Cause Of Death Research Articles

Impaired intestinal FXR signaling is involved in aberrant stem cell function leading to intestinal failure-associated liver disease in pediatric patients with short bowel syndrome.

Intestinal failure-associated liver disease (IFALD) is a serious complication of long-term parenteral nutrition in patients with short bowel syndrome (SBS), and is the main cause of death in SBS patients. Prevention of IFALD is one of the major challenges in the treatment of SBS. Impairment of intestinal barrier function is a key factor in triggering IFALD, therefore promoting intestinal repair is particularly important. Intestinal repair mainly relies on the function of intestinal stem cells (ISC), which require robust mitochondrial fatty acid oxidation (FAO) for self-renewal. Herein, we report that aberrant LGR5+ ISC function in IFALD may be attributed to impaired farnesoid X receptor (FXR) signaling, a transcriptional factor activated by steroids and bile acids. In both surgical biopsies and patient-derived organoids (PDOs), SBS patients with IFALD represented lower population of LGR5+ cells and decreased FXR expression. Moreover, treatment with T-βMCA in PDOs (an antagonist for FXR) dose-dependently reduced the population of LGR5+ cells and the proliferation rate of enterocytes, concomitant with decreased key genes involved in FAO including CPT1a. Interestingly, however, treatment with Tropifexor in PDOs (an agonist for FXR) only enhanced FAO capacity, without improvement in ISC function and enterocyte proliferation. In conclusion, these findings suggested that impaired FXR may accelerate the depletion of LGR5 + ISC population through disrupted FAO processes, which may serve as a new potential target of preventive interventions against IFALD for SBS patients.

Trends and multiple causes of deaths in hypertensive and diabetic patients in Rio Branco, Acre

Trends and multiple causes of deaths in hypertensive and diabetic patients in Rio Branco, Acre

Alzheimer's disease and related dementia diagnoses among American Indian and Alaska Native adults aged ≥45 years, Indian Health Service System, 2016-2020.

Alzheimer's disease is the most common type of dementia and is responsible for up to 80% of dementia diagnoses and is the sixth leading cause of death in the United States. An estimated 38,000 American Indian/Alaska Native (AI/AN) people aged ≥65 years were living with Alzheimer's disease and related dementias (ADRD) in 2020, a number expected to double by 2030 and quadruple by 2050. Administrative healthcare data from the Indian Health Service (IHS) were used to estimate ADRD among AI/AN populations. Administrative IHS healthcare data from federal fiscal years 2016 to 2020 from the IHS National Data Warehouse were used to calculate the count and rate per 100,000 AI/AN adults aged ≥45 years with at least one ADRD diagnosis code on their medical record. This study identified 12,877 AI/AN adults aged ≥45 years with an ADRD diagnosis code, with an overall rate of 514 per 100,000. Of those, 1856 people were aged 45-64. Females were 1.2 times (95% confidence interval: 1.1-1.2) more likely than males to have a medical visit with an ADRD diagnosis code. Many AI/AN people with ADRD rely on IHS, tribal, and urban Indian health programs. The high burden of ADRD in AI/AN populations aged 45-64 utilizing IHS health services highlights the need for implementation of ADRD risk reduction strategies and assessment and diagnosis of ADRD in younger AI/AN populations. This study provides a baseline to assess future progress for efforts addressing ADRD in AI/AN communities.

Detection of Psychological Dysfunction and Suicide Risk Among Postpartum Women.

Prevalence rates of perinatal mood disorders range from 5 to 25%. Furthermore, suicide is a leading cause of death in postpartum women. Various factors have been associated with an increased risk of suicide in postpartum women, including co-occurring mental health disorders, lack of mental health care, and substance use. It is important for mental health screening and psychological assessment used within OB-GYN clinics to be current with regard to postpartum mood dysfunction and suicide risk assessment. We collected data from a sample of 78 postpartum women (0-6-month post-delivery), focusing specifically on patterns of emotional/internalizing dysfunction, using three different screening measures as predictors. Contrary to hypotheses, our sample did not produce significant elevations on target criterion scales of the Minnesota multiphasic personality inventory-3 (MMPI-3). Although the multidimensional behavioral health screen (MBHS) was better at differentially capturing MMPI-3 elevations when compared to the Edinburgh postnatal depression scale (EDPS) and patient health questionnaire-9 (PHQ-9), two of the three comparisons were not statistically significant. Statistical analyses were challenged by our extremely low base rate for elevated suicide risk. Despite this, the MBHS performed better than the EPDS and PHQ-9 at accurately capturing elevated suicide risk.

PDPN/CCL2/STAT3 feedback loop alter CAF heterogeneity to promote angiogenesis in colorectal cancer.

Colorectal cancer (CRC) is one of the common clinical malignancies and the fourth leading cause of cancer-related death in the world. The tumor microenvironment (TME) plays a crucial role in promoting tumor angiogenesis, and cancer-associated fibroblasts (CAFs) are one of the key components of the tumor microenvironment. However, due to the high heterogeneity of CAFs, elucidating the molecular mechanism of CAF-mediated tumor angiogenesis remained elusive. In our study, we found that there is pro-angiogenic functional heterogeneity of CAFs in colorectal cancer and we clarified that Podoplanin (PDPN) can specifically label CAF subpopulations with pro-angiogenic functions. We also revealed that PDPN + CAF could maintain CAF heterogeneity by forming a PDPN/CCL2/STAT3 feedback loop through autocrine CCL2, while activate STAT3 signaling pathway in endothelial cells to promote angiogenesis through paracrine CCL2. We demonstrated WP1066 could inhibit colorectal cancer angiogenesis by blocking both the PDPN/CCL2/STAT3 feedback loop in CAFs and the STAT3 signaling pathway in endothelial cells. Altogether, our study suggests that STAT3 could be a potential therapeutic target for blocking angiogenesis in colorectal cancer. We provide theoretical basis and new therapeutic strategies for the clinical treatment of colorectal cancer.

Transcriptomic observations of Intra and extracellular immunotherapy targets for pediatric brain tumors.

Despite surgical resection, chemoradiation and targeted therapy, brain tumors remain a leading cause of cancer related death in children. Immunotherapy has shown some promise and is actively being investigated for treating childhood brain tumors. However, a critical step in advancing immunotherapy for these patients is to uncover targets that can be effectively translated into therapeutic interventions. In this study, our team performed a transcriptomic analysis across pediatric brain tumor types to identify potential targets for immunotherapy. Additionally, we assessed components that may impact patient response to immunotherapy, including the expression of genes essential for antigen processing and presentation, inhibitory ligands and receptors, interferon signature, and overall predicted T cell infiltration. We observed distinct expression patterns across tumor types. These included elevated expression of antigen genes and antigen processing machinery in some tumor types while other tumors had elevated inhibitory checkpoint receptors, known to be associated with response to checkpoint inhibitor immunotherapy. These findings suggest that pediatric brain tumors exhibit distinct potential for specific immunotherapies. We believe our findings can guide investigators in their assessment of appropriate immunotherapy classes and targets in pediatric brain tumors.

Prognostic value of 18F-FDG PET/CT in postoperative recurrence of retroperitoneal liposarcoma: a single-center retrospective study.

Recurrence is the leading cause of tumor-related death in retroperitoneal liposarcoma (RPLPS). Variant subtypes of RPLPS determine different recurrence 18F]-fluoro-2-deoxy-D-glucose (18F-FDG) PET/computed tomography (PET/CT). This study analyzed the characteristics of different histologic subtypes of 18F-FDG PET/CT and their associations with recurrence and prognosis. Clinical-pathological information, 18F-FDG PET/CT data, recurrence, and progression-free survivals (PFS) of 83 patients with RPLPS were collected. Maximum and peak standardized uptake values (SUVmax and SUVpeak, respectively) and mean CT value (CTmean) of tumors were measured and correlated with histologic subtype. The predictability of SUVmax, SUVpeak, and CTmean for the histologic subtype was evaluated using receiver operating characteristics (ROC) max and SUVpeak for recurrence. Kaplan-Meier analysis was performed to max and SUVpeak were risk factors for recurrence. Studied patients with different types of liposarcomas. Dedifferentiated liposarcomas (DDLPS) had higher SUVmax and SUVpeak than well-differentiated (WDLPS) and myxoid/round cell (MLPS) types. WDLPS had lower CTmean values compared to MLPS and DDLPS. Using ROC curves, determined cut-off values for SUVmax (5.1) to differentiate DDLPS, SUVpeak (3.0) for WDLPS, and CTmean (12.3 Hu) for WDLPS. These cut-offs were found to be best for predicting recurrence. Kaplan-Meier analysis showed that histologic subtype, SUVmax, and SUVpeak were all linked to recurrence-free survival. The use of SUV and CT features on 18F-FDG PET/CT imaging may increase confidence in subtype diagnosis. Patients with SUVmax > 5.1 or SUVpeak > 3.0 suggest a poor prognosis.

Neurologic complications in patients receiving aortic versus subclavian versus femoral arterial cannulation for post-cardiotomy extracorporeal life support: results of the PELS observational multicenter study

BackgroundCerebral perfusion may change depending on arterial cannulation site and may affect the incidence of neurologic adverse events in post-cardiotomy extracorporeal life support (ECLS). The current study compares patients' neurologic outcomes with three commonly used arterial cannulation strategies (aortic vs. subclavian/axillary vs. femoral artery) to evaluate if each ECLS configuration is associated with different rates of neurologic complications.MethodsThis retrospective, multicenter (34 centers), observational study included adults requiring post-cardiotomy ECLS between January 2000 and December 2020 present in the Post-Cardiotomy Extracorporeal Life Support (PELS) Study database. Patients with Aortic, Subclavian/Axillary and Femoral cannulation were compared on the incidence of a composite neurological end-point (ischemic stroke, cerebral hemorrhage, brain edema). Secondary outcomes were overall in-hospital mortality, neurologic complications as cause of in-hospital death, and post-operative minor neurologic complications (seizures). Association between cannulation and neurological outcomes were investigated through linear mixed-effects models.ResultsThis study included 1897 patients comprising 26.5% Aortic (n = 503), 20.9% Subclavian/Axillary (n = 397) and 52.6% Femoral (n = 997) cannulations. The Subclavian/Axillary group featured a more frequent history of hypertension, smoking, diabetes, previous myocardial infarction, dialysis, peripheral artery disease and previous stroke. Neuro-monitoring was used infrequently in all groups. Major neurologic complications were more frequent in Subclavian/Axillary (Aortic: n = 79, 15.8%; Subclavian/Axillary: n = 78, 19.6%; Femoral: n = 118, 11.9%; p < 0.001) also after mixed-effects model adjustment (OR 1.53 [95% CI 1.02–2.31], p = 0.041). Seizures were more common in Subclavian/Axillary (n = 13, 3.4%) than Aortic (n = 9, 1.8%) and Femoral cannulation (n = 12, 1.3%, p = 0.036). In-hospital mortality was higher after Aortic cannulation (Aortic: n = 344, 68.4%, Subclavian/Axillary: n = 223, 56.2%, Femoral: n = 587, 58.9%, p < 0.001), as shown by Kaplan–Meier curves. Anyhow, neurologic cause of death (Aortic: n = 12, 3.9%, Subclavian/Axillary: n = 14, 6.6%, Femoral: n = 28, 5.0%, p = 0.433) was similar.ConclusionsIn this analysis of the PELS Study, Subclavian/Axillary cannulation was associated with higher rates of major neurologic complications and seizures. In-hospital mortality was higher after Aortic cannulation, despite no significant differences in incidence of neurological cause of death in these patients. These results encourage vigilance for neurologic complications and neuromonitoring use in patients on ECLS, especially with Subclavian/Axillary cannulation.Graphical abstract

Prognostic factors for pediatric patients with severe intestinal motility disorders: a single institution's experience.

To identify the prognostic factors for pediatric severe intestinal motility disorder (IMD). We reviewed the medical records of patients with severe IMD, who required total parenteral nutrition (TPN) for ≥ 60days at our institution between April, 1984 and March, 2023, examining their characteristics to identify prognostic factors. The types of IMD in the 14 patients enrolled in this study were as follows: isolated hypoganglionosis (IHG, n = 6), extensive aganglionosis (EAG: n = 6), and chronic idiopathic intestinal pseudo-obstruction (CIIP, n = 2). There was no significant difference in mortality among the three types of severe IMD. Weaning-off TPN and the use of the colon were not significant prognostic factors, but cholestasis was a significant prognostic factor (p = 0.005). There was a high mortality rate (50%), with the major causes of death being intestinal failure-associated liver disease (IFALD) following hepatic failure, and catheter-related blood stream infection (CRBSI). One IHG patient underwent small bowel transplantation but died of acute rejection. Severe IMD is still associated with a high mortality rate and cholestasis predicts the prognosis. Thus, preventing or improving IFALD and CRBSI caused by long-term TPN is important for reducing the mortality rate.

Applying whole genome sequencing to predict phenotypic drug resistance in Mycobacterium tuberculosis: leveraging 20 years of nationwide data from Denmark.

Infection with Mycobacterium tuberculosis remains one of the biggest causes of death from a single microorganism worldwide, and the continuous emergence of drug resistance aggravates our ability to cure the disease. New improved resistance detection methods are needed to provide adequate treatment, such as whole genome sequencing (WGS), which has been used increasingly to identify resistance-conferring mutations over the last decade. The steadily increasing knowledge of resistance-conferring mutations increases our ability to predict resistance based on genomic data alone. This study evaluates the performance of WGS to predict M. tuberculosis complex resistance. It compares WGS predictions with the phenotypic (culture-based) drug susceptibility results based on 20 years of nationwide Danish data. Analyzing 6,230 WGS-sequenced samples, the sensitivities for isoniazid, rifampicin, ethambutol, and pyrazinamide were 82.5% [78.0%-86.5%, 95% confidence interval (CI)], 97.3% (90.6%-99.7%, 95% CI), 58.0% (43.2%-71.8%, 95% CI), and 60.5% (49.0%-71.2%, 95% CI), respectively, and specificities were 99.8% (99.7%-99.9%, 95% CI), 99.8% (99.7%-99.9%, 95% CI), 99.4% (99.2%-99.6%, 95% CI), and 99.9% (99.7%-99.9%, 95% CI), respectively. A broader range of both sensitivities and specificities was observed for second-line drugs. The results conform with previously reported values and indicate that WGS is reliable for routine resistance detection in resource-rich tuberculosis low-incidence and low-resistance settings such as Denmark.

The Role of Short-Chain Fatty Acids in Myocardial Ischemia-Reperfusion Injury.

This study aims to review the effects of short-chain fatty acids (SCFAs) in regulating the myocardial ischemia-reperfusion injury (MIRI). Coronary heart disease (CHD) is a well-known leading cause of death and disability worldwide. Cardiac substrate metabolism plays the determinant role in assessing the severity of heart injury due to the abruptly shifted energy production during the MIRI. Fatty acids are the main energy fuels for the heart, which are classified into long-, medium- and short chain fatty acids by the length of carbon chain. SCFAs are the main metabolites derived from the anaerobic bacterial fermentation of fiber-rich diets, which are shown to play a protective role in cerebrovascular disease previously. Meanwhile, accumulating evidences suggest that SCFAs can also play a crucial role in cardiac energy metabolism. Results of various studies revealed the cardioprotective effects of SCFAs by displaying anti-inflammatory and anti-ferroptotic function, connecting gut-brain neural circuit and regulating the intestinal flora.

Aging Delays Completion of Head Rotation Cycles in Continuous Gaze Stabilization Exercises Despite Putative Healthy Vestibular Function.

aging is associated with loss of balance, with falls being the leading cause of death among elderly in the United States. Gaze stabilization exercises (GSE) improve balance control in vestibular populations and could be useful to prevent falls in healthy individuals. However, the extent to which aging affects head kinematics in GSE is unknown. forty-eight young (n=25, 24 ± 6 years, 60% female) and older (n=23, 66 ± 5 years, 56% female) adults completed six 30-second GSE. Participants were asked to maintain gaze fixation on a stationary target while continuously performing head movements in pitch (e.g., vertical) and yaw (e.g., horizontal) directions. The visual target was placed on the wall 1m or 2m away, or hand-held at arm's length. Head kinematics were recorded with an inertial measurement unit placed on the back of the participants' head. older adults took significantly more time (e.g., delay) to complete cycles of head rotation compared to young participants across all GSE. Such delay was further increased during pitch head rotation while fixating gaze of the 1m target. The range of velocity (ROV) of head rotation, however, was equivalent between groups in all GSE. aging leads to the maintenance of head cycle ROV at the expense of delayed cycles of head rotation, suggesting an age-dependent prioritization strategy (e.g., adapt duration first vs range second) during continuous head movements. The distance of the visual target and head movement direction influenced elderly performance and should be considered when prescribing GSE to older populations.

Minocycline alleviates microglia ferroptosis by inhibiting HO-1 during cerebral ischemia-reperfusion injury.

Ischemic stroke is a leading cause of death and disability in individuals worldwide. Cerebral ischemia-reperfusion injury (CIRI) typically results in severe secondary injury and complications following reperfusion therapy. Microglia play critical roles in the inflammatory reaction of CIRI. However, less attention has been given to microglial death in this process. Our study aims to explore microglial death in CIRI and the effects and mechanism of minocycline treatment on microglia. A middle cerebral artery occlusion (MCAO) model was applied to induce CIRI in rats. At 0h, 24h and 48h post-operation, rats were intraperitoneally injected with 45mg/kg minocycline. Neurological deficit scoring, 2,3,5-triphenyltetrazolium chloride (TTC) staining, assessment of activated microglia and examination of mitochondrial structure were conducted and checked at 72h after reperfusion. Additionally, an in vitro model of oxygen-glucose deprivation/reperfusion (OGD/R) model was established. BV-2 cells were treated with various pharmacological inhibitors of cell death or minocycline. Cell viability, lipid peroxidation, mitochondrial structure and function, and labile Fe2+ and ferroptosis-associated gene/protein levels were measured. Hemin was used for further validation after transcriptome analysis. In the MCAO and OGD/R models, ferroptosis was identified as a major form of microglial death. Minocycline inhibited microglia ferroptosis by reducing HO-1 expression. In addition, minocycline improved mitochondrial membrane potential, mitochondrial structures and microglial survival in vivo. Minocycline also decreased labile Fe2+ levels, lipid peroxidation, and expression of ferritin heavy chain (FTH) and it improved mitochondrial structure and function in vitro. Upregulation of HO-1 counteracted the protective effect of minocycline. Ferroptosis is a major form of microglial death in CIRI. The protective mechanism of minocycline in CIRI partially hinges on its ability to effectively ameliorate microglia ferroptosis by downregulating HO-1 expression. Consequently, targeting microglia ferroptosis is a promising treatment for CIRI.

Stopping the bleed when tourniquets cannot: a technique for Foley catheter balloon compression in trauma.

Hemorrhage is a leading cause of death in trauma. Prehospital hemorrhage control techniques include tourniquet application for extremity wounds and direct compression; however, tourniquets are not effective in anatomic junctions, and direct compression is highly operator dependent. Balloon catheter compression has been employed previously in trauma care, but its use has been confined to the operating room and restricted to specific anatomic injuries. In a single-center retrospective review, we describe a technique for balloon catheter compression for hemorrhage control that can be employed across the continuum of trauma care, from the prehospital setting to the trauma bay, the operating room, and postoperative period. Of 18,303 trauma patients in Venezuela, 45% of the 1757 patients with vascular injuries received Foley catheter compression for hemorrhage control. Of these catheters, the majority (75%) were placed in the emergency department, 5% in the prehospital setting, and 20% in the operating room. Over half (53.2%) of the balloon catheters were placed for hemorrhage control in non-compressible anatomic junctions. Foley catheter balloon compression is a useful addition to a provider's arsenal of hemorrhage control techniques, as it is effective in anatomic junctions, preserves collateral circulation through focused compression, and requires minimal active physical attention to maintain hemostasis.

Rates of Sudden Death After Myocardial Infarction-Insights From the VALIANT and PARADISE-MI Trials.

Sudden death is a leading cause of death after acute myocardial infarction (AMI). The Prospective ARNi vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI (PARADISE-MI) and Valsartan in Acute Myocardial Infarction (VALIANT) trials enrolled patients with pulmonary congestion and/or left ventricular dysfunction after AMI. Whether the prognosis in such patients has changed over time has not been examined. To compare the rate of sudden death/resuscitated cardiac arrest (RCA) after AMI in the PARADISE-MI and VALIANT trials. This was a secondary analysis of multicenter randomized clinical trials enrolling patients after AMI. In the primary analysis, the VALIANT cohort was restricted to patients with "PARADISE-MI-like" characteristics (eg, at least 1 augmenting risk factor and no history of heart failure). The baseline characteristics of people in both trials were compared. The VALIANT trial enrolled from December 1998 to June 2001, and the PARADISE-MI trial enrolled between December 2016, and March 2020. The median follow-up in the VALIANT and PARADISE-MI trials was 24.7 and 22 months, respectively. People with AMI, complicated by pulmonary congestion and/or left ventricular dysfunction, were included in the analysis. Sudden death after AMI. A total of 5661 patients were included in the PARADISE-MI cohort (mean [SD] age, 63.7 [11.5] years; 4298 male [75.9%]), 9617 were included in the VALIANT (PARADISE-MI-like) cohort (mean [SD] age, 66.1 [11.5] years; 6504 male [67.6%]), and 14 703 patients were included in the VALIANT (total) cohort (mean [SD] age, 64.8 [11.8] years; 10 133 male [68.9%]). In the PARADISE-MI-like cohort of the VALIANT trial, 707 of 9617 participants (7.4%) experienced sudden death/RCA. A total of 148 of 5661 people (2.6%) in the PARADISE-MI trial experienced sudden death/RCA. Sudden death rates were highest in the first month after infarction in both trials: 19.3 (95% CI, 16.4-22.6) per 100 person-years in the VALIANT trial and 9.5 (95% CI, 7.0-12.7) per 100 person-years in the PARADISE-MI trial, and these rates declined steadily thereafter. Compared with the VALIANT cohort, people in the PARADISE-MI trial were more often treated with percutaneous coronary intervention for their qualifying AMI and received a β-blocker, statin, and mineralocorticoid receptor antagonist more frequently. After AMI, the risk of sudden death/RCA was highest in the first month, declining rapidly thereafter. Results revealed that compared with counterparts from 20 years ago, the rate of sudden death/RCA in patients with a reduced left ventricular ejection fraction and/or pulmonary congestion was 2- to 3-fold lower in people receiving contemporary management. Interventions to further protect people in the highest risk first month after infarction are needed. ClinicalTrials.gov Identifier: NCT02924727.

Outcomes 10-years after traumatic spinal cord injury in Botswana - a long-term follow-up study

Study designProspective follow-up study.ObjectivesTo describe outcomes, survival, and attendance to routine follow-up visits 10 years post-SCI.SettingThe national SCI-rehabilitation center in Botswana.MethodsAll persons who were admitted with traumatic SCI during a 2-year period, 2011–2013, and survived up to 2 years post-injury were included. Data were collected from the medical records from the follow-up assessment closest to 10 years post-SCI and included demographic and clinical characteristics, functional outcomes, and secondary complications. Data regarding mortalities were received from relatives. Statistical comparisons were made, when possible, between those who attend follow-up assessment and those who did not, and between those who survived up to 10 years post-SCI and those who died.ResultsThe follow-up rate was 76% (19/25) of known survivors. No statistically significant factors were found to affect the follow-up rate. Secondary complications rates were for pressure ulcers and urinary tract infections 21%. Self-catheterisation and suprapubic catheter were the preferred methods to manage neurogenic bladder dysfunction. Ten persons (26%) had deceased since 2nd follow-up assessment. The causes of death were probably SCI-related in more than half of the cases.ConclusionsThis was a follow-up study at year 10 after acute TSCI in Botswana conducted at the national SCI-rehabilitation center. The study supports previous reports regarding the importance of that having specialized SCI units and the need of structured follow-ups, a responsible person in charge of scheduling, and updated patient registers. We found high follow-up rate, low rates of complications and of patients being lost to follow-up.

A noncanonical E3 ubiquitin ligase RNF41-mediated MYO1C stability promotes prostate cancer metastasis by inducing actin remodeling.

Prostate cancer bone metastasis is a predominant cause of death for prostate cancer (PCa) patients. However, the underlying mechanisms are poorly understood. Here, we report that high levels of RNF41 are associated with metastatic human prostate cancer. RNF41 silencing inhibits prostate cancer cell growth, cell migration and invasion in vitro and in vivo. Mechanistically, we identify that RNF41 induces K27- and K63-linked noncanonical polyubiquitination of MYO1C to enhance its stability and induce actin remodeling, which promotes PCa bone metastasis. RNF41 was significantly upregulated in metastatic prostate cancer tissues and positively associated with MYO1C expression. Furthermore, we show in intraarterial injected-bone metastasis xenograft model that targeting MYO1C stability by inhibition of RNF41 markedly suppressed PCa bone metastasis. Collectively, our findings identify RNF41 is an important regulator of prostate cancer cell growth and metastasis and targeting RNF41/MYO1C could be a valuable strategy to ameliorate prostate cancer progression and metastasis.

PPIC-labeled CAFs: Key players in neoadjuvant chemotherapy resistance for gastric cancer

BackgroundGastric cancer (GC) is the fourth leading cause of cancer deaths, with advanced cases having a median survival of less than one year. Neoadjuvant chemotherapy (NCT) is vital but faces drug resistance issues, partly due to cancer-associated fibroblasts (CAFs). Yet, specific CAF subpopulations contributing to resistance are poorly understood. MethodsDifferentially expressed genes (DEGs) between chemosensitive and resistant GC patients were identified using GEO2R. Single-cell sequencing (scRNA-seq) identified CAF-related genes. Immunohistochemistry verified key genes in NCT-treated GC samples, analyzing their correlation with tumor regression grade (TRG) and clinicopathological characteristics. ResultsPPIC as a gene highly expressed in CAFs was closely associated with NCT resistance in gastric cancer. Immunohistochemistry results revealed positivity for the expression of cyclophilin C (CypC), encoded by PPIC, in the 5-fluorouracil and cisplatin NCT resistant and -sensitive groups of gastric cancer patients at rates of 69.7 % (76/109) and 43.6 % (24/55), respectively (p < 0.001). The high expression of CypC in CAFs was positively correlated to tumor size (p = 0.025), T stage (p = 0.004), TNM stage (p = 0.004), and vascular invasion (p = 0.027). In cancer cells the expression of CypC was associated with OS (p = 0.026). However, in CAFs, CypC expression was not related to OS (p = 0.671). ConclusionsPPIC-labeled CAF subgroups are related to NCT resistance and poor prognosis in GC and they may cause drug resistance through signaling pathways such as glucose metabolism and extracellular matrix remodeling. However, the exact mechanism behind the involvement of PPIC-labeled CAF in drug resistance of GC requires further study.

Perspectives of providing magnesium sulfate to patients with preeclampsia and eclampsia: A qualitative study amongst nurse-midwives in Dar es Salaam, Tanzania.

Preeclampsia and eclampsia are among the leading direct causes of maternal death and morbidity worldwide. Up to 34% of maternal deaths in Tanzania are due to preeclampsia/ eclampsia. Magnesium sulfate is recommended for preventing and treating convulsions in women with Preeclampsia or eclampsia. However, evidence suggests limited knowledge of its dosage and proper toxicity assessment after administration among health care providers. This study explored nurse-midwives' perspectives on providing MgSO4 to patients with preeclampsia or eclampsia in Tanzania. A descriptive exploratory qualitative study using in-depth interviews was conducted to understand nurse-midwives' perspectives on providing magnesium sulfate to patients with PE/E. Nineteen nurse-midwives were interviewed from three hospitals in the Dar es Salaam region. We used a semi-structured interview guide in Kiswahili language to collect data. All interviews were digitally recorded and transcribed verbatim. We analyzed data using inductive content analysis. This study revealed that nurse-midwives provide magnesium sulfate to save the lives of women and their unborn children. Nurse-midwives reasoned that confidence in their skill enhances provision of magnesium sulfate. However, they were concerned about its effect on the progress of labour. Ineffective use of magnesium sulfate emerged from inadequate training, an unsupportive work environment, and underutilization of the existing guidelines. Nurse-midwives have clear drive to provide magnesium sulfate to women with preeclampsia or eclampsia. However, inadequate training, underutilization of guidelines and unsupportive work environment lead to ineffective use of magnesium sulfate. Targeted practical training should be emphasized for nurse-midwives mastery of clinical competencies.

Prognostic Significance of Caudal-type Homeobox Gene 2 and Sex-determining Region Y-Box 2 Immunohistochemistry Markers in Gastric Cancer – A Clinicopathological Study

Abstract Background: Gastric cancer is one of the most commonly diagnosed cancers and the third leading cause of cancer-related deaths in the world as it has a poor prognosis due to its delayed presentation. Adenocarcinoma (intestinal or diffuse type) is the most common type histologically, and tumor, node, and metastasis staging is essential for prognosis and treatment planning. Gastric cancer patients may have different clinical presentation even within the same cancer stage group, hence it is important to evaluate additional markers in such patients which can help in prognosticating them to aid in effective management of such patients. This study evaluates two new immunohistochemistry (IHC) markers and their clinical correlation which will help in prognosticating gastric cancer patients. Materials and Methods: Biopsy tissues from 30 patients between April 2016 and April 2019, who underwent upper gastrointestinal endoscopy in a tertiary care center of Armed Forces and were found to have gastric cancer, were studied. Caudal-type homeobox gene 2 (CDX2) and sex-determining region Y-box 2 (SOX2) immunoreactivity was correlated with histomorphology, clinical presentation, and staging of tumor. Results: CDX2 positivity (P = 0.002) as well as SOX2 negativity (P = 0.058) was associated with an advanced stage of disease in our study. CDX2+/SOX2− profile was also noted to be statistically correlating (P = 0.014) with poor prognosis in gastric cancer. Conclusion: Loss of SOX2 together with positive CDX2 expression had a good correlation with advanced disease and poor outcome. Further studies should be undertaken for targeted therapy for these IHC markers.