Menopausal hormone therapy and breast cancer risk: a population-based cohort study of 1.3 million women in Norway.

BACKGROUND: It is important to monitor the association between menopausal hormone therapy (HT) use and breast cancer (BC) risk with contemporary estimates, and specifically focus on HT types and new drugs. METHODS: We estimated hazard ratios (HR) of BC risk according to HT type, administration route and individual drugs, overall and stratified by body mass index (BMI), molecular subtype and detection mode, with non-HT use as reference. RESULTS: We included 1,275,783 women, 45+ years, followed from 2004, for a median of 12.7 years. Oral oestrogen combined with daily progestin was associated with the highest risk of BC (HR 2.42, 95% confidence interval (CI) 2.31-2.54), with drug-specific HRs ranging from Cliovelle®: 1.63 (95% CI 1.35-1.96) to Kliogest®: 2.67 (2.37-3.00). Vaginal oestradiol was not associated with BC risk. HT use was more strongly associated with luminal A cancer (HR 1.97, 95% CI 1.86-2.09) than other molecular subtypes, and more strongly with interval (HR 2.00, 95% CI: 1.83-2.30) than screen-detected (HR 1.33, 95% CI 1.26-1.41) BC in women 50-71 years. HRs for HT use decreased with increasing BMI. CONCLUSIONS: The use of oral and transdermal HT was associated with an increased risk of BC. The associations varied according to HT type, individual drugs, molecular subtype, detection mode and BMI.

A lineage-specific requirement for YY1 Polycomb Group protein function in early T cell development.

Yin Yang 1 (YY1) is a ubiquitous transcription factor and mammalian Polycomb Group protein (PcG) with important functions for regulating lymphocyte development and stem cell self-renewal. YY1 mediates stable PcG-dependent transcriptional repression via recruitment of PcG proteins that result in histone modifications. Many questions remain unanswered regarding how cell- and tissue-specificity is achieved by PcG proteins. Here, we demonstrate that a conditional knockout of Yy1 in the hematopoietic system results in an early T cell developmental blockage at the double negative (DN) 1 stage with reduced Notch1 signaling. There is a lineage-specific requirement for YY1 PcG function. YY1 PcG domain is required for T and B cell development but not necessary for myeloid cells. YY1 functions in early T cell development are multicomponent and involve both PcG-dependent and -independent regulations. Although YY1 promotes early T cell survival through its PcG function, its function to promote the DN1-to-DN2 transition and Notch1 expression and signaling is independent of its PcG function. Our results reveal how a ubiquitously expressed PcG protein mediates lineage-specific and context-specific functions to control early T cell development.

Corrigendum to "Tanshinone-I for the treatment of uterine fibroids: Molecular docking, simulation, and density functional theory investigations" [Saudi Pharm. J. 31(6) (2023) 1061-1067].

[This corrects the article DOI: 10.1016/j.jsps.2023.05.002.].

Tanshinone-I for the treatment of uterine fibroids: Molecular docking, simulation, and density functional theory investigations.

Uterine fibroids (UF), most prevalent gynecological disorder, require surgery when symptomatic. It is estimated that between 25 and 35 percent of women wait until the symptoms have worsened like extended heavy menstrual bleeding and severe pelvic pain. These UF may be reduced in size through various methods such as medical or surgical intervention. Progesterone (prog) is a crucial hormone that restores the endometrium and controls uterine function. In the current study, 28 plant-based molecules are identified from previous literature and docked onto the prog receptors with 1E3K and 2OVH. Tanshinone-I has shown the best docking score against both proteins. The synthetic prog inhibitor Norethindrone Acetate is used as a standard to evaluate the docking outcomes. The best compound, tanshinone-I, was analyzed using molecular modeling and DFT. The RMSD for the 1E3K protein-ligand complex ranged from 0.10 to 0.42 Å, with an average of 0.21 Å and a standard deviation (SD) of 0.06, while the RMSD for the 2OVH protein-ligand complex ranged from 0.08 to 0.42 Å, with an average of 0.20 Å and a SD of 0.06 showing stable interaction. In principal component analysis, the observed eigen values of HPR-Tanshinone-I fluctuate between -1.11 to 1.48 and -1.07 to 1.25 for PC1 and PC2, respectively (1E3K), and the prog-tanshinone-I complex shows eigen values of -38.88 to -31.32 and -31.32 to 35.87 for PC1 and PC2, respectively (2OVH), which shows Tanshinone-I forms a stable protein-ligand complex with 1E3K in comparison to 2OVH. The Free Energy Landscape (FEL) analysis shows the Gibbs free energy in the range of 0 to 8 kJ/mol for Tanshinone-I with 1E3K and 0 to 14 kJ/mol for Tanshinone-I with the 2OVH complex. The DFT calculation reveals ΔE value of 2.8070 eV shows tanshinone-I as a stable compound. 1E3K modulates the prog pathway, it may have either an agonistic or antagonistic effect on hPRs. Tanshinone-I can cause ROS, apoptosis, autophagy (p62 accumulation), up-regulation of inositol requiring protein-1, enhancer-binding protein homologous protein, p-c-Jun N-terminal kinase (p-JNK), and suppression of MMPs. Bcl-2 expression can change LC3I to LC3II and cause apoptosis through Beclin-1 expression.

Global patterns of Hodgkin lymphoma incidence and mortality in 2020 and a prediction of the future burden in 2040.

Our study examines global patterns of Hodgkin lymphoma (HL) in 2020 and predicts the future incidence and mortality burden in 2040 using IARC's GLOBOCAN estimates of the number of new cases and deaths of HL in 185 countries. A total of 83 000 new cases of HL and 23 000 deaths from HL were estimated in 2020. In general, incidence and mortality rates were consistently higher in males (50% more cases and deaths than females) across world regions and countries. Incidence rates varied markedly by world region, at least 10-fold in both sexes, with the highest incidence rates observed in Southern Europe. Mortality exhibited an inverse pattern compared to incidence, with rates elevated in Western Asia and Northern Africa. The number of HL incident cases is predicted to rise to around 107 000 cases (a 30% increase) by 2040 due to demographic changes, assuming global rates in 2020 remains unchanged. The findings provide a baseline and impetus for developing strategies that aim to reduce the burden of HL in future decades.

COVID-19: clinical presentation and detection methods.

The unending outburst of COVID-19 has reinforced the necessity of SARS-CoV-2 identification approaches for the prevention of infection transmission and the proper care of severe and critical patients. As there is no cure, a prompt and reliable diagnosis of SARS-CoV2 is vital to counter the spread and to provide adequate care and treatment for the infection. Currently, RT-PCR is a gold standard detection method for the qualitative and quantitative detection of viral nucleic acids. Besides, enzyme-linked immunosorbent assay is also a primarily used method for qualitative estimation of viral load. However, almost all the detection methods have their pros and cons in terms of specificity, accuracy, sensitivity, cost, time consumption, the need for sophisticated laboratories, and the requirement of skilled technical experts to carry out the detection tests. Thus, it is suggested to integrate different techniques to enhance the detection efficiency and accurateness for SARS-CoV2. This review focuses on preliminary, pre-confirmatory, and confirmatory methods of detection such as imaging techniques (chest-X-ray and chest- computed tomography), nucleic acid detection methods, serological assay methods, and viral culture and identification methods that are currently being employed to detect the presence of SARS-CoV-2 infection along with recent detection method and applicability for COVID-19.

Atypical neurological manifestations of dengue fever: a case series and mini review.

BACKGROUND: In this mini review, we discuss some of the atypical neurological manifestations of dengue virus and attempt to bring them to attention to highlight the neurotropic property of the dengue virus. METHODS: Cases were chosen from retrospective hospital and outpatient records of all patients seropositive for dengue who attended the neurology referral. Seven patients have been chosen as illustrative examples of dengue-associated neurological involvement. We discuss the various central and peripheral nervous system involvement of patients and discuss the relevant findings in them. CONCLUSION: Through this case series, we wish to highlight that the dengue virus can affect the nervous system at various targets, using multiple mechanisms of pathogenesis to generate a plethora of presentations. Hence, it is vital to be aware of its presentations to be able to diagnose dengue and treat it accordingly.

Cancer incidence and mortality patterns in women with breast symptoms in the mammography screening programme: A matched cohort analysis.

Efforts to reduce mortality through early detection and diagnosis has intensified in the recent decade. An important risk factor, 'breast symptoms' reported by women during screening visit, remains overlooked. In this population based matched cohort study using Finnish National Breast Cancer Screening Program (FNBCSP), we assessed the association between breast symptoms reported at screening visit and the risk of cancer incidence and breast cancer mortality and all-cause mortality followed-up over a period of 24 years. For each visit with symptoms, non-symptomatic controls were matched (1:1 for lump and retraction; 1:2 for nipple discharge) based on age at screening visit, year of invitation, number of invited visits, and municipality of invitation. Women who reported lump or retraction had about two-fold risk of breast cancer incidence, three-fold risk of breast cancer mortality and all-cause mortality respectively as compared to women without respective symptoms (p-value<0.05). We found a substantial difference (p-value<0.05) in mortality rates throughout the follow-up period between symptomatic and asymptomatic group. In absolute terms, after the follow-up period for women who reported lump, 180 died from breast cancer as compared to 70 deaths in those without lump, per 10,000 person-years of follow-up, and 315 versus 160 all-cause deaths per 10,000 person-years in women with and without lump respectively. our study provides comprehensive evidence that women with breast symptoms remain in a higher risk of dying over a very long period. The findings indicate needs to develop improvements in the guidelines for screening and clinical services for women presenting with symptoms.

Correction: Association of symptoms and interval breast cancers in the mammography-screening programme: population-based matched cohort study.

The authors report that the labels indicating the symptom types and no symptom lines in the original version of Figure 2 were missing. The correct version of Figure 2 with the labels included is provided below.

Scleroderma: An insight into causes, pathogenesis and treatment strategies.

Scleroderma is an autoimmune disorder, characterized by morphological changes in skin followed by visceral organs. The pathogenesis of scleroderma involves immune imbalance and generation of auto antibodies. The major causes of scleroderma include multitude of factors such as immune imbalance, oxidative stress, genetics and environment factors. A constant effort has been made to treat scleroderma through different approaches and necessitates life time administration of drugs for maintenance of a good quality life. It has been reported more in women compared to men. Traditional treatment strategies are restricted by limited therapeutic capability due to associated side effects. Advancement in development of novel drug delivery approaches has opened a newer avenue for efficient therapy. Current review is an effort to reflect scleroderma in provisions of its pathogenesis, causative factors, and therapeutic approaches, with concern to mode of action, pharmacokinetics, marketed products, and side effects of drugs.

Decompression retinochoroidopathy: a unique presentation post-trabeculectomy.

PURPOSE: To present a unique case of decompression retinochoroidopathy presenting with intraretinal, subretinal and preretinal hemorrhages. METHODS: A 65-year-old hypertensive female presented with diminution of vision in right eye of 1-week duration. She had been a known case of primary open-angle glaucoma and had undergone trabeculectomy with mitomycin C in right eye 1 week back. Her day 1 postoperative intraocular pressure was 6 mmHg. Her left eye had undergone Ahmed glaucoma valve surgery for the same 2 years back. RESULT: Right eye vision at 1 week of presentation was 6/36, N36 and left eye hand movements. Both eyes were pseudophakic. Intraocular pressure in right eye was 35 mmHg with nonfunctional bleb and in left eye 15 mmHg. Right eye fundus shows multiple subretinal, intraretinal, preretinal and some white-centered blot hemorrhage in all the four quadrants including the posterior pole. Disk had glaucomatous cupping with no dilatation or tortuosity of retinal blood vessels. Left eye had total glaucomatous optic atrophy. CONCLUSION: Old hypertensive females may not tolerate hemodynamic changes in retinal and choroidal vasculature so well, and if the autoregulation of retinal capillaries and choriocapillaris fails because of IOP spikes or rise of IOP to high levels in a relatively short duration, sudden lowering of IOP after trabeculectomy may cause decompression retinopathy and choroidopathy.

Association of symptoms and interval breast cancers in the mammography-screening programme: population-based matched cohort study.

BACKGROUND: We assessed the association between symptoms reported at breast cancer screening visits and interval cancers (ICs) in a prospective manner. METHODS: This population-based matched cohort study uses data of the Finnish National Breast Cancer Screening Programme that invites women aged 50-69 years old during 1992-2012. Subjects who attended screening with symptoms were matched with asymptomatic reference cohorts based on age at screening visit, year of invitation, number of invited visits and municipality of invitation. The primary outcome was ICs. RESULTS: Women with a lump had a threefold (hazard ratio 3.7, 95% confidence interval (CI) 3.0-4.6) risk of ICs and a higher risk (hazard ratio 1.7, 95% CI 1.4 to 2.0) at the subsequent visit compared with those without a lump. The fatal interval cancer risk increased by 0.39 per 1000 screens with a lump. The cumulative incidences of interval cancer increased within a month of a mammography-negative visit with a lump and after about 6 months of the visit with retraction or nipple discharge. CONCLUSION: Women with breast symptoms have a clearly increased risk of interval breast cancer after the screening visit. Our findings indicate the need for different screening strategies in symptomatic women.

Primary hyperparathyroidism: insights from the Indian PHPT registry.

The presentation of primary hyperparathyroidism (PHPT) is variable throughout the world. The present study explored retrospective data submitted to the Indian PHPT registry ( http://www.indianphptregistry.com ) between July 2005 and June 2015 from 5 centres covering four different geographical regions. The clinical, biochemical, radiological and histopathological characteristics of PHPT patients across India were analysed for similarity and variability across the centres. A total of 464 subjects (137 men and 327 women) with histopathologically proven PHPT were analysed. The mean age was 41 ± 14 years with a female:male ratio of 2.4:1. The majority (95%) of patients were symptomatic. Common clinical manifestations among all the centres were weakness and fatigability (58.7%), bone pain (56%), renal stone disease (31%), pancreatitis (12.3%) and gallstone disease (11%). Mean serum calcium, parathyroid hormone and inorganic phosphorus levels were 11.9 ± 1.6 mg/dL, 752.4 ± 735.2 pg/mL and 2.8 ± 0.9 mg/dL, respectively. Sestamibi scanning had better sensitivity than ultrasonography in the localisation of parathyroid adenoma; however, when these two modalities were combined, 93% of the cases were correctly localised. Mean parathyroid adenoma weight was 5.6 ± 6.5 g (0.1-54 g). It was concluded that the majority of PHPT patients within India are still mainly symptomatic with >50% of patients presenting with bone disease and one-third with renal impairment. Compared to Western countries, Indian patients with PHPT are younger, biochemical abnormalities are more severe, and adenoma weight is higher. As our observation is largely derived from a tertiary care hospital (no routine screening of serum calcium level), the results do not reflect racial differences in susceptibility to PHPT.

Cumulative risk of false positive test in relation to breast symptoms in mammography screening: a historical prospective cohort study.

Mammography has been found effective as the primary screening test for breast cancer. We estimated the cumulative probability of false positive screening test results with respect to symptom history reported at screen. A historical prospective cohort study was done using individual screening data from 413,611 women aged 50-69 years with 2,627,256 invitations for mammography screening between 1992 and 2012 in Finland. Symptoms (lump, retraction, and secretion) were reported at 56,805 visits, and 48,873 visits resulted in a false positive mammography result. Generalized linear models were used to estimate the probability of at least one false positive test and true positive at screening visits. The estimates were compared among women with and without symptoms history. The estimated cumulative probabilities were 18 and 6 % for false positive and true positive results, respectively. In women with a history of a lump, the cumulative probabilities of false positive test and true positive were 45 and 16 %, respectively, compared to 17 and 5 % with no reported lump. In women with a history of any given symptom, the cumulative probabilities of false positive test and true positive were 38 and 13 %, respectively. Likewise, women with a history of a 'lump and retraction' had the cumulative false positive probability of 56 %. The study showed higher cumulative risk of false positive tests and more cancers detected in women who reported symptoms compared to women who did not report symptoms at screen. The risk varies substantially, depending on symptom types and characteristics. Information on breast symptoms influences the balance of absolute benefits and harms of screening.

Association of symptoms and breast cancer in population-based mammography screening in Finland.

The study purpose was to assess association of symptoms at screening visits with detection of breast cancer among women aged 50-69 years during the period 2006-2010. Altogether 1.2 million screening visits were made and symptoms (lump, retraction, secretion etc.) were reported either by women or radiographer. Breast cancer risk was calculated for each symptom separately using logistic regression [odds ratio (OR)] and 95% confidence intervals (CIs). Of the 1,198,410 screening visits symptoms were reported in 298,220 (25%) visits. Breast cancer detection rate for women with and without symptoms was 7.8 per 1,000 and 4.7 per 1,000 screening visits, respectively, whereas lump detected 32 cancers per 1,000 screens. Women with lump or retraction had an increased risk of breast cancer, OR = 6.47, 95% CI 5.89-7.09 and OR = 2.19, 95% CI 1.92-2.49, respectively. The sensitivity of symptoms in detecting breast carcinoma was 35.5% overall. Individual symptoms sensitivity and specificity ranged from, 0.66 to 14.8% and 87.4 to 99.7%, respectively. Of 5,541 invasive breast cancers, 1,993 (36%) reported symptoms at screen. Breast cancer risk among women with lump or retraction was higher in large size tumors (OR = 9.20, 95% CI 8.08-10.5) with poorly differentiated grades (OR = 5.91, 95% CI 5.03-6.94) and regional lymph nodes involvement (OR = 6.47, 95% CI 5.67-7.38). This study was done in a setting where breast tumors size is generally small, and symptoms sensitivity and specificity in diagnosing breast tumors were limited. Importance of breast cancer symptoms in the cancer prevention and control strategy needs to be evaluated also in other settings.

Multifunctional iron bound lactoferrin and nanomedicinal approaches to enhance its bioactive functions.

Lactoferrin (Lf), an iron-binding protein from the transferrin family has been reported to have numerous functions. Even though Lf was first isolated from milk, it is also found in most exocrine secretions and in the secondary granules of neutrophils. Antimicrobial and anti-inflammatory activity reports on lactoferrin identified its significance in host defense against infection and extreme inflammation. Anticarcinogenic reports on lactoferrin make this protein even more valuable. This review is focused on the structural configuration of iron-containing and iron-free forms of lactoferrin obtained from different sources such as goat, camel and bovine. Apart for emphasizing on the specific beneficial properties of lactoferrin from each of these sources, the general antimicrobial, immunomodulatory and anticancer activities of lactoferrin are discussed here. Implementation of nanomedicinial strategies that enhance the bioactive function of lactoferrin are also discussed, along with information on lactoferrin in clinical trials.

Human DNA ligases: a comprehensive new look for cancer therapy.

Living organisms belonging to all three domains of life, viz., eubacteria, archaeabacteria, and eukaryotes encode one or more DNA ligases. DNA ligases are indispensable in various DNA repair and replication processes and a deficiency or an inhibition of their activity can lead to accumulation of DNA damage and strand breaks. DNA damage, specially strand breaks at unsustainable levels can lead to replication block and/or cell death. DNA ligases as potential anticancer targets have been realized only recently. There is enough rationale to suggest that ligases have a tremendous potential for novel therapeutics including anticancer and antibacterial therapy, specially when the world is facing acute problems of drug resistance and chemotherapy failure, with an immediate need for new therapeutic targets. Here, we review the current state of the art in the development of human ligase inhibitors, their structures, molecular mechanisms, physiological effects, and their potential in future cancer therapy. Citing examples, we focus on strategies for improving the activity and specificity of existing and novel inhibitors by using structure-based rational approaches. In the end, we describe potential new sites on the ligase I protein that can be targeted for the development of novel inhibitors. This is the first comprehensive review to compile all known human ligase inhibitors and to provide a rationale for the further development of ligase inhibitors for cancer therapy.

Pharmacophore-based screening and identification of novel human ligase I inhibitors with potential anticancer activity.

Human DNA ligases are enzymes that are indispensable for DNA replication and repair processes. Among the three human ligases, ligase I is attributed to the ligation of thousands of Okazaki fragments that are formed during lagging strand synthesis during DNA replication. Blocking ligation therefore can lead to the accumulation of thousands of single strands and subsequently double strand breaks in the DNA, which is lethal for the cells. The reports of the high expression level of ligase I protein in several cancer cells (versus the low ligase expression level and the low rate of division of most normal cells in the adult body) support the belief that ligase I inhibitors can target cancer cells specifically with minimum side effects to normal cells. Recent publications showing exciting data for a ligase IV inhibitor exhibiting antitumor activity in mouse models also strengthens the argument for ligases as valid antitumor targets. Keeping this in view, we performed a pharmacophore-based screening for potential ligase inhibitors in the Maybridge small molecule library and procured some of the top-ranking compounds for enzyme-based and cell-based in vitro screening. We report here the identification of novel ligase I inhibitors with potential anticancer activity against a colon cancer cell line.