Dominant Subtype Research Articles

Prediction of Cytotoxicity Against HepG2 by Quantitative Structure-Activity Relation (QSAR) Modelling

Hepatocellular carcinoma (HCC) is the dominant subtype of liver cancer with very low survival rate but the chemotherapy for HCC is still in grey zone due to the limited efficacy and high toxicity profile of approved drugs raising the heavy demand on drug development for HCC. The study aimed to establish a desirability based quantitative structure activity relation (QSAR) model to predict the activity of chemical compounds against one of HCC cell line (HepG2). Different support vector machine (SVM) models were constructed and ensembled to 10 virtual screening protocols. These protocols were validated by an external dataset in combination with decoys as interference. Results showed that ensemble models exhibited improved area under the Receiver Operating Characteristic Curve (ROC), sensitivity, and specificity compared to base models in training and test set. When being validated for virtual screening to recover known active molecules in the mixture with known inactive and decoy compounds, all virtual screening protocols have good performance with good Boltzmann-Enhanced Discrimination of ROC (BEDROC) and enrichment factor (EF). The best protocol with BEDROC of 0.63 and EF of 29.55 was suitable for further screening of active compounds against HepG2 cell line. HIGHLIGHTS Ensemble quantitative structure-activity relationship (QSAR) models improved the performance of single models Cytotoxicity prediction was transformed to desirability score as a general output for easily integration in multi-objective optimization Virtual models for screening of HepG2 cytotoxicity compounds were well validated GRAPHICAL ABSTRACT

Molecular characterization of Blastocystis subtypes in symptomatic patients from the southern region of Syria.

Blastocystis sp. is an enteric protist found in humans and a wide range of animal hosts. Genetic variations were established among the 38 different subtypes detected so far, 14 of which are commonly found in human and animal hosts. The aim of the present study is to estimate the prevalence of the common Blastocystis subtypes and evaluate the possible correlation with several variables (gender, age, symptoms, domestic animals…), among patients from the southern region of Syria. Fecal samples were collected from individuals suffering from gastrointestinal complaints. Microscopic examination along with genotype analyses using seven pairs of subtype-specific primers was performed. Our results revealed the presence of Blastocystis sp. in 46 isolates out of the 60 samples microscopically studied (76.7%); single infection was detected in 24 isolates whereas co-infection with other protozoa was identified in 22 ones. Molecular detection targeting the SSU rRNA gene revealed a 100% positive presence of Blastocystis sp. in all the samples. Genotyping results detected the presence of five different subtypes (ST1-ST5) with varying proportions. However, ST1 was the dominant subtype observed (66.7%). Mixed subtype infections were found in 9 isolates (15%). Three samples remained undefined, nonetheless. Our statistical results showed no significant correlation between Blastocystis STs infection and the different studied variables. In conclusion, this study provides the first genetic characterization of Blastocystis subtypes prevalence in patients from the southern region of Syria. ST1 distribution was highly predominant. Further molecular studies are needed to estimate the prevalence of Blastocystis sp. infection in other regions in Syria and to understand the epidemiology and sources of transmission to humans.

First identification of Blastocystis sp. subtypes in Rex rabbits in China

Blastocystis sp. is a common protist that colonizes the intestinal tract in both humans and animals worldwide. A total of 666 fecal samples of Rex rabbits were collected from 12 farms in three administrative regions in Henan, China. Blastocystis sp. was screened and subtyped by PCR amplification of the small subunit ribosomal DNA. The results indicated that 31 (4.7%, 31/666) rabbits were positive for Blastocystis sp. across three farms (25.0%, 3/12). The infection rate of Blastocystis sp. in Rex rabbits was highest in Jiyuan at 9.1% (30/331), followed by Luoyang (0.5%, 1/191), with no positive infections found in Zhengzhou. The Blastocystis sp. infection rate in adults (10.2%, 14/287) was higher than that in young rabbits (4.5%, 17/379) (χ2=0.0027, P>0.50). Four Blastocystis sp. subtypes (ST1, ST3, ST4, and ST17) were identified in rabbits in the present study. Among them, the subtypes ST1 (n=15) and ST3 (n=14) were dominant, followed by ST4 (n=1) and ST17 (n=1). Blastocystis sp. ST1 was the dominant subtype in adult rabbits, and ST3 was the dominant subtype in young rabbits. This study enriches the data on the prevalence and subtype distributions of Blastocystis sp. in rabbits. More studies are needed among humans, domestic animals, and wild animals to obtain a better understanding of their role in the spread of Blastocystis sp.

Involvement of beta3-adrenergic receptors in relaxation mediated by nitric oxide in chicken basilar artery

The response of basilar arteries to noradrenaline varies among many animal species, but remains little studied in poultry. Accordingly, we aimed to characterize the adrenergic receptor (AR) subtypes that modulate vascular response in basilar arteries in the chicken, with isometric recording of arterial ring tension using an organ bath. We demonstrated the presence of both alpha and beta (α and β) receptor subtypes through evaluating the response to noradrenaline, with and without a range of β-AR and α-AR antagonists. The concentration-dependent relaxations then induced by a range of β-AR agonists indicated a potency ranking of isoproterenol > noradrenaline > adrenaline > procaterol. We then investigated the effects of β-AR antagonists that attenuate the effect of isoproterenol (propranolol for β1,2,3-ARs, atenolol for β1-ARs, butoxamine for β2-ARs, and SR 59230A for β3-ARs), with Schild regression analysis, ascertaining multiple β-AR subtypes, with neither the β1-AR nor the β2-AR as the dominant subtype. SR 59230A was the only antagonist to yield a pA2 value (7.52) close to the reported equivalent for the relevant receptor subtype. Furthermore, treatment with SR 58611 (a β3-AR agonist) induced relaxation, which was inhibited (P < 0.01) by L-NNA and SR 59230A. Additionally, treating basilar arterial strips (containing endothelium) with SR 58611 induced nitric oxide (NO) production, which was inhibited (P < 0.01) by L-NNA and SR 59230A. Based on this first characterization of AR subtypes in chicken basilar arteries (to our knowledge), we suggest that α- and β-ARs are involved in contraction and relaxation, and that β3-ARs, especially those on the endothelium, may play an important role in vasodilation via NO release.

Status and prognostic value of immunological biomarkers of breast cancer.

The immune response to cancer serves an important role in disease progression and patient prognosis. For triple-negative breast cancer showing aggressive behavior, immunotherapy has a good efficacy because of the potent immunogenicity of this type of cancer. However, the dominant subtype, luminal human epidermal growth factor receptor-2 (HER2)-negative breast cancer, is less immunogenic. To determine whether luminal HER2-negative cancer reacts to the anticancer immune response, the present study analyzed the status and prognostic value of the principal immunological biomarkers of breast cancer, including tumor-infiltrating lymphocytes (TILs), CD8+ T lymphocytes, the major histocompatibility complex and programmed cell death ligand-1 (PD-L1). The biomarkers were compared between patients with luminal HER2-negative breast cancer and those with immunogenic subtypes including triple-negative and HER2-overexpressed breast cancer. A total of 71 patients with primary breast cancer were classified into the immunogenic non-luminal (n=23) and less immunogenic luminal HER2-negative groups (n=48) based on immunogenicity. In the luminal HER2-negative group, compared with patients with low TIL levels, those with high TIL levels were at an advanced stage of cancer (P=0.024) and showed worse relapse-free survival (P=0.057); however, the remaining biomarkers exhibited no association with cancer progression or prognosis. In the non-luminal group, patients with high TIL levels showed significantly better RFS than those with low TIL levels (P=0.014). Compared with non-luminal patients negative for PD-L1, those positive for PD-L1 exhibited better overall survival (P=0.064). Notably, TIL status was found to exhibit contrasting prognostic predictions based on immunogenicity. In conclusion, TILs are a strong candidate for prognostic prediction in breast cancer, regardless of the subtype. PD-L1 is a potential candidate for prognostic prediction in immunogenic breast cancers, but not in the luminal HER2-negative subtype.

High Prevalence of Influenza A (H1N1 and H3N2) Infection in South Iran

Background: Influenza A is divided into a number of subtypes, the most common of which are circulating H3N2 and H1N1. Influenza A and B viruses, which normally circulate in humans (human influenza viruses), are responsible for seasonal influenza pandemics each year. This study evaluated the prevalence of influenza in Hormozgan province and determined the type and subtypes of influenza circulating in the community. Materials and Methods: The present study was conducted in a single center on 1237 patients with acute respiratory syndrome and flu-like symptoms in Hormozgan province, Iran from August 2022 to December 2022. Eventually, patients’ data such as the age, gender, and hospitalization rate of patients with influenza underwent investigation. Results: Out of a total of 1237 samples of patients, 349 (28.2%) cases were diagnosed with positive influenza and 888 (71.80%) cases were negative. Of 349 cases of positive influenza, 3 and 346 cases were diagnosed with influenza B and A, respectively. The results represented that out of a total of 349 positive cases of influenza, 216 (61.90%) and 133 (38.10%) people were hospitalized and visited as outpatients, respectively. Conclusion: From August 2022 to December 2022, Hormozgan province in the south of Iran witnessed an influenza peak with an increase in the prevalence of H1N1 and H3N2 subtypes. The dominant subtype of this peak was H3N2 influenza, but the prevalence of the H1N1 subtype also demonstrated a significant increase. Finally, the cases of hospitalization of patients with positive influenza represented an increase.

Structure-Based Virtual Screening and Molecular Dynamics Simulation Assessments of Depsidones as Possible Selective Cannabinoid Receptor Type 2 Agonists.

The discovery of natural drug metabolites is a leading contributor to fulfilling the sustainable development goal of finding solutions to global health challenges. Depsidones are a class of polyketides that have been separated from lichens, fungi, sponges, and plants and possess various bioactivities, including cytotoxic, antimicrobial, antimalarial, antituberculosis, acetylcholinesterase and α-glucosidase inhibition, and anti-inflammatory effects. Endocannabinoid receptors (CB1 and CB2) are G-protein-coupled receptors (GPCRs), and their activation mediates many physiological processes. CB1 is the dominant subtype in the central nervous system, while CB2 is mainly expressed in the immune system. The two receptors exhibit high heterogeneity, making developing selective ligands a great challenge. Attempts to develop CB2 selective agonists for treating inflammatory diseases and neuropathic pain have not been successful due to the high homology of the binding sites of the CB receptors. In this work, 235 depsidones from various sources were investigated for the possibility of identifying CB2-selective agonists by performing multiple docking studies, including induced fit docking and Prime/molecular mechanics-generalized Born surface area (MM-GBSA) calculations to predict the binding mode and free energy. Simplicildone J (10), lobaric acid (110), mollicellin Q (101), garcinisidone E (215), mollicellin P (100), paucinervin Q (149), and boremexin C (161) had the highest binding scores (-12.134 kcal/mol, -11.944 kcal/mol, -11.479 kcal/mol, -11.394 kcal/mol, -11.322 kcal/mol, -11.305 kcal/mol, and -11.254 kcal/mol, respectively) when screened against the CB2 receptor (PDB ID: 6KPF). The molecular dynamic simulation was performed on the compounds with the highest binding scores. The computational outcomes show that garcinisidone E (215) and paucinervin Q (149) could be substantial candidates for CB2 receptor activation and warrant further in vivo and in vitro investigations.

Cryptosporidium parvum and gp60 genotype prevalence in dairy calves worldwide: a systematic review and meta-analysis

Cryptosporidium is a significant zoonotic pathogen that often occurs in dairy cattle. We conducted a systematic review and meta-analysis of the prevalence of Cryptosporidium parvum infection in dairy calves worldwide to help improve global animal husbandry and public policy implementation. Published articles were obtained from PubMed and Web of Science from January 1, 2000 to December 31, 2021. The prevalence of C. parvum infection in dairy calves was estimated using a random effects model, and the sources of heterogeneity were explored using meta-regression. In total, 118 datasets were included in the final quantitative analysis. The results showed that the global prevalence of C. parvum in dairy calves was 21.9% (7755/42,890; 95% confidence interval: 19.9–23.9%). C. parvum infection was high in pre-weaned dairy calves (24.9%, 6706/29,753) and diarrhea dairy calves (33.6%, 1637/6077). In countries with low dairy stocking density (<10 cows/farm), the prevalence of C. parvum in dairy calves was also relatively low (15.2%, 1960/16,584). Three subtype families [IIa (72.2%, 2293/3177), IId (27.4%, 872/3177), and IIl (0.4%, 12/3177)] were detected in dairy calves globally from selected studies. C. parvum IIa was the dominant zoonotic subtype. In the IIa subtype family of C. parvum, the proportions of subtypes from high to low (top nine) were IIaA15G2R1 (32.4%, 742/2293), IIaA18G3R1 (11.8%, 271/2293), IIaA13G2R1 (8.2%, 187/2293), IIaA16G1R1 (6.4%, 147/2293), IIaA20G1R1 (3.5%, 81/2293), IIaA16G3R1 (3.4%, 78/2293), IIaA17G2R1 (2.7%, 62/2293), IIaA18G1R1 (2.5%, 58/2293), and IIaA15G1R1 (2.4%, 56/2293). In the IId subtype family of C. parvum, the proportions of subtypes (top four) were IIdA19G1 (36.0%, 314/872), IIdA15G1 (27.3%, 238/872), IIdA20G1 (16.2%, 141/872), and IIdA14G1 (13.0%, 113/872). Furthermore, IId is commonly found in China (771/872). The study results indicated that the IIa subtype family is globally prevalent, while IId is found in Asia, Europe, and Africa and IIl is only found in Europe. Diarrhea in dairy calves is associated with C. parvum infection and a significantly higher prevalence is observed in diarrheic calves. Age and stock density are two significant risk factors in the prevalence of C. parvum in dairy calves. The prevention and control of this zoonosis in dairy calves should receive greater attention, especially in regions with a high degree of intensive dairy farming.

Dual-omics reveals temporal differences in acute sympathetic stress-induced cardiac inflammation following α1 and β-adrenergic receptors activation.

Sympathetic stress is prevalent in cardiovascular diseases. Sympathetic overactivation under strong acute stresses triggers acute cardiovascular events including myocardial infarction (MI), sudden cardiac death, and stress cardiomyopathy. α1-ARs and β-ARs, two dominant subtypes of adrenergic receptors in the heart, play a significant role in the physiological and pathologic regulation of these processes. However, little is known about the functional similarities and differences between α1- and β-ARs activated temporal responses in stress-induced cardiac pathology. In this work, we systematically compared the cardiac temporal genome-wide profiles of acute α1-AR and β-AR activation in the mice model by integrating transcriptome and proteome. We found that α1- and β-AR activations induced sustained and transient inflammatory gene expression, respectively. Particularly, the overactivation of α1-AR but not β-AR led to neutrophil infiltration at one day, which was closely associated with the up-regulation of chemokines, activation of NF-κB pathway, and sustained inflammatory response. Furthermore, there are more metabolic disorders under α1-AR overactivation compared with β-AR overactivation. These findings provide a new therapeutic strategy that, besides using β-blocker as soon as possible, blocking α1-AR within one day should also be considered in the treatment of acute stress-associated cardiovascular diseases.

Genotype Diversity, Wild Bird-to-Poultry Transmissions, and Farm-to-Farm Carryover during the Spread of the Highly Pathogenic Avian Influenza H5N1 in the Czech Republic in 2021/2022.

In 2021/2022, the re-emergence of highly pathogenic avian influenza (HPAI) occurred in Europe. The outbreak was seeded from two sources: resident and reintroduced viruses, which is unprecedented in the recorded history of avian influenza. The dominant subtype was H5N1, which replaced the H5N8 subtype that had predominated in previous seasons. In this study, we present a whole genome sequence and a phylogenetic analysis of 57 H5N1 HPAI and two low pathogenic avian influenza (LPAI) H5N1 strains collected in the Czech Republic during 2021/2022. Phylogenetic analysis revealed close relationships between H5N1 genomes from poultry and wild birds and secondary transmission in commercial geese. The genotyping showed considerable genetic heterogeneity among Czech H5N1 viruses, with six different HPAI genotypes, three of which were apparently unique. In addition, second-order reassortment relationships were observed with the direct involvement of co-circulating H5N1 LPAI strains. The genetic distance between Czech H5N1 HPAI and the closest LPAI segments available in the database illustrates the profound gaps in our knowledge of circulating LPAI strains. The changing dynamics of HPAI in the wild may increase the likelihood of future HPAI outbreaks and present new challenges in poultry management, biosecurity, and surveillance.

Blastocystis subtypes in raw vegetables from street markets in northern Thailand.

Blastocystis is a stramenopile protist of controversial pathogenicity. The organism colonizes a broad range of vertebrate and invertebrate hosts. Blastocystis has also been found in the environment both in water and soil. Several routes of transmission have been proposed including human to human, animal to human, and via contaminated food and water. In recent years, the presence of Blastocystis in vegetables has started to be explored. However, most studies have focused on microscopic detection. Moreover, works of this type from Asia are barely available. Hence, the aim of this preliminary study was to examine the occurrence of Blastocystis in raw vegetables sold in markets in northern Thailand. Fresh produce (n = 20) commonly used in Thai cuisine (Lanna) was purchased from two street markets and screened for Blastocystis using qPCR. Blastocystis was detected in 45% of the samples with the dominant subtype being ST3. Produce growing underground, such as galangal, carrot, and beetroot, were positive for the organism suggesting soil or inadequately composted manure as the source of contamination. To our knowledge, our study is the first to perform subtyping of Blastocystis in vegetables. Our results hint toward fresh produce being a, as yet, not widely explored, transmission route of Blastocystis in the studied community. Looking forward, large-scale investigations on the prevalence of this and other organisms under the One Health umbrella should be undertaken.

Expression of PD-L1 through evolution phase from pre-invasive to invasive lung adenocarcinoma

BackgroundThis study evaluated programmed cell death-ligand 1 (PD-L1) expression from pre-invasive adenocarcinoma to invasive lung adenocarcinoma, aimed to investigate the potential association of PD-L1 pathway with lung adenocarcinoma early evolution.MethodsWe evaluated PD-L1 expression in 1123 resected lung specimens of adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC) of stage IA1–IA3. PD-L1 expression was defined based on the proportion of stained tumor cells using the tumor proportion score: < 1% (negative), ≥ 1% (positive) and ≥ 50% (strongly positive). Correlations between PD-L1 expression and T stage, pathological subtype, adenocarcinoma grade, spread through air space (STAS), vascular invasion, lymphatic invasion and driven genes were analyzed.ResultsThere was almost no PD-L1 expression in AIS or MIA. However, PD-L1 expression was correlated with invasiveness of lung adenocarcinoma. The percentages of PD-L1 positive in IA1–IA3 were 7.22%, 11.29%, and 14.20%, respectively. The strongly positive rates of PD-L1 were 0.38%, 1.64%, and 3.70% in IA1–IA3, respectively. PD-L1 expression and positive rate were also associated with poor pathological subtype and poor biological behavior, such as adenocarcinoma Grade 3, micropapillary or solid dominant subtype, STAS and vascular invasion. Finally, PD-L1 positive rate seems also corrected with driven gene ALK, ROS-1 and KRAS.ConclusionsPD-L1 expression was positively correlated with the emergence of invasiveness and poor pathological subtype or biological behavior of early-stage lung adenocarcinoma. PD-L1 pathway may be involved in the early evolution of lung adenocarcinoma from AIS to IAC.

Copy number variations in SPAST and ATL1 are rare among Brazilians.

Copy number variations (CNV) may represent a significant proportion of SPG4 and SPG3A diagnosis, the most frequent autosomal dominant subtypes of hereditary spastic paraplegias (HSP). We aimed to assess the frequency of CNVs in SPAST and ATL1 and to update the molecular epidemiology of HSP families in southern Brazil. A cohort study that included 95 Brazilian index cases with clinical suspicion of HSP was conducted between April 2011 and September 2022. Multiplex Ligation Dependent Probe Amplification (MLPA) was performed in 41 cases without defined diagnosis by different massive parallel sequencing techniques (MPS). Diagnosis was obtained in 57/95 (60%) index cases, 15/57 (26.3%) being SPG4. Most frequent autosomal recessive HSP subtypes were SPG7 followed by SPG11, SPG76 and cerebrotendinous xanthomatosis. No CNVs in SPAST and ATL1 were found. Copy number variations are rare among SPG4 and SPG3A families in Brazil. Considering the possibility of CNVs detection by specific algorithms with MPS data, we consider that this is likely the most cost-effective approach to investigate CNVs in these genes in low-risk populations, with MLPA being reserved as an orthogonal confirmatory test.

Membranous Nephropathy in Syphilis is Associated with Neuron-Derived Neurotrophic Factor.

Syphilis is a common worldwide sexually transmitted infection. Proteinuria may occur in patients with syphilis. Membranous nephropathy (MN) is the most common cause of proteinuria in syphilis. The target antigen of MN in syphilis is unknown. This study shows that MN in syphilis is associated with a novel target antigen called neuron-derived neurotrophic factor (NDNF). NDNF-associated MN has distinctive clinical and pathologic manifestations and NDNF appears to be the target antigen in syphilis-associated MN. Syphilis is a common sexually transmitted infection. Membranous nephropathy (MN) is a common cause of proteinuria in syphilis. The target antigen is not known in most cases of syphilis-associated MN. We performed laser microdissection of glomeruli and mass spectrometry (MS/MS) in 250 cases (discovery cohort) of phospholipase A2 receptor-negative MN to identify novel target antigens. This was followed by immunohistochemistry/confocal microscopy to localize the target antigen along the glomerular basement membrane (GBM). Western blot analyses using IgG eluted from frozen biopsy tissue were performed to detect binding to target antigen. MS/MS studies of the discovery cohort revealed high total spectral counts of a novel protein, neuron-derived neurotrophic factor (NDNF), in three patients: one each with syphilis and hepatitis B, HIV (syphilis status not known), and lung tumor. Next, MS/MS studies of five cases of syphilis-MN (validation cohort) confirmed high total spectral counts of NDNF (average 45±20.4) in all (100%) cases. MS/MS of 14 cases of hepatitis B were negative for NDNF. All eight cases of NDNF-associated MN were negative for known MN antigens. Electron microscopy showed stage I MN in all cases, with superficial and hump-like deposits without GBM reaction. IgG1 was the dominant IgG subtype on MS/MS and immunofluorescence microscopy. Immunohistochemistry/confocal microscopy showed granular staining and colocalization of NDNF and IgG along GBM. Western blot analyses using eluate IgG of NDNF-MN showed binding to both nonreduced and reduced NDNF, while IgG eluate from phospholipase A2 receptor-MN showed no binding. NDNF is a novel antigenic target in syphilis-associated MN.

Polarity-Ultrasensitive and Lipophilicity-Enhanced Structurally Modified Hemicyanine for Two-Color Staining to Reveal Cell Apoptosis during Chemotherapy.

Programmed cell death (PCD) is a precisely controlled physiological process to sustain tissue homeostasis. Even though the PCD pathways have been explicitly subdivided, the individual cell death process seems to synergistically operate to eliminate cells rather than separately execute signal transduction. Apoptosis is the dominant intracellular PCD subtype, which is intimately regulated and controlled by mitochondria, thus tracing mitochondrial actions could reveal the dynamic changes of apoptosis, which may provide important tools for screening preclinical therapeutic agents. Herein, we exploited an innovative fluorophore Cy496 based on the light-initiated cleavage reaction. Cy496 bears the typical D-π-A structure and serves as a versatile building block for chemosensor construction through flexible side chains. By regulating lipophilicity and basicity through bis-site substitution, we synthesized a series of fluorescence probes and screened a novel mitochondria-targeted ratiometric probe Cy1321, which can real-time evaluate the dynamic changes of mitochondrial micropolarity mediated by bis-cholesterol anchoring. Cy1321 has realized two-color quantification and real-time visualization of polarity fluctuations on chemotherapy agent (cisplatin)-induced apoptosis through flow cytometry and confocal imaging and also achieved the purpose of detecting mitochondria-related apoptosis at the level of tissues. It is envisioned that Cy1321 has sufficient capability as a promising and facile tool for the evaluation of apoptosis and contributing to therapeutic drug screening.

Evidence and gap map report: Social and Behavior Change Communication (SBCC) interventions for strengthening HIV prevention and research among adolescent girls and young women (AGYW) in low- and middle-income countries (LMICs).

Evidence and gap map report: Social and Behavior Change Communication (SBCC) interventions for strengthening HIV prevention and research among adolescent girls and young women (AGYW) in low- and middle-income countries (LMICs).

Immune evasion in esophageal squamous cell cancer: From the perspective of tumor microenvironment.

Esophageal cancer (EC) is one of the most life-threatening malignancies worldwide. Esophageal squamous cell carcinoma (ESCC) is the dominant subtype, accounting for approximately 90% of new incident EC each year. Although multidisciplinary treatment strategies have advanced rapidly, patients with ESCC are often diagnosed at advanced stage and the long-term prognosis remains unsatisfactory. In recent decades, immunotherapy, such as immune checkpoint inhibitors (ICIs), tumor vaccines, and chimeric antigen receptor T-cell (CAR-T) therapy, has been successfully used in clinical practice as a novel therapy for treating tumors, bringing new hope to ESCC patients. However, only a small fraction of patients achieved clinical benefits due to primary or acquired resistance. Immune evasion plays a pivotal role in the initiation and progression of ESCC. Therefore, a thorough understanding of the mechanisms by which ESCC cells escape from anti-tumor immunity is necessary for a more effective multidisciplinary treatment strategy. It has been widely recognized that immune evasion is closely associated with the crosstalk between tumor cells and the tumor microenvironment (TME). TME is a dynamic complex and comprehensive system including not only cellular components but also non-cellular components, which influence hallmarks and fates of tumor cells from the outside. Novel immunotherapy targeting tumor-favorable TME represents a promising strategy to achieve better therapeutic responses for patients with ESCC. In this review, we provide an overview of immune evasion in ESCC, mainly focusing on the molecular mechanisms that underlie the role of TME in immune evasion of ESCC. In addition, we also discuss the challenges and opportunities of precision therapy for ESCC by targeting TME.

Correlation of Menstrual Abnormalities with Endometrial Histopathology: A Review

Background: AUB (Abnormal uterine bleeding) is defined as excessive menstrual blood loss which interferes withwomen’s physical, social, emotional and maternal quality of life. Any uterine bleeding outside the normal volume,duration, regularity or frequency is considered abnormal uterine bleeding (AUB).Objective: To study the various types of menstrual abnormalities prevalent in women and to correlate it withdifferent histopathology features in endometrial curettage.Study Design: The study design was prospective observational study with study population being abnormal uterinebleeding newly registered at the opd/ ipd of Saraswathi Institute Of Medical Sciences, Hapur Uttar Pradesh. Asample size of 136 patients were included during study periods from august 2020 to march 2021.Result: Most common endometrial lesion was endometrial hyperplasia (38.2%), followed by proliferative change(35.29%), others were polyp, fibroid, atrophic endometrium. Endometrial carcinoma was detected in 0.78% of cases.Hyperplasia when further categorised, showed simple hyperplasia as the dominant sub-type. Hyperplasia wasthe dominant change observed in menorrhagia, polymenorrhoea, metrorrhagia, and postmenopausal bleeding.Conclusion: Most common cause of AUB was hormonal imbalance around perimenopausal age group. In elderlyage hyperplasia and malignancy was more commonly seen.

Molecular Epidemiology of HIV-1 in Ghana: Subtype Distribution, Drug Resistance and Coreceptor Usage.

The greatest HIV-1 genetic diversity is found in West/Central Africa due to the pandemic’s origins in this region, but this diversity remains understudied. We characterized HIV-1 subtype diversity (from both sub-genomic and full-genome viral sequences), drug resistance and coreceptor usage in 103 predominantly (90%) antiretroviral-naive individuals living with HIV-1 in Ghana. Full-genome HIV-1 subtyping confirmed the circulating recombinant form CRF02_AG as the dominant (53.9%) subtype in the region, with the complex recombinant 06_cpx (4%) present as well. Unique recombinants, most of which were mosaics containing CRF02_AG and/or 06_cpx, made up 37% of sequences, while “pure” subtypes were rare (<6%). Pretreatment resistance to at least one drug class was observed in 17% of the cohort, with NNRTI resistance being the most common (12%) and INSTI resistance being relatively rare (2%). CXCR4-using HIV-1 sequences were identified in 23% of participants. Overall, our findings advance our understanding of HIV-1 molecular epidemiology in Ghana. Extensive HIV-1 genetic diversity in the region appears to be fueling the ongoing creation of novel recombinants, the majority CRF02_AG-containing, in the region. The relatively high prevalence of pretreatment NNRTI resistance but low prevalence of INSTI resistance supports the use of INSTI-based first-line regimens in Ghana.

Changes in endemic patterns of respiratory syncytial virus infection in pediatric patients under the pressure of nonpharmaceutical interventions for COVID-19 in Beijing, China.

A series of nonpharmaceutical interventions (NPIs) was launched in Beijing, China, on January 24, 2020, to control coronavirus disease 2019. To reveal the roles of NPIs on the respiratory syncytial virus (RSV), respiratory specimens collected from children with acute respiratory tract infection between July 2017 and Dec 2021 in Beijing were screened by capillary electrophoresis-based multiplex PCR(CEMP) assay. Specimens positive for RSV were subjected to a polymerase chain reaction(PCR) and genotyped by G gene sequencing and phylogenetic analysis using iqtree v1.6.12. The parallel and fixed (paraFix) mutations were analyzed with the R package sitePath. Clinical data were compared using SPSS 22.0 software. Before NPIs launched, each RSV endemic season started from October/November to February/March of the next year in Beijing. After that, the RSV positive rate abruptly dropped from 31.93% in January to 4.39% in February 2020; then, a dormant state with RSV positive rates ≤1% from March to September, a nearly dormant state in October (2.85%) and November (2.98%) and a delayed endemic season in 2020, and abnormal RSV positive rates remaining at approximately 10% in summer until September 2021 were detected. Finally, an endemic RSV season returned in October 2021. There was a game between Subtypes A and B, and RSV-A replaced RSV-B in July 2021 to become the dominant subtype. Six RSV-A and eightRSV-B paraFix mutations were identified on G. The percentage of severe pneumonia patients decreased to 40.51% after NPIs launched.NPIs launched in Beijing seriously interfered with the endemic season of RSV.