Inpatient palliative care utilisation among patients with gallbladder cancer in the United States: A 10-year perspective.

OBJECTIVES: Gallbladder cancer (GBC) is a rare, poor-prognosis cancer with unique demographics, comorbidities and a paucity of research. This study investigated inpatient palliative care and its associations with demographics, comorbidities (e.g., obesity), length of stay and hospital charges in GBC in US hospitals (2007-2016). METHODS: Data were extracted from the National Inpatient Sample (NIS) database that contains deidentified clinical and nonclinical information for each hospitalisation. Inpatient palliative care utilisation was identified using the International Classification of Diseases (ICD-9 and ICD-10) codes (V66.7 and Z51.5). Generalised regression analysis was conducted with adjustment for variations in predictors. RESULTS: Of the 4921 reported GBC hospitalizations, only 10.3% encountered palliative care. Palliative care was associated with reduced hospital charges by $12,405 per hospitalisation (P < 0.0001) with no change in length of stay. Palliative care utilisation increased over time (P = 0.004). It was associated with age >80 years, with more severe disease, and in-hospital death (P < 0.0001). Obesity had a negative association with palliative care utilisation (P = 0.0029). DISCUSSION: Our novel study found that obese people were less likely to use palliative care services in GBC. Interventions are needed to increase palliative care consultation in GBC patients, particularly in obese patients.

Ten-year trends of utilizing palliative care and palliative procedures in patients with gastric Cancer in the United States from 2009 to 2018 - a nationwide database study.

OBJECTIVES: Little is known about the current status and the changing trends of hospitalization and palliative care consultation of patients with gastric cancer in the United States. The aim of this study was to evaluate the changing trend in the number of hospitalization, palliative care consultation, and palliative procedures in the US during a recent 10-year period using a nationwide database. METHODS: This was a retrospective study that analyzed the National Inpatient Sample (NIS) database of 2009-2018. Patients aged more than 18 years who were diagnosed with a gastric cancer using International Classification of Diseases (ICD)-9 and 10 codes were included. Palliative care consultation included palliative care (ICD-9, V66.7; ICD-10, Z51.5) and advanced care planning (ICD-9, V69.89; ICD-10, Z71.89). Palliative procedures included percutaneous or endoscopic bypass, gastrostomy or enterostomy, dilation, drainage, nutrition, and irrigation for palliative purpose. RESULTS AND DISCUSSION: A total of 86,430 patients were selected and analyzed in this study. Using a compound annual growth rate (CAGR) approach, the annual number of hospitalizations of gastric cancer patients was found to be decreased during 2009-2018 (CAGR: -0.8%, P = 0.0084), while utilization rates of palliative care and palliative procedures increased (CAGR: 9.3 and 1.6%, respectively; P < 0.0001). Multivariable regression analysis revealed that palliative care consultation was associated with reduced total hospital charges (-$34,188, P < 0.0001). CONCLUSION: Utilization of palliative care consultation to patients with gastric cancer may reduce use of medical resources and hospital costs.

The host mTOR pathway and parasitic diseases pathogenesis.

The mechanistic (or mammalian) target of rapamycin (mTOR) is considered as a critical regulatory enzyme involved in essential signaling pathways affecting cell growth, cell proliferation, protein translation, regulation of cellular metabolism, and cytoskeletal structure. Also, mTOR signaling has crucial roles in cell homeostasis via processes such as autophagy. Autophagy prevents many pathogen infections and is involved on immunosurveillance and pathogenesis. Immune responses and autophagy are therefore key host responses and both are linked by complex mTOR regulatory mechanisms. In recent years, the mTOR pathway has been highlighted in different diseases such as diabetes, cancer, and infectious and parasitic diseases including leishmaniasis, toxoplasmosis, and malaria. The current review underlines the implications of mTOR signals and intricate networks on pathogen infections and the modulation of this master regulator by parasites. Parasitic infections are able to induce dynamic metabolic reprogramming leading to mTOR alterations in spite of many other ways impacting this regulatory network. Accordingly, the identification of parasite effects and interactions over such a complex modulation might reveal novel information regarding the biology of the abovementioned parasites and might allow the development of therapeutic strategies against parasitic diseases. In this sense, the effects of inhibiting the mTOR pathways are also considered in this context in the light of their potential for the prevention and treatment of parasitic diseases.

Altered frequency of CD8+ CD11c+ T cells and expression of immunosuppressive molecules in lymphoid organs of mouse model of colorectal cancer.

CD11c is a member of the ß2-integrin family typically used to define myeloid dendritic cells (DCs). Recent reports identify CD11c-expressing CD8+ T cells as a new subset of CD8+ regulatory T cells (Treg). Evidence exists that CD11c+ CD8+ T cells may exert their effector or regulatory functions under different conditions. To date, no studies have addressed the frequency of CD11c+ T cells in cancer. Limited evidence exists in terms of expression of immune-checkpoint receptors, programmed cell death protein 1 (PD-1) and T-lymphocyte-associated antigen 4 (CTLA-4), as well as forkhead box P3 (Foxp3) in mouse lymphoid organs. Here, we have assessed CD11c+ CD8+ and CD11c+ CD4+ T cells, Foxp3, PD-1, and CTLA-4 expressing CD4+ T cells and CD8+ T cells in different tissues from three groups of male BALB/c mice-young, mature, and those with colorectal cancer (CRC). Analysis of CD3+ CD11c+ T cells in the bone marrow (BM), spleen, and lymph nodes (LN) in each group showed a higher percentage of CD3+ CD11c+ T cells in the BM from all groups and in the lymphoid organs of the cancer group compared with the young and mature groups. CD4low and CD4high cell fractions in mice BM have different expression patterns for Foxp3 and CTLA-4. We have observed a higher frequency of CD8+ PD-1+ T cells in the BM, spleen, and LN of CRC mice compared with normal mice. T-cell exhaustion is associated with inhibitory receptor PD-1. According to the regulatory roles of CD11c expression in CD8+ T cells, we have proposed that the elevated percentage of CD11c, Foxp3, CTLA-4, and PD-1 expressing T cells were associated with immune response dysregulation in CRC.

Association of PD-1.5 C/T, but Not PD-1.3 G/A, with Malignant and Benign Brain Tumors in Iranian Patients.

Programmed death-1 (PD-1) negatively regulates the immune response. The aims of this study were to assess the association of two single nucleotide polymorphisms in the PD-1 gene, PD-1.5 (+7785 C/T-rs2227981) and PD-1.3 (+7146 G/A- rs11568821), with benign and malignant brain tumors. Patients with brain tumors (96 patients with benign and 56 with malignant brain tumors) and 150 healthy control individuals were included. PCR-RFLP was performed for genotyping. It was revealed that the genotype and allele frequencies of PD-1.5 C/T polymorphism were significantly different between all brain tumor patients and the control group. The frequencies of the CT genotype and T allele were higher in brain tumor patients. In contrast, the frequency of PD-1.3 G/A genotypes and alleles showed no significant difference between all brain tumor patients and controls. Patients were then divided into malignant and benign groups. The results revealed a significant difference in both patients groups compared with the controls only at PD-1.5 C/T position. Arlequin analysis showed the GC haplotype was the most frequent haplotype in the whole group of patients and controls, and the GT haplotype was significantly different between patient and control groups. In conclusion, we demonstrate that PD-1.5 C/T polymorphism, but not PD-1.3 G/A, is associated with brain tumors in Iranian patients.

The Effects of NDRG2 Overexpression on Cell Proliferation and Invasiveness of SW48 Colorectal Cancer Cell Line.

BACKGROUND: Colorectal cancer (CRC) is one of the most common causes of cancer-related death in the world. The expression of N-myc downstream-regulated gene 2 (NDRG2) is down-regulated in CRC. The aim of this study was to investigate the effect of NDRG2 overexpression on cell proliferation and invasive potential of SW48 cells. METHODS: SW48 cells were transfected with a plasmid overexpressing NDRG2. After stable transfection, the effect of NDRG2 overexpression on cell proliferation was evaluated by MTT assay. The effects of NDRG2 overexpression on cell migration, invasion and cell motility and matrix metalloproteinase 9 (MMP9) activities were also investigated using matrigel transwell assay, wound healing assay and gelatin zymography, respectively. RESULTS: MTT assay showed that overexpression of NDRG2 caused attenuation of SW48 cell proliferation. Transwell and wound healing assay revealed that NDRG2 overexpression led to inhibition of migration, invasion, and motility of SW48 cells. The overexpression of NDRG2 also reduced the activity of secreted MMP-9. CONCLUSIONS: The results of this study suggest that NDRG2 overexpression inhibits proliferation and invasive potential of SW48 cells, which likely occurs via suppression of MMP-9 activity.

Umbelliprenin induced production of IFN-γ and TNF-α, and reduced IL-10, IL-4, Foxp3 and TGF-ß in a mouse model of lung cancer.

Umbelliprenin is a member of the 7-prenyloxycoumarins with potential therapeutic properties such as cytotoxic effects on various cancer cells. The present study investigates the effect of umbelliprenin on predominance of Th1 and Th2 responses in Lewis lung cancer (LLC) mouse model. The cytotoxic effect of umbelliprenin was explored on LLC cells and mouse splenocytes by MTT assay. Mice into which LLC had been transplanted were treated with umbelliprenin on alternate days, at 2.5 mg/200 µl intraperitoneally. Foxp3, TNF-α and TGF-ß mRNA expressions were assessed in tumor and lung tissues of LLC mice. In addition, IL-10, IFN-γ and IL-4 levels were determined in sera and also in splenocyte culture supernatants at the presence of tumor cell lysate (10 µg/ml) and Con A (3 µg/ml) after 72 h. Results showed the cytotoxic effects of umbelliprenin on LLC cells (IC50 = 51.6 ± 5.4 µM) while no adverse effect was seen at this concentration on normal splenocytes. TNF-α mRNA expression in both lung and tumor tissues was increased. However, Foxp3 and TGF-ß expressions were decreased in tumor tissues. Serum level of IFN-γ was elevated in the umbelliprenin treated cancerous mice compared to the control group while IL-10 and IL-4 secretions were reduced. Tumor size was also decreased in umbelliprenin treated group. In summary, umbelliprenin has shown a partially Th1 bias with a reduction of regulatory immune response. Although the mechanism behind this action is not known, it is speculated that upon changing the Th1/Th2 balance in favour of Th1, umbelliprenin induces its antitumor activity.

Genetic Polymorphisms of CCL22 and CCR4 in Patients with Lung Cancer.

BACKGROUND: An association between lung cancer and chemokines has been advocated in the recent years. This study aims at investigating the association between lung cancer and 16C/A single nucleotide polymorphism (SNP) (rs. 4359426) in C-C motif chemokine 22 (CCL22) as well as C1014T SNP (rs. 2228428) in C-C chemokine receptor type 4 (CCR4), which serves as the receptor for CCL22. METHODS: Genotyping was performed in 148 lung cancer patients and 148 normal controls using Polymerase Chain Reaction-Restriction-Fragment Length Polymorphism (PCR-RFLP). The data were verified by direct automated sequencing. RESULTS: Frequencies of CC, CA and AA genotypes of 16C/A SNP in CCL22 gene were 112 (75.7%), 33 (22.3%) and 3 (2.0%) in patients, and 119 (80.4%), 24 (16.2%) and 5 (3.4%) in controls respectively. No significant differences were observed in genotype frequencies at this position between cases and controls (P=0.34). Moreover, there was no significant association between CCL22 polymorphism and types of lung cancer in patients. The distribution of CC, CT and TT genotypes of C1014T SNP in CCR4 gene, was 76 (51.4%), 60 (40.5%) and 12 (8.1%) in patients, and 80 (54.1%), 49 (33.1%) and 19 (12.8%) in controls respectively. No statistically significant differences were observed in genotypes frequencies of CCR4 gene between patients and controls (P=0.24). The genotype inherited by patients observed not to be associated with the type of lung cancer (P>0.05). CONCLUSION: RESULTS reveal that CCL22 gene polymorphism at position 16C/A and CCR4 gene polymorphism at position C1014T, appear not to be associated with susceptibility to lung cancer.

Intracellular CTLA4 and regulatory T cells in patients with laryngeal squamous cell carcinoma.

To explore if the increased percentages of Regulatory T (Treg) cells, as well as, overexpression of Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) are involved in laryngeal-squamous cell carcinoma (SCC), 45 patients with laryngeal-SCC and 27 healthy controls were enrolled. Flow cytometry was performed to investigate, in the peripheral blood, the prevalence of CD4+CD25+FoxP3+ Treg cells, as well as, surface and intracellular expression of CTLA-4 by the main lymphocyte subsets (CD4+, CD8+ and CD19+). The results indicated intracellular (In)CTLA4 with considerable higher expression in the CD8+ lymphocytes among patients with laryngeal-SCC compared with the control group (8.2 ± 8.7 versus 2.3 ± 3.5, P = 0.001). The mean percentage of InCTLA4+CD4+ and InCTLA4+CD19+ lymphocytes was also significantly higher in patients (8.7 ± 7.8 versus 4.4 ± 4.2, P = 0.018 and 0.6 ± 0.8 versus 0.2 ± 0.2, P = 0.024, respectively). With respect to surface (Sur)CTLA4, the difference between patients and controls was, however, significant only in the case of CD8+ lymphocytes (0.7 ± 0.6 versus 0.3 ± 0.3, P = 0.003, respectively). The percentage of Treg cells was observed to be significantly higher in patients (7.5 ± 6.3 and 3.2 ± 1.9, P < 0.0001). Furthermore, association analysis revealed the association of Treg cell increase with the higher tumor-size and lymphnode stage (P < 0.005). These data collectively suggest that patients with laryngeal-SCC may benefit from immunotherapy targeting CTLA4 and Treg cells.

Home Palliative Care during the COVID-19 Pandemic: A Scoping Review.

Palliative care (PC), which improves the quality of life for patients with serious illnesses, can be offered in multiple settings, such as the hospital, community, and home. The trend toward delivering PC at home has been recently accelerated during the COVID-19 pandemic. The pandemic has created challenges for patients with serious illnesses who have been proven to be susceptible to serious COVID-19 illnesses. This review of the literature presents research studies on home PC (HPC) during the pandemic. Databases (PubMed, Scopus, and Web of Science Core Collection) were searched. Twelve research/case studies were found to be relevant. These articles gathered information either through qualitative (surveys/interviews) methods or medical records. Most qualitative articles focused on perceived challenges and opportunities from HPC professionals' perspectives. Adopting telehealth was frequently discussed as a key tool to adjust to the pandemic. In general, HPC professionals and patients had a positive attitude toward telehealth, and this attitude was much more pronounced among professionals than patients. Among HPC professionals, some reports indicated that their burnout rates reduced, and job satisfaction increased during the pandemic. Regarding clinical and cost outcomes, there is a gap in the literature on HPC during the pandemic. In conclusion, despite challenges, it seems that the pandemic has gifted some long-term opportunities for promoting HPC in combination with telehealth. COVID-19 will not be the last pandemic, and we should be prepared for the next one by updating policies and building concrete infrastructure for HPC.

Telehealth Utilization and Good Care among Informal Caregivers: Health Information National Trends Survey, 2022.

BACKGROUND: The COVID-19 pandemic accelerated the adoption of telehealth services. Informal caregivers provide vital support to family and friends. Studying telehealth among informal caregivers is crucial to understanding how technology can support and enhance their caregiving responsibilities, potentially enhancing telehealth services for them as well as their patients. The present study aims to nationally investigate telehealth utilization and quality among informal caregivers. METHODS: This cross-sectional investigation employed the 2022 Health Information National Trends Survey (HINTS) dataset. Informal caregivers, telehealth variables (utilization, good care, technical problems, convenience, and concerns about infection exposure), and sociodemographic factors (age, gender, race/ethnicity, income, education, health insurance, and census regions) were identified based on questions in the survey. Weighted multivariable logistic regression models were employed to calculate odds ratios (ORs), 95% confidence intervals (CIs), and p-values. RESULTS: Significant disparities in telehealth utilization were detected among informal caregivers (N = 831), when telehealth users were compared to non-users. Those aged 50-64 (OR = 0.36, 95% CI = 0.20-0.65) and 65+ (OR = 0.40, 95% CI = 0.21-0.74) had significantly lower odds of using telehealth than those aged 35-49. Men had significantly lower odds of telehealth utilization (OR = 0.47, 95% CI = 0.25-0.87). Black caregivers compared to Whites had significantly lower odds (OR = 0.49, 95% CI = 0.24-0.99), while health insurance increased odds (OR = 5.31, 95% CI = 1.67-16.86) of telehealth utilization. Informal caregivers who used telehealth were more likely to be perceived as good telehealth caregivers if they had no telehealth technical issues compared to caregivers who had (OR = 4.61, CI = 1.61-13.16; p-value = 0.0051) and if they were from the South compared to the West (OR = 2.95, CI = 1.18-7.37, p-value = 0.0213). CONCLUSIONS: For the first time, to the best of our knowledge, we have nationally investigated telehealth utilization and quality among informal caregivers. Disparities in telehealth utilization among informal caregivers are evident, with age, gender, race, and health insurance being significant determinants. Telehealth quality is significantly influenced by technical problems and census regions, emphasizing the importance of addressing these aspects in telehealth service development for informal caregivers.

Mental Health Conditions- and Substance Use-Associated Emergency Department Visits during the COVID-19 Pandemic in Nevada, USA.

Background-Mental health conditions and substance use are linked. During the COVID-19 pandemic, mental health conditions and substance use increased, while emergency department (ED) visits decreased in the U.S. There is limited information regarding how the pandemic has affected ED visits for patients with mental health conditions and substance use. Objectives-This study examined the changes in ED visits associated with more common and serious mental health conditions (suicidal ideation, suicide attempts, and schizophrenia) and more commonly used substances (opioids, cannabis, alcohol, and cigarettes) in Nevada during the COVID-19 pandemic in 2020 and 2021 compared with the pre-pandemic period. Methods-The Nevada State ED database from 2018 to 2021 was used (n = 4,185,416 ED visits). The 10th Revision of the International Classification of Diseases identified suicidal ideation, suicide attempts, schizophrenia, and the use of opioids, cannabis, alcohol, and cigarette smoking. Seven multivariable logistic regression models were developed for each of the conditions after adjusting for age, gender, race/ethnicity, and payer source. The reference year was set as 2018. Results-During both of the pandemic years (2020 and 2021), particularly in 2020, the odds of ED visits associated with suicidal ideation, suicide attempts, schizophrenia, cigarette smoking, and alcohol use were all significantly higher than those in 2018. Conclusions-Our findings indicate the impact of the pandemic on mental health- and substance use-associated ED visits and provide empirical evidence for policymakers to direct and develop decisive public health initiatives aimed at addressing mental health and substance use-associated health service utilization, especially during the early stages of large-scale public health emergencies, such as the COVID-19 pandemic.

Changes in characteristics of inpatient respiratory conditions from 2019 to 2021 (before and during the COVID-19 pandemic).

Background: The COVID-19 pandemic has resulted in an increase in the number of individuals with respiratory conditions that require hospitalization, posing new challenges for the healthcare system. Recent respiratory condition studies have been focused on the COVID-19 period, with no comparison of respiratory conditions before and during the pandemic. This study aimed to examine hospital-setting respiratory conditions regarding potential changes in length of stay (LOS), mortality, and total charge, as well as socioeconomic disparities before and during the pandemic. Methods: The study employed a pooled cross-sectional design based on the State Inpatient Data Nevada for 2019 (prior to the COVID-19 pandemic) and 2020-2021 (during the pandemic) and investigated all respiratory conditions, identified by the International Classification of Disease, 10th Revision codes (n = 227,338). Descriptive analyses were carried out for the three years. Generalized linear regression models were used for multivariable analyses. Outcome measures were hospital LOS, mortality, and total charges. Results: A total of 227,338 hospitalizations with a respiratory condition were included. Hospitalizations with a respiratory condition increased from 65,896 in 2019 to 80,423 in 2020 and 81,018 in 2021. The average LOS also increased from 7.9 days in 2019 to 8.8 days in 2020 but decreased to 8.1 days in 2021; hospital mortality among patients with respiratory conditions increased from 7.7% in 2019 to 10.2% but decreased to 9.6% in 2021; and the total charges per discharge were $159,119, $162,151, and $161,733 from 2019 to 2021, respectively (after adjustment for the inflation rate). Hispanic, Asian, and other race patients with respiratory conditions were 1-3 times more likely than white patients to have higher mortality and LOS. Medicaid patients and non-White patients were predictors of a higher respiratory-related hospital total charge. Conclusion: Demographic and socioeconomic factors were significantly associated with respiratory-related hospital utilization in terms of LOS, mortality, and total charge.

Umbelliprenin is cytotoxic against QU-DB large cell lung cancer cell line but anti-proliferative against A549 adenocarcinoma cells.

BACKGROUND: Umbelliprenin is a natural compound, belonging to the class of sesquiterpene coumarins. Recently, umbelliprenin has attracted the researchers' attention for its antitumor activities against skin tumors. Its effect on lung cancer is largely unknown. The aim of our study was to investigate the effects of this natural compound, which is expected to have low adverse effects, on lung cancer. METHODS: The QU-DB large cell and A549 adenocarcinoma lung cancer cell lines were treated with umbelliprenin. IC50 values were estimated using methyl thiazolely diphenyl-tetrazolium bromide (MTT) assay, in which a decrease in MTT reduction can occur as a result of cell death or cell proliferation inhibition. To quantify the rate of cell death at IC50 values, flow cytometry using Annexin V-FITC (for apoptotic cells), and propidium iodide (for necrotic cells) dyes were employed. RESULTS: Data from three independent MTT experiments in triplicate revealed that IC50 values for QU-DB and A549 were 47 ± 5.3 µM and 52 ± 1.97 µM, respectively. Annexin V/PI staining demonstrated that umbelliprenin treatment at IC50 induced 50% cell death in QU-DB cells, but produced no significant death in A549 cells until increasing the umbelliprenin concentration to IC80. The pattern of cell death was predominantly apoptosis in both cell lines. When peripheral blood mononuclear cells were treated with 50 µM and less concentrations of umbelliprenin, no suppressive effect was observed. CONCLUSIONS: We found cytotoxic/anti-proliferative effects of umbelliprenin against two different types of lung cancer cell lines.

Awareness of Obesity-Related Cancers: A Complex Issue.

Cancer rates are on the rise across the world, making the illness a public health crisis, particularly in developed countries where cancer has become a leading cause of death [...].

Disparities in Adverse Maternal Outcomes Among Five Race and Ethnicity Groups.

Background: Racial/ethnic disparities are evident in adverse maternal health outcomes, but they are shifting due to interventions, initiatives, changing demographics, and the prevalence of preexisting conditions. This study examined the current racial/ethnic disparities in adverse maternal outcomes. Materials and Methods: In a cross-sectional study, the International Classification of Diseases-10 codes for the principal diagnosis and secondary diagnoses were retrieved from the National Inpatient Sample database (2016-2018). A weighted multiple logistic regression model assessed disparities in seven adverse maternal outcomes, including preterm labor, gestational hypertension (GHTN) and diabetes, premature rupture of membranes (PRM), infection of the amniotic cavity (INFAC), placental abruption, and postpartum hemorrhage (PPH). A weighted linear regression model assessed disparities in a composite variable of maternal outcomes. A maternal-specific comorbidity index assessed risk adjustment, and other clinical, sociodemographic, and hospital factors were considered. Results: A total of 2,211,345 pregnancies were included. Preterm labor, GHTN, and placental abruption had the highest raw rate among Black women compared to all races. After adjusting for control variables in the regression analysis, these adverse outcomes also showed the highest odds ratio (OR) among Black women compared to White women (the reference group). Gestational diabetes, PRM, and INFAC had the highest raw rate among Asians/Pacific Islanders (PIs). After adjusting for control variables, these adverse outcomes also showed the highest OR among Asians/PIs compared to White women. The OR for PPH was the highest for Native Americans compared to White women. Furthermore, results of the composite outcome variable indicated that all minority groups experienced the overall poorer maternal outcome than White women. Conclusions: Overall, all four minority women had higher raw rates and also odds of experiencing the studied adverse outcomes than White women. Existing efforts should be strengthened to continue reducing racial/ethnic disparities in adverse maternal outcomes.

1Menstruation: a possible independent health promoter, aging and COVID-19.

Women live longer than men. Cardiovascular disorders, cancers, and serious infectious conditions are less common among women than men. Recent data also indicate that women, particularly before menopause, are less susceptible to severe COVID-19, a viral infection hitting less-healthy individuals. The superiority of women regarding health has not been completely understood and partly been explained by estradiol beneficial effects on the microenvironment of the body, notably cytokine network. Estradiol cycles are aligned with menstruation cycles, a challenge for distinguishing their individual effects on human health. Large-scale, long-term studies indicate that hysterectomy, particularly at younger ages, is associated with an increased risk of mortality, cancer, or heart disorders. The underlying mechanisms for the increased risk in hysterectomized women are hard to be investigated in animal models since only a few primates menstruate. However, blood exchange models could resemble menstruation and provide some insight into possible beneficial effects of menstruation. Sera from animal models (neutral blood exchange) and also humans that have undergone therapeutic plasma exchange enhance the proliferation of progenitor cells in the culture and contain lower levels of proinflammatory factors. If menstruation resembles a blood exchange model, it can contribute to a healthier cytokine network in women. Consequently, menstruation, independently from estradiol health beneficial effects, can contribute to greater longevity and protection against certain disorders, e.g., COVID-19, in women. Investigation of COVID-19 rate/severity in hysterectomized women will provide insight into the possible beneficial effects of menstruation in COVID-19.

Immunosuppressive Effects and Potent Anti-tumor Efficacy of mTOR Inhibitor Everolimus in Breast Tumor-bearing Mice.

To investigate the effects of everolimus, a mechanistic/mammalian target of rapamycin (mTOR) inhibitor, on tumor growth and immune response in a mouse model of breast cancer. Human hormone receptor-positive (HR+)/human epidermal growth receptor 2-negative (HER2-) MC4-L2 cell line was used to establish a mouse model of breast cancer. The inhibitory effects of high (10 mg/kg) and low (5 mg/kg) doses of everolimus were investigated on tumor growth. Additionally, the frequency of CD4+Foxp3+ regulatory T cells (Tregs), CD8+Foxp3+ Tregs, and CD4+ and CD8+ T cells expressing cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) was explored by flow cytometry in bone marrow, lymph nodes, and spleen. Our results showed that both 10 mg/kg and 5 mg/kg doses of everolimus efficiently inhibited tumor growth, resulting in reduced breast tumor volume. In addition, it was revealed that everolimus-treated mice induced a higher frequency of CD4+Foxp3+ Tregs, CD8+Foxp3+ Tregs, and CD4+Foxp3+CTLA-4+ Tregs as well as CD4+ and CD8+ T cells expressing CTLA-4 in their bone marrow, lymph nodes, and spleen compared with standard control (vehicle-treated) in a dose-dependent manner. Furthermore, we found that everolimus treatment with 10 mg/kg and 5 mg/kg increased the frequency of Helios+Foxp3+ Tregs in the bone marrow of treated mice compared with the control group. Our results indicate that treatment with everolimus not only inhibits tumor growth but also exerts an immunomodulatory effect by inducing Tregs in the lymphoid organs of breast cancer-bearing mice. The combination of therapy with other anti-cancer agents may negate immune suppression and improve the efficacy of mTOR-targeted breast cancer therapy.

COVID-19 and Flu Pandemics Follow a Pattern: A Possible Cross-immunity in the Pandemic Origin and Graver Disease in Farther Regions.

So far, the COVID-19 pandemic has caused less casualty in Eastern Asia areas compared to the other parts of the world. The pattern of less casualty in the pandemic origin has also been observed in the three main flu pandemics in the last century. It is reasonable to speculate that less casualty of COVID-19/flu in the pandemic origin is likely due to the preexisting cross-immunity to some close viruses being more prevalent in those regions. Experts and modelers should scale up the severity of a flu-like viral epidemic to predict its real severity for the rest of the world.