourth decades of life, and they are often not diagnosed until surgery because histological pathology is necessary to confirm the diagnosis.

Effect of long-chain omega-3 polyunsaturated fatty acids on cardiometabolic factors in children with acute lymphoblastic leukemia undergoing treatment: a secondary analysis of a randomized controlled trial.

Introduction: Increased triglycerides (TGs) are a major risk factor for cardiovascular disease. Furthermore, hypertriglyceridemia is commonly associated with a reduction of high-density lipoprotein cholesterol (HDL-C) and an increase in atherogenic small-dense low-density lipoprotein (LDL-C) levels. Studies provide support that polyunsaturated omega-3 fatty acids (ω3-LCPUFAs) are cardioprotective and have antithrombotic and anti-inflammatory effects. The potential effects of ω3-LCPUFAs on cardiometabolic factors and anti-inflammatory actions in children with acute lymphoblastic leukemia (ALL) are limited. This is a secondary analysis of a previous clinical trial registered at clinical trials.gov (# NCT01051154) that was conducted to analyze the effect of ω3-LCPUFAs in pediatric patients with ALL who were receiving treatment.Objective: To examine the effect of supplementation with ω3-LCPUFAs on cardiometabolic factors in children with ALL undergoing treatment. Methods: Thirty-four children (placebo group: 20 patients; ω3-LCPUFAs group: 14 patients) aged 6.7 ± 2.7 years who were newly diagnosed with ALL were evaluated. Children were randomized to receive either ω3-LCPUFAs or placebo capsules (sunflower oil). ω3-LCPUFAs were administered in the form of 500-mg soft capsules. The ω3-LCPUFA capsules contained 225 mg of DHA, 45 mg of EPA, and 20 mg of another ω3-LCPUFAs. The omega-3 dose was administered at a rate of 0.100 g/kg of body weight/day for three months. Main outcomes: Fasting cholesterol, HDL-C, very-low-density lipoprotein (VLDL-C), TGs, atherogenic index of plasma (AIP), android/gynoid ratio (A/GR), IL-6, TNF-α, and percentage of fat mass (DXA) were measured in all patients. Fatty acid analyses in red blood cells were performed with gas chromatography. Results: We found significantly lower levels of TGs (p=0.043), VLDL-C (p=0.039), IL-6 (p=0.025), and AIP (p=0.042) in the ω3-LCPUFAs group than in the placebo group at three months. In contrast, the total cholesterol concentration was higher at 3 months in the ω3-LCPUFAs group than in the placebo group (155 mg/dl vs. 129 mg/dl, p=0.009). The number of children with hypertriglyceridemia (85% vs. 50%; p=0.054) tended to be lower between the time of diagnosis and after 3 months of supplementation with ω3-LCPUFAs. Conclusion: These findings support the use of ω3-LCPUFAs to reduce some adverse cardiometabolic and inflammatory risk factors in children with ALL. Clinical trial registration: ClinicalTrials.gov, identifier NCT01051154.

Heterogeneous Catalysts for Glycerol Biorefineries: Hydrogenolysis to 1,2-Propylene Glycol.

Research on the use of biomass resources for the generation of energy and chemical compounds is of great interest worldwide. The development and growth of the biodiesel industry has led to a parallel market for the supply of glycerol, its main by-product. Its wide availability and relatively low cost as a raw material make glycerol a basic component for obtaining various chemical products and allows for the development of a biorefinery around biodiesel plants, through the technological integration of different production processes. This work proposes a review of one of the reactions of interest in the biorefinery environment: the hydrogenolysis of glycerol to 1,2-propylene glycol. The article reviews more than 300 references, covering literature from about 20 years, focusing on the heterogeneous catalysts used for the production of glycol. In this sense, from about 175 catalysts, between bulk and supported ones, were revised and discussed critically, based on noble metals, such as Ru, Pt, Pd, and non-noble metals as Cu, Ni, Co, both in liquid (2-10 MPa, 120-260 °C) and vapor phase (0.1 MPa, 200-300 °C). Then, the effect of the main operational and decision variables, such as temperature, pressure, catalyst/glycerol mass ratio, space velocity, and H2 flow, are discussed, depending on the reactors employed. Finally, the formulation of several kinetic models and stability studies are presented, discussing the main deactivation mechanisms of the catalytic systems such as coking, leaching, and sintering, and the presence of impurities in the glycerol feed. It is expected that this work will serve as a tool for the development of more efficient catalytic materials and processes towards the future projection of glycerol biorefineries.

New drug-like small molecule antagonizes phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in patients with conotruncal heart defects.

Objectives: Conotruncal heart defects (CTDs) are highly heritable, and approximately one-third of all congenital heart defects are due to CTDs. Through post-analysis of GWAS data relevant to CTDs, a new putative signal transduction pathway, called Vars2-Pic3ca-Akt, associated with CTD has been hypothesized. Here, we aimed to validate the Vars2-Pic3ca-Akt pathway experimentally by measuring Vars2 and PIP3 in patients with CTDs and controls, and to construct a PIP3 inhibitor, as one of harmful-relevant CTD pathogenesis, through an Akt-based drug design strategy. Methods: rs2517582 genotype and relative Vars2 expression in 207 individuals were determined by DNA sequencing and qPCR respectively, and free plasma PIP3 in 190 individuals was quantified through ELISA. An Akt-pharmacophore feature model was used to discover PIP3 antagonists with multiple computational and drug-like estimation tools. Results: CTD pathogenesis due to Vars2-Pic3ca-Akt overstimulation was confirmed by elevated Vars2 and PIP3 in patients with CTDs. We identified a new small molecule, 322PESB, that antagonizes PIP3 binding. This molecule was prioritized via virtual screening of 21 hypothetical small molecules and it showed minimal RMSD change, high binding affinity andlower dissociation constant than PIP3-Akt complex by 1.99 Kcal/Mol, thus resulting in an equilibrium shift toward 322PESB-Akt complex formation. Moreover, 322PESB exhibited acceptable pharmacokinetics and drug likeness features according to ADME and Lipinski's rule of five classifiers. This compound is the first potential drug-like molecule reported for patients with CTDs with elevated PIP3. Conclusion: PIP3 is a useful diagnostic biomarker for patients with CTDs. The Akt-pharmacophore feature model is a feasible approach for discovery of PIP3 signalling antagonists. Further 322PESB development and testing are recommended.

Modeling and in-vivo evaluation of fibrinolytic enzyme produced by Bacillus subtilis Egy under solid state fermentation.

Blood clot formation increases cases of myocardial infarction (AMI) and stroke, thus urges directing much research works for treatment and prevention of the causes. One of these directions is the microbial production of fibrinolytic enzymes as thrombolytic agents. In the current work, Bacillus subtilis Egy has been used for enzyme production under solid state fermentation. Among twelve nutrient meals in addition to wheat bran as a control fodder yeast yielded the highest enzyme activity reaching 114U/g. Applying statistical model for optimization of enzyme production revealed that 3.6%, fodder yeast; 40%, moisture content; 6 days, incubation period and 2%, inoculum size were the optimum conditions for maximum fibrinolytic enzyme production (141.02 U/g) by Bacillus subtilis Egy under solid-state fermentation The model was significant and data were experimentally validated. The produced fibrinolytic enzyme was evaluated for in vitro and in vivo cytotoxicity. In-vivo examination of the enzyme resulted in no mortality during the first 24 h after treatment. After 14 days, the results revealed no significant changes detected in hematological parameters (RBCs, MCV, hemoglobin except WBCs which showed an increase for both sexes. Histopathological examination of liver and kidney of rats received oral and subcutaneous treatments showed normal architecture. The data showed the applicability of the produced enzyme for the treatment of blood clot with no significant effect on living cells or on physiological functions.

Tibialis Anterior Muscle Hernia in a Young Woman.

Muscle herniation is defined as a myofascial defect resulting in protruding of the muscle through the fascia covering it. It can present anywhere in the body, the most common is the lower limbs. Tibialis muscle herniation is considered a rare entity with few reported cases. Here, we present the case of a 24-year-old Saudi female patient who complained of swelling and pain in the anterior aspect of the left leg for three months. She underwent surgical repair of the fascia with a good outcome. This case presentation aims to contribute to the literature on myofascial herniation by specifically addressing tibialis anterior herniation of the leg and emphasizing the importance of considering it a differential diagnosis in similar presentations. This report highlights the excellent surgical outcomes and satisfactory results in patients with muscle herniation.

The Association of Cone-shaped Epiphysis and Poland Syndrome.

Poland syndrome is a congenital anomaly with two clinical features: unilateral agenesis of the pectoralis major and ipsilateral hand symbrachydactyly. We report a rare case of bilateral Poland syndrome with several unique features. Poland syndrome is thought to be due to a vascular insult to the subclavian axis around the sixth week of gestation. Our patient has multiple rare and unique features of Poland syndrome. For the first time in the literature, we associate Poland syndrome with cone-shaped epiphysis of the metacarpals of all fingers. Bilaterality, cleft hand deformity, and dextrocardia were also rare features in our patient.

Geographical variations and district-level factors associated with COVID-19 mortality in Indonesia: a nationwide ecological study.

BACKGROUND: Ensuring health equity, especially for vulnerable populations in less developed settings with poor health system is essential for the current and future global health threats. This study examined geographical variations of COVID-19 mortality and its association with population health characteristics, health care capacity in responding pandemic, and socio-economic characteristics across 514 districts in Indonesia. METHODS: This nationwide ecological study included aggregated data of COVID-19 cases and deaths from all 514 districts in Indonesia, recorded in the National COVID-19 Task Force database, during the first two years of the epidemic, from 1 March 2020 to 27 February 2022. The dependent variable was district-level COVID-19 mortality rate per 100,000 populations. The independent variables include district-level COVID-19 incidence rate, population health, health care capacity, and socio-demographics data from government official sources. We used multivariable ordinal logistic regression to examine factors associated with higher mortality rate. RESULTS: Of total 5,539,333 reported COVID-19 cases, 148,034 (2.7%) died, and 5,391,299 (97.4%) were recovered. The district-level mortality rate ranged from 0 to 284 deaths per 100,000 populations. The top five districts with the highest mortality rate were Balikpapan (284 deaths per 100,000 populations), Semarang (263), Madiun (254), Magelang (250), and Yogyakarta (247). A higher COVID-19 incidence (coefficient 1.64, 95% CI 1.22 to 1.75), a higher proportion of ≥ 60 years old population (coefficient 0.26, 95% CI 0.06 to 0.46), a higher prevalence of diabetes mellitus (coefficient 0.60, 95% CI 0.37 to 0.84), a lower prevalence of obesity (coefficient -0.32, 95% CI -0.56 to -0.08), a lower number of nurses per population (coefficient -0.27, 95% CI -0.50 to -0.04), a higher number of midwives per population (coefficient 0.32, 95% CI 0.13 to 0.50), and a higher expenditure (coefficient 0.34, 95% CI 0.10 to 0.57) was associated with a higher COVID-19 mortality rate. CONCLUSION: COVID-19 mortality rate in Indonesia was highly heterogeneous and associated with higher COVID-19 incidence, different prevalence of pre-existing comorbidity, healthcare capacity in responding the pandemic, and socio-economic characteristics. This study revealed the need of controlling both COVID-19 and those known comorbidities, health capacity strengthening, and better resource allocation to ensure optimal health outcomes for vulnerable population.

Congenital hairy nevus: A case report of long-term follow-up following curettage of the nevus at the age of 6 hrs.

INTRODUCTION: Management of giant hairy nevi depends on various factors including the size and anatomical area. CASE PRESENTATION: We report a case of a giant hairy nevus treated successfully with curettage at the age of 6 hrs after birth. There was partial recurrence of pigmentation and hair on long-term (10 years) follow-up. DISCUSSION: Although curettage is a known method of treating hairy nevi, long term results are lacking when the nevus is treated in the first few hours after birth. CONCLUSION: Following curettage of hairy nevi in the first few hours after birth, recurrence of pigmentation and hair may still occur on long term follow up.

miR-454-3p and miR-194-5p targeting cardiac sarcolemma ion exchange transcripts are potential noninvasive diagnostic biomarkers for childhood dilated cardiomyopathy in Egyptian patients.

BACKGROUND: Childhood dilated cardiomyopathy (CDCM) is the most common cardiomyopathy in children and it is risk factor to heart failure and sudden death. Most of the different etiologic factors which have been postulated to DCM are idiopathic, and its pathogenesis remains uncertain. So it was worth investigating the potential DCM pathogenicity models to establish early noninvasive diagnosis parameters especially in CDCM patients. Beside that miRNAs in the circulatory blood are genetically considered the best option for noninvasive diagnosis; also, implementation of miRNAs as early diagnostic markers for children with DCM is urgent because those children have high risk to sudden heart death. We aimed to identify discriminator diagnostic circulatory miRNA expression levels in CDCM patients. RESULTS: The expression levels of miR-454-3p and miR-194-5p were found significant upregulated (p value = 0.001 and 0.018; CI 95%, respectively), while miR-875-3p was found significant downregulated (p value = 0.040; CI 95%). A receiver operating characteristic (ROC) curve analysis showed significant AUC = 1.000 and 0.798 for miR-454-3p and miR-194-5p, respectively, and the optimal discriminated diagnostic cut-points were computed by index of union (IU) method. Enrichment analysis for the potential targeted mature mRNAs by miR-454-3p and miR-194-5p pointed that Ca, Na and K ions homeostasis in cardiac sarcolemma consider potential CDCM pathogenicity model. CONCLUSIONS: miR-454-3p and miR-194-5p are highly influencing noninvasive biomarkers for CDCM, and further circulatory miRNAs-implicated studies are highly recommended.

Heterogeneity and district-level factors associated with COVID-19 mortality during three epidemic waves in Indonesia: a nationwide ecological study

IntroductionEnsuring health equity, especially for vulnerable populations in less developed settings with poor health system is essential for the current and future global health threats. This study examined the heterogeneity of COVID-19 mortality and its association with population health characteristics, health care capacity in responding pandemic, and socio-economic characteristics across 514 districts in Indonesia. MethodsThis nationwide ecological study included aggregated COVID-19 cases data from all 514 districts in Indonesia, recorded in the National COVID-19 Task Force database, during the first two years of the epidemic, from 1 March 2020 to 27 February 2022. We calculated incidence and mortality rate by time, sex, and age. We extracted district-level socio-demographics, population health, and health care capacity data from government official sources. We used multivariable linear regression to examine factors associated with higher mortality rate. ResultsOf total 5,539,333 reported cases, 148,034 (2{middle dot}7%) died, and 5,391,299 (97.4%) were recovered. The national mortality rate was 55 per 100,000 population, ranged from 13 per 100,000 population in Papua to 156 per 100,000 population in East Kalimantan province. At district-level, higher mortality rate was associated with higher COVID-19 incidence (p<0.0001), higher proportion of [≥]60 years old population (p<0.0001), higher prevalence of diabetes mellitus (p<0.0001), lower prevalence of obesity (p=0.019), lower number of doctors per population (p=0.001), higher life expectancy at birth (p=0.035), and lower formal education (p=0.021). There was no association between COVID-19 mortality rate with expenditure, prevalence of hypertension and pneumonia, vaccine coverage for [≥]60 years old population, number of nurses, midwives, and hospitals per population (p>0.05 each). ConclusionCOVID-19 mortality rate in Indonesia was highly heterogeneous and associated with different prevalence of pre-existing comorbidity, healthcare capacity in responding the pandemic, and socio-economic characteristics. This study revealed the need of health capacity strengthening and better resource allocation to ensure optimal health outcomes for vulnerable population. What is already known on this topicO_LIThe severity of COVID-19 illness and clinical outcomes can be affected by the concentration of comorbidities in susceptible groups in communities, and through disparities of access to health care for preventive measures or prompt diagnosis and treatment. C_LIO_LIHowever, evidence on the heterogeneity of COVID-19 impact from low- and middle-income country (LMIC) where differences in age distribution, comorbidities, access to quality health services, and other factors, may greatly influence mortality risk, are limited. C_LI What this study addsO_LIThis study affirmed that COVID-19 disproportionately affected areas with high proportion of elder population, high prevalence of diabetes mellitus, lower doctor to population ratio, higher life expectancy at birth, and lower level of formal education. C_LIO_LIThese findings indicate that vulnerability to death associated with COVID-19 in LMIC includes not only elder and comorbid, but also males and communities living in area with lower health care capacity and with lower level of education. C_LI How this study might affect research, practice and/or policyO_LIThese findings may inform decisions on health resource allocation against COVID-19 delivering the greatest possible health dividends by prioritising interventions, including even distribution of essential health care need such as doctors, and a tailored risk communication and community engagement for the most vulnerable communities in LMIC, especially with decentralised health systems like in Indonesia. C_LI

Red blood cell distribution width as a prognostic biomarker for viral infections: prospects and challenges.

Viral diseases remain a significant global health threat, and therefore prioritization of limited healthcare resources is required to effectively manage dangerous viral disease outbreaks. In a pandemic of a newly emerged virus that is yet to be well understood, a noninvasive host-derived prognostic biomarker is invaluable for risk prediction. Red blood cell distribution width (RDW), an index of red blood cell size disorder (anisocytosis), is a potential predictive biomarker for severity of many diseases. In view of the need to prioritize resources during response to outbreaks, this review highlights the prospects and challenges of RDW as a prognostic biomarker for viral infections, with a focus on hepatitis and COVID-19, and provides an outlook to improve the prognostic performance of RDW for risk prediction in viral diseases.

Molecular profiling reveals a hypoxia signature in breast implant-associated anaplastic large cell lymphoma.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently characterized T-cell malignancy that has raised significant patient safety concerns and led to worldwide impact on the implants used and clinical management of patients undergoing reconstructive or cosmetic breast surgery. Molecular signatures distinguishing BIA-ALCL from other ALCLs have not been fully elucidated and classification of BIA-ALCL as a WHO entity remains provisional. We performed RNA sequencing and gene set enrichment analysis comparing BIA-ALCLs to non-BIA-ALCLs and identified dramatic upregulation of hypoxia signaling genes including the hypoxia-associated biomarker CA9 (carbonic anyhydrase-9). Immunohistochemistry validated CA9 expression in all BIA-ALCLs, with only minimal expression in non-BIA-ALCLs. Growth induction in BIA-ALCL-derived cell lines cultured under hypoxic conditions was proportional to up-regulation of CA9 expression, and RNA sequencing demonstrated induction of the same gene signature observed in BIA-ALCL tissue samples compared to non-BIA-ALCLs. CA9 silencing blocked hypoxia-induced BIA-ALCL cell growth and cell cycle-associated gene expression, whereas CA9 overexpression in BIA-ALCL cells promoted growth in a xenograft mouse model. Furthermore, CA9 was secreted into BIA-ALCL cell line supernatants and was markedly elevated in human BIA-ALCL seroma samples. Finally, serum CA9 concentrations in mice bearing BIA-ALCL xenografts were significantly elevated compared to control serum. Together, these findings characterize BIA-ALCL as a hypoxia-associated neoplasm, likely attributable to the unique microenvironment in which it arises. These data support classification of BIA-ALCL as a distinct entity and uncover opportunities for investigating hypoxia-related proteins such as CA9 as novel biomarkers and therapeutic targets in this disease.