Transdermal microarrayed electroporation for enhanced cancer immunotherapy based on DNA vaccination.

Despite the tremendous clinical potential of nucleic acid-based vaccines, their efficacy to induce therapeutic immune response has been limited by the lack of efficient local gene delivery techniques in the human body. In this study, we develop a hydrogel-based organic electronic device (µEPO) for both transdermal delivery of nucleic acids and in vivo microarrayed cell electroporation, which is specifically oriented toward one-step transfection of DNAs in subcutaneous antigen-presenting cells (APCs) for cancer immunotherapy. The µEPO device contains an array of microneedle-shaped electrodes with pre-encapsulated dry DNAs. Upon a pressurized contact with skin tissue, the electrodes are rehydrated, electrically triggered to release DNAs, and then electroporate nearby cells, which can achieve in vivo transfection of more than 50% of the cells in the epidermal and upper dermal layer. As a proof-of-concept, the µEPO technique is employed to facilitate transdermal delivery of neoantigen genes to activate antigen-specific immune response for enhanced cancer immunotherapy based on a DNA vaccination strategy. In an ovalbumin (OVA) cancer vaccine model, we show that high-efficiency transdermal transfection of APCs with OVA-DNAs induces robust cellular and humoral immune responses, including antigen presentation and generation of IFN-γ+ cytotoxic T lymphocytes with a more than 10-fold dose sparing over existing intramuscular injection (IM) approach, and effectively inhibits tumor growth in rodent animals.

A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects.

Notch signaling is a conserved pathway that converts extracellular receptor-ligand interactions into changes in gene expression via a single transcription factor (CBF1/RBPJ in mammals; Su(H) in Drosophila). In humans, RBPJ variants have been linked to Adams-Oliver syndrome (AOS), a rare autosomal dominant disorder characterized by scalp, cranium, and limb defects. Here, we found that a previously described Drosophila Su(H) allele encodes a missense mutation that alters an analogous residue found in an AOS-associated RBPJ variant. Importantly, genetic studies support a model that heterozygous Drosophila with the AOS-like Su(H) allele behave in an opposing manner to heterozygous flies with a Su(H) null allele, due to a dominant activity of sequestering either the Notch co-activator or the antagonistic Hairless co-repressor. Consistent with this model, AOS-like Su(H) and Rbpj variants have decreased DNA binding activity compared to wild type proteins, but these variants do not significantly alter protein binding to the Notch co-activator or the fly and mammalian co-repressors, respectively. Taken together, these data suggest a cofactor sequestration mechanism underlies AOS phenotypes associated with RBPJ variants, whereby the AOS-associated RBPJ allele encodes a protein with compromised DNA binding activity that retains cofactor binding, resulting in Notch target gene dysregulation.

UM171 suppresses breast cancer progression by inducing KLF2.

PURPOSE: Breast cancer is the most frequent cancer in women with significant death rate. Morbidity is associated with drug resistance and metastasis. Development of novel drugs is unmet need. The aim of this study is to show potent anti-neoplastic activity of the UM171 compound on breast cancer cells and its mechanism of action. METHODS: The inhibitory effect of UM171 on several breast cancer (BC) cell lines was examined using MTT and colony-forming assays. Cell cycle and apoptosis assays were utilized to determine the effect of UM171 on BC cell proliferation and survival. Wound healing scratch and transwell migration assays were used to examine the migration of BC cell lines in culture. Xenograft of mouse model with 4T1 cells was used to determine inhibitory effect of UM171 in vivo. Q-RT-PCR and western blotting were used to determine the expression level of genes effected by UM171. Lentivirus-mediated shRNAs were used to knockdown the expression of KLF2 in BC cells. RESULTS: UM171 was previously identified as a potent agonist of human hematopoietic stem cell renewal and inhibitor of leukemia. In this study, UM171 was shown to inhibit the growth of multiple breast cancer cell lines in culture. UM171-mediated growth inhibition was associated with the induction of apoptosis, G2/M cell cycle arrest, lower colony-forming capacity, and reduced motility. In a xenotransplantation model of mouse triple-negative breast cancer 4T1 cells injected into syngeneic BALB/c mice, UM171 strongly inhibited tumor growth at a level comparable to control paclitaxel. UM171 increased the expression of the three PIM genes (PIM1-3) in breast cancer cells. Moreover, UM171 strongly induced the expression of the tumor suppressor gene KLF2 and cell cycle inhibitor P21CIP1. Accordingly, knockdown of KLF2 using lentivirus-mediated shRNA significantly attenuated the growth suppressor activity of UM171. As PIM1-3 act as oncogenes and are involved in breast cancer progression, induction of these kinases likely impedes the inhibitory effect of KLF2 induction by UM171. Accordingly, combination of UM171 with a PAN-PIM inhibitor LGH447 significantly reduced tumor growth in culture. CONCLUSION: These results suggested that UM171 inhibited breast cancer progression in part through activation of KLF2 and P21. Combination of UM171 with a PAN-PIM inhibitor offer a novel therapy for aggressive forms of breast cancer.

FLI1 induces erythroleukemia through opposing effects on UBASH3A and UBASH3B expression.

BACKGROUND: FLI1 is an oncogenic transcription factor that promotes diverse malignancies through mechanisms that are not fully understood. Herein, FLI1 is shown to regulate the expression of Ubiquitin Associated and SH3 Domain Containing A/B (UBASH3A/B) genes. UBASH3B and UBASH3A are found to act as an oncogene and tumor suppressor, respectively, and their combined effect determines erythroleukemia progression downstream of FLI1. METHODS: Promoter analysis combined with luciferase assays and chromatin immunoprecipitation (ChIP) analysis were applied on the UBASH3A/B promoters. RNAseq analysis combined with bioinformatic was used to determine the effect of knocking-down UBASH3A and UBASH3B in leukemic cells. Downstream targets of UBASH3A/B were inhibited in leukemic cells either via lentivirus-shRNAs or small molecule inhibitors. Western blotting and RT-qPCR were used to determine transcription levels, MTT assays to assess proliferation rate, and flow cytometry to examine apoptotic index. RESULTS: Knockdown of FLI1 in erythroleukemic cells identified the UBASH3A/B genes as potential downstream targets. Herein, we show that FLI1 directly binds to the UBASH3B promoter, leading to its activation and leukemic cell proliferation. In contrast, FLI1 indirectly inhibits UBASH3A transcription via GATA2, thereby antagonizing leukemic growth. These results suggest oncogenic and tumor suppressor roles for UBASH3B and UBASH3A in erythroleukemia, respectively. Mechanistically, we show that UBASH3B indirectly inhibits AP1 (FOS and JUN) expression, and that its loss leads to inhibition of apoptosis and acceleration of proliferation. UBASH3B also positively regulates the SYK gene expression and its inhibition suppresses leukemia progression. High expression of UBASH3B in diverse tumors was associated with worse prognosis. In contrast, UBASH3A knockdown in erythroleukemic cells increased proliferation; and this was associated with a dramatic induction of the HSP70 gene, HSPA1B. Accordingly, knockdown of HSPA1B in erythroleukemia cells significantly accelerated leukemic cell proliferation. Accordingly, overexpression of UBASH3A in different cancers was predominantly associated with good prognosis. These results suggest for the first time that UBASH3A plays a tumor suppressor role in part through activation of HSPA1B. CONCLUSIONS: FLI1 promotes erythroleukemia progression in part by modulating expression of the oncogenic UBASH3B and tumor suppressor UBASH3A.

Self-feedback loop-containing synthetic mRNA switches for controlled microRNA sensing.

Synthetic mRNA switches are powerful cell fate manipulation tools that sense cellular input molecules to directly control protein expression at the translational level. The lack of available switch designs that can mimic the natural sophisticated protein regulation is a fundamental issue that limits the application of synthetic mRNA switches. Here we report a new set of synthetic mRNA switches by incorporating self-feedback loop machineries to dynamically control protein expression levels upon sensing cellular microRNAs. We redesigned the coding region of the switch to express output protein along with mRNA regulatory proteins. RNA-binding proteins (RBPs) and RBP-binding RNA motifs (aptamers) guide the regulatory proteins to act on their own mRNAs, enhancing or flattening the effect of microRNA sensing. Importantly, we demonstrated that the switches with the positive feedback feature can enlarge a high-or-low microRNA effect into a nearly all-or-none pattern, substantially boosting the use of synthetic mRNA switches as high-performance microRNA sensors or binary cell regulation tools. We believe these novel mRNA switch designs provide new strategies to construct complex mRNA-based genetic circuits for future molecular sensing and cell engineering.

Suffering and adjustment: a grounded theory of the process of coping with financial toxicity among young women with breast cancer.

PURPOSE: To explore the process of coping with financial toxicity among young women with breast cancer and formulate a grounded theory that serves as a foundation for creating intervention strategies aimed at supporting cancer survivors. METHODS: A qualitative study using the Corbin and Strauss variant of grounded theory. A series of in-depth interviews were carried out with young women with breast cancer (n = 29) using the theoretical sampling method. We analyzed data by coding core categories in the patients' coping processes and developing theory around these categories. Data collection and analysis were performed simultaneously. RESULTS: A substantial theory of the process of coping with financial toxicity among young female breast cancer survivors was constructed. Two core concepts, suffering and adjustment, were identified. Young women with breast cancer suffered from financial toxicity, which was related to risk factors, coping resources, and unmet needs. To overcome financial toxicity, young women with breast cancer adjusted by reshaping consumption concept, re-dividing of family functions, re-planning of occupation career, and rebuilding life confidence. CONCLUSION: This qualitative study constructed a theory delineating the coping strategies employed by young women with breast cancer in response to financial toxicity, offering profound insights into the intricacies of cancer-related financial toxicity. Identifying risk factors, enhancing coping resources, and meeting unmet needs would be helpful to patients' adjustment to financial stress.

Enhancers with cooperative Notch binding sites are more resistant to regulation by the Hairless co-repressor.

Notch signaling controls many developmental processes by regulating gene expression. Notch-dependent enhancers recruit activation complexes consisting of the Notch intracellular domain, the Cbf/Su(H)/Lag1 (CSL) transcription factor (TF), and the Mastermind co-factor via two types of DNA sites: monomeric CSL sites and cooperative dimer sites called Su(H) paired sites (SPS). Intriguingly, the CSL TF can also bind co-repressors to negatively regulate transcription via these same sites. Here, we tested how synthetic enhancers with monomeric CSL sites versus dimeric SPSs bind Drosophila Su(H) complexes in vitro and mediate transcriptional outcomes in vivo. Our findings reveal that while the Su(H)/Hairless co-repressor complex similarly binds SPS and CSL sites in an additive manner, the Notch activation complex binds SPSs, but not CSL sites, in a cooperative manner. Moreover, transgenic reporters with SPSs mediate stronger, more consistent transcription and are more resistant to increased Hairless co-repressor expression compared to reporters with the same number of CSL sites. These findings support a model in which SPS containing enhancers preferentially recruit cooperative Notch activation complexes over Hairless repression complexes to ensure consistent target gene activation.

Modified technique of Hepatojejunostomy for biliary tract reconstruction after resection of tumors affecting the perihilar region: a case series.

BACKGROUNDS: Radical resection is the most effective treatment for perihilar tumors. Biliary tract reconstruction after resection is one of the key steps in this surgery. Mucosa-to-mucosa cholangiojejunostomy is traditionally performed, in which the bile ducts at the resection margin are separately anastomosed to the jejunum. However, this approach is associated with long operative time and high risk of postoperative complications. The present study presents a modified technique of hepatojejunostomy and its outcomes. METHODS: The data of patients who underwent hepatojejunostomy using the modified technique at the Department of Hepatobiliary Surgery, Daping Hospital, Army Medical University, Chongqing, China, from January 2016 to December 2021, were retrospectively analyzed. RESULTS: A total of 13 patients with perihilar tumors underwent R0 resection and bilioenteric reconstruction using the modified hepatojejunostomy technique during the study period. During the operation, the alignment of the bile duct stumps was improved, the posterior wall of the anastomosis was reinforced, internal stents were placed in the smaller bile ducts, external stents were placed in the larger bile ducts, and hepatojejunostomy was performed using 4 - 0 prolene. No serious postoperative complications, such as death or bile leakage, occurred during the hospitalization. Furthermore, there were no cases of biliary stricture or cholangitis after the six-month follow-up period. CONCLUSION: The modified hepatojejunostomy technique is a safe and effective technique of biliary reconstruction after the resection of perihilar tumors. This can be easily performed for difficult cases with multiple bile ducts that require reconstruction after resection.

Optimal Post-Operative Nalbuphine Dose Regimen: A Randomized Controlled Trial in Patients with Laparoscopic Cholecystectomy.

Background and Objectives: Optimal opioid analgesia is an excellent analgesia that does not present unexpected adverse effects. Nalbuphine, acting on the opioid receptor as a partial mu antagonist and kappa agonist, is considered a suitable option for patients undergoing laparoscopic surgery. Therefore, we aim to investigate the appropriate dosage of nalbuphine for post-operative pain management in patients with laparoscopic cholecystectomy. Materials and Methods: Patients were randomly categorized into low, medium, and high nalbuphine groups. In each group, a patient control device for post-operative pain control was programed with a low (0.05 mg/kg), medium (0.10 mg/kg), or high (0.20 mg/kg) nalbuphine dose as a loading dose and each bolus dose with a lockout interval of 7 min and without background infusion. Primary and secondary outcomes included the post-operative pain scale and nalbuphine consumption, and episodes of post-operative opioid-related adverse events and satisfactory scores. Results: The low-dosage group presented a higher initial self-reported pain score in comparison to the other two groups for the two hours post-op (p = 0.039) but presented lower nalbuphine consumption than the other two groups for four hours post-op (p = 0.047). There was no significant difference in the analysis of the satisfactory score and adverse events. Conclusions: An appropriate administration of nalbuphine could be 0.1 to 0.2 mg/kg at the initial four hours; this formula could be modified to a lower dosage (0.05 mg/kg) in the post-operative management of laparoscopic cholecystectomy.

Achieving High-Efficient Photoelectrocatalytic Degradation of 4-Chlorophenol via Functional Reformation of Titanium-Oxo Clusters.

Rational design of crystalline catalysts with superior light absorption and charge transfer for efficient photoelectrocatalytic (PEC) reaction coupled with energy recovery remains a great challenge. In this work, we elaborately construct three stable titanium-oxo clusters (TOCs, Ti10Ac6, Ti10Fc8, and Ti12Fc2Ac4) modified with a monofunctionalized ligand (9-anthracenecarboxylic acid (Ac) or ferrocenecarboxylic acid (Fc)) and bifunctionalized ligands (Ac and Fc). They have tunable light-harvesting and charge transfer capacities and thus can serve as outstanding crystalline catalysts to achieve efficient PEC overall reaction, that is, the integration of anodic organic pollutant 4-chlorophenol (4-CP) degradation and cathodic wastewater-to-H2 conversion. These TOCs can all exhibit very high PEC activity and degradation efficiency of 4-CP. Especially, Ti12Fc2Ac4 decorated with bifunctionalized ligands exhibits better PEC degradation efficiency (over 99%) and H2 generation than Ti10Ac6 and Ti10Fc8 modified with a monofunctionalized ligand. The study of the 4-CP degradation pathway and mechanism revealed that such better PEC performance of Ti12Fc2Ac4 is probably due to its stronger interactions with the 4-CP molecule and better •OH radical production. This work not only presents the effective combination of organic pollutant degradation and simultaneously H2 evolution reaction using crystalline coordination clusters as both anodic and cathodic catalyst but also develops a new PEC application for crystalline coordination compounds.

AAV-glycine receptor α3 alleviates CFA-induced inflammatory pain by downregulating ERK phosphorylation and proinflammatory cytokine expression in SD rats.

BACKGROUND: Glycine receptors (GlyRs) play key roles in the processing of inflammatory pain. The use of adeno-associated virus (AAV) vectors for gene therapy in human clinical trials has shown promise, as AAV generally causes a very mild immune response and long-term gene transfer, and there have been no reports of disease. Therefore, we used AAV for GlyRα1/3 gene transfer in F11 neuron cells and into Sprague-Dawley (SD) rats to investigate the effects and roles of AAV-GlyRα1/3 on cell cytotoxicity and inflammatory response. METHODS: In vitro experiments were performed using plasmid adeno-associated virus (pAAV)-GlyRα1/3-transfected F11 neurons to investigate the effects of pAAV-GlyRα1/3 on cell cytotoxicity and the prostaglandin E2 (PGE2)-mediated inflammatory response. In vivo experiment, the association between GlyRα3 and inflammatory pain was analyzed in normal rats after AAV-GlyRα3 intrathecal injection and after complete Freund's adjuvant (CFA) intraplantar administration. Intrathecal AAV-GlyRα3 delivery into SD rats was evaluated in terms of its potential for alleviating CFA-induced inflammatory pain. RESULTS: The activation of mitogen-activated protein kinase (MAPK) inflammatory signaling and neuronal injury marker activating transcription factor 3 (ATF-3) were evaluated by western blotting and immunofluorescence; the level of cytokine expression was measured by ELISA. The results showed that pAAV/pAAV-GlyRα1/3 transfection into F11 cells did not significantly reduce cell viability or induce extracellular signal-regulated kinase (ERK) phosphorylation or ATF-3 activation. PGE2-induced ERK phosphorylation in F11 cells was repressed by the expression of pAAV-GlyRα3 and administration of an EP2 inhibitor, GlyRαs antagonist (strychnine), and a protein kinase C inhibitor. Additionally, intrathecal AAV-GlyRα3 administration to SD rats significantly decreased CFA-induced inflammatory pain and suppressed CFA-induced ERK phosphorylation, did not induce obvious histopathological injury but increased ATF-3 activation in dorsal root ganglion (DRGs). CONCLUSIONS: Antagonists of the prostaglandin EP2 receptor, PKC, and glycine receptor can inhibit PGE2-induced ERK phosphorylation. Intrathecal AAV-GlyRα3 administration to SD rats significantly decreased CFA-induced inflammatory pain and suppressed CFA-induced ERK phosphorylation, did not significantly induce gross histopathological injury but elicited ATF-3 activation. We suggest that PGE2-induced ERK phosphorylation can be modulated by GlyRα3, and AAV-GlyRα3 significantly downregulated CFA-induced cytokine activation.

Dysregulation of memory B cells and circulating T follicular helper cells is a predictor of poor immune recovery in HIV-infected patients on antiretroviral therapy.

T follicular helper (Tfh) cells and their interactions with B cells within the germinal center play extensive roles in human immunodeficiency virus (HIV) pathology. However, their association with immune reconstitution during antiretroviral therapy (ART) is still unclear. The aim of this study was to determine the impact of Tfh and memory B cell function on T helper cell recovery in patients with acute or chronic HIV infection. A total of 100 HIV-infected individuals were enrolled in our study, classified into acute and chronic HIV infection groups (60 and 40, respectively), and subsequently classified into immunological responder (IR) and immunological nonresponder (INR) subgroups according to immune recovery outcomes after 96 weeks of ART. Liquid chromatography-mass spectrometry was used to quantify the temporal regulation patterns of B and CD4+ T-cell profiles among patients, and flow cytometry was used to investigate certain subsets of B and T cells. Here we showed that the prevalence of Tfh cells in the T helper cell population correlated negatively with CD4+ T-cell recovery. The proportion of CXCR3-  Tfh cells in patients with acute or chronic infection was associated with CD4+ T-cell count recovery, and the proportion of CD21+ memory B cells at baseline was significantly higher in those with improved immune recovery outcomes. Universal proteomic dysregulation of B and CD4+ T cells at baseline was detected in patients with acute infected and poor CD4+ T-cell recovery. Proteomics analysis revealed distinct temporal regulation profiles of both T helper cells and B cells between IRs and INRs among patients with acute infection. Our results suggest that the functions of memory B cells in INRs are dysregulated at the early stage of ART, possibly through disruption of Tfh cell function. The frequency and function of Tfh cells and their subsets are potential predictors of poor immune recovery.

Integration of metabolomics and transcriptomics analyses reveals sphingosine-1-phosphate-mediated S1PR2/PI3K/Akt pathway involved in Talaromyces marneffei infection of macrophages.

Talaromycosis is a fatal mycosis caused by the thermally dimorphic fungus Talaromyces marneffei (T. marneffei). The pathogenic mechanisms of talaromycosis are still poorly understood. This work combined metabolomics, transcriptomics, and verification experiments in vivo and in vitro to detect metabolic profiles and differentially expressed genes (DEGs) in T. marneffei infected and uninfected macrophages to explore possible pathogenesis and underlying mechanisms. A total of 256 differential metabolites (117 up-regulated and 148 down-regulated) and 1320 DEGs (1286 up-regulated and 34 down-regulated) were identified between the two groups. Integrative metabolomics and transcriptomics analysis showed sphingolipid signaling pathway is the most influential. Verification experiments showed that compared with the control group, the production of sphingosine-1-phosphate (S1P) and the expression of the S1PR1, S1PR2, phosphor-PI3K, and phosphor-Akt genes involved in the sphingolipid signaling pathway have significantly increased in the T. marneffei infection group (p < 0.05). T. marneffei activates the S1PR2/PI3K/Akt pathways in J774A.1 macrophage, regulation of the S1P singling might serve as a promising therapeutic strategy for talaromycosis.

Thalidomide promotes NLRP3/caspase-1-mediated pyroptosis of macrophages in Talaromyces marneffei infection.

Macrophage-derived inflammatory cytokines are critical for host defense against Talaromyces marneffei (T. marneffei) infection among HIV/AIDS patients, and excessive inflammatory cytokines are associated with poor outcomes of AIDS-associated talaromycosis. However, the underlying mechanisms of macrophage-caused pyroptosis and cytokine storm are poorly understood. Here, in the T. marneffei-infected mice and macrophages, we show that T. marneffei induced pyroptosis in macrophages through the NLRP3/caspase-1 pathway. The immunomodulatory drug thalidomide could promote the pyroptosis of macrophages infected T. marneffei. In T. marneffei-infected mice, the splenic macrophages underwent increasing pyroptosis as talaromycosis deteriorated. Thalidomide ameliorated inflammation of mice, while amphotericin B (AmB) in combination with thalidomide did not improve overall survival compared with AmB alone. Taken together, our findings suggest that thalidomide promotes NLRP3/caspase-1-mediated pyroptosis of macrophages in T. marneffei infection.

Lovastatin inhibits erythroleukemia progression through KLF2-mediated suppression of MAPK/ERK signaling.

BACKGROUND: Lovastatin, an HMG-CoA inhibitor and an effective cholesterol lowering drug, exhibits anti-neoplastic activity towards several types of cancer, although the underlying mechanism is still not fully understood. Herein, we investigated mechanism of growth inhibition of leukemic cells by lovastatin. METHODS: RNAseq analysis was used to explore the effect of lovastatin on gene expression in leukemic cells. An animal model of leukemia was used to test the effect of this statin in vivo. FAM83A and DDIT4 expression was knocked-downed in leukemia cells via lentivirus-shRNA. Western blotting, RT-qPCR, cell cycle analysis and apoptosis assays were used to determine the effect of lovastatin-induced growth suppression in leukemic cells in vitro. RESULTS: Lovastatin treatment strongly inhibited cancer progression in a mouse model of erythroleukemia induced by Friend virus. In tissue culture, lovastatin inhibited cell proliferation through induction of G1 phase cell cycle arrest and apoptosis. Interestingly, lovastatin induced most known genes associated with cholesterol biosynthesis in leukemic cells. Moreover, it suppressed ERK1/2 phosphorylation by downregulating FAM83A and DDIT4, two mediators of MAP-Kinase signaling. RNAseq analysis of lovastatin treated leukemic cells revealed a strong induction of the tumor suppressor gene KLF2. Accordingly, lentivirus-mediated knockdown of KLF2 antagonized leukemia cell suppression induced by lovastatin, associated with higher ERK1/2 phosphorylation compared to control. We further show that KLF2 induction by lovastatin is responsible for lower expression of the FAM83A and DDIT4 oncogenes, involved in the activation of ERK1/2. KLF2 activation by lovastatin also activated a subset of cholesterol biosynthesis genes that may further contribute to leukemia suppression. CONCLUSIONS: These results implicate KLF2-mediated FAM83A/DDIT4/MAPK suppression and activation of cholesterol biosynthesis as the mechanism of leukemia cell growth inhibition by lovastatin.

Notch dimerization and gene dosage are important for normal heart development, intestinal stem cell maintenance, and splenic marginal zone B-cell homeostasis during mite infestation.

Cooperative DNA binding is a key feature of transcriptional regulation. Here we examined the role of cooperativity in Notch signaling by CRISPR-mediated engineering of mice in which neither Notch1 nor Notch2 can homo- or heterodimerize, essential for cooperative binding to sequence-paired sites (SPS) located near many Notch-regulated genes. Although most known Notch-dependent phenotypes were unaffected in Notch1/2 dimer-deficient mice, a subset of tissues proved highly sensitive to loss of cooperativity. These phenotypes include heart development, compromised viability in combination with low gene dose, and the gut, developing ulcerative colitis in response to 1% dextran sulfate sodium (DSS). The most striking phenotypes-gender imbalance and splenic marginal zone B-cell lymphoma-emerged in combination with gene dose reduction or when challenged by chronic fur mite infestation. This study highlights the role of the environment in malignancy and colitis and is consistent with Notch-dependent anti-parasite immune responses being compromised in Notch dimer-deficient animals.

Racial disparities in new-onset diabetes mellitus in prostate cancer patients on androgen deprivation therapy: a retrospective analysis of TriNetX data.

BACKGROUND: Prostate cancer (PCa) is the most common cancer in men in the US and androgen deprivation therapy (ADT) is the most frequently used systemic therapy for PCa. Data suggest that ADT is associated with an increased risk of new-onset diabetes mellitus (NODM) and cardiovascular complications. As the incidence and mortality of PCa are highest among the African American (AA) population, it is important to evaluate the difference in the incidence of NODM and ischemic heart disease (IHD) between AA men compared to Caucasian men. METHODS: This is a retrospective cohort study utilizing the TriNetX database to assess NODM and IHD risk, risk difference, and risk ratio (RR) after recent ADT initiation in an AA cohort and a Caucasian cohort of patients with PCa. Propensity score matching (PSM) was performed by age, BMI, and confounding comorbidities. RESULTS: After matching, the cohort included 1159 AA patients and 843 Caucasian patients with NODM after ADT initiation. The IHD cohort included 1269 AA patients and 1248 Caucasian patients. The risk of incidence of NODM is higher among AA men at 11.6% risk compared to Caucasian men at 7.4%. The risk difference is 4.1% (95% CI = 3.4, 4.9) p = 0.000. The RR is 1.56 (95% CI = 1.43, 1.70). In contrast, risk difference and risk ratio of IHD was not significant between AA and Caucasian groups. CONCLUSION: ADT exposure increases the risk of NODM in men with PCa, especially among AA men compared with Caucasian men. Men receiving ADT should be monitored routinely for signs and symptoms of metabolic syndrome and diabetes. Targeted close monitoring of AA men on ADT would be critical to prevent and treat metabolic complications with potential of reducing disparities in PCa morbidity.

Communication of costs and financial burdens between cancer patients and healthcare providers: a qualitative systematic review and meta-synthesis.

OBJECTIVES: The aim of this study was to synthesize qualitative research regarding communication of costs and financial burdens between patients and healthcare providers to provide evidence for the subsequent development of intervention programs. METHODS: Studies published prior to 11 February 2023 were collected from electronic databases, including PubMed/MEDLINE, MEDLINE (Ovid), Web of Science, EMBASE (Ovid), CINAHL (EBSCO), and ProQuest. A checklist for qualitative research drawn from the Joanna Briggs Institute Reviewer's Manual was applied to assess the quality of the included studies. Meta-aggregation was performed to synthesize the findings of the included studies. RESULTS: Four synthesized findings were derived from 15 studies: cost communication offered more benefits than drawbacks, and most patients were willing to engage in cost communication; cost communication has been implemented in clinical practice but continued to face shortcomings and barriers; an expected cost communication should take into account timing, location, personnel, personality, and content; healthcare providers required education, information, tools, standardized processes, and policy and organizational support to increase their ability to deliver cost communication. CONCLUSIONS: Cost communication can help optimize decision-making and reduce the risk of financial difficulties, as has been widely recognized by patients and healthcare providers. However, a complete clinical practice plan to facilitate cost communication has not yet been created.

The lived experience of patients with breast cancer on adjuvant endocrine therapy: side effects and coping strategies during the first year of medication initiation.

PURPOSE: Adjuvant endocrine therapy (AET) is pivotal for hormone receptor-positive breast cancer patients, significantly enhancing survival rates. Yet, adherence to AET remains challenging due to side effects. This study delves into the lived experience of breast cancer survivors concerning AET-induced side effects and examines differences in symptom profiles between Tamoxifen and aromatase inhibitors (AIs). METHODS: We interviewed 35 breast cancer survivors on AET, conducting qualitative iterative analysis using grounded theory. A codebook was developed to aid data coding and interpretation. NVIVO software facilitated comprehensive transcript analysis. RESULTS: Survivors reported a spectrum of side effects like hot flashes, sexual issues, joint pain, stiffness, mood swings, and fertility concerns. Symptom profiles differed based on AET type. Tamoxifen users experienced more frequent sexual side effects and mood swings, while AIs were linked to joint pain, stiffness, and bone health worries. Those on AET for over 6 months expressed heightened concerns about side effects. CONCLUSION: Tailored patient education, aligned with AET type, empowers survivors to manage side effects using self-regulatory strategies. Acknowledging distinct symptom profiles enables informed decisions, improving adherence and quality of life. IMPLICATIONS: This study underscores tailored survivorship support, equipping patients with tools to manage side effects, enhancing adherence, and long-term outcomes. The findings inform the integration of comprehensive survivorship programs, emphasizing individualized strategies for managing side effects and promoting better adherence and improved quality of life.

Clinical characteristics of patients with human immunodeficiency virus and immune-mediated photodermatoses: A retrospective study of 39 patients.

BACKGROUND: HIV/AIDS patients are susceptible to various infectious and inflammatory dermatoses. No systemic work has been done on HIV/AIDS patients with immune-mediated photodermatoses in China. Here, we aim to determine the clinical features of immune-mediated photodermatoses in HIV/AIDS patients. METHODS: A retrospective analysis of HIV/AIDS patients with immune-mediated photodermatoses was carried out with demographic data, clinical characteristics, laboratory data, and follow-up data at the First Affiliated Hospital of Kunming Medical University between 2012 and 2019. The data were subjected to statistical analysis. RESULTS: A total of 39 HIV/AIDS patients with immune-mediated photodermatoses were enrolled, including 22 cases of polymorphic light eruption (PLE), 16 cases of chronic actinic dermatitis (CAD), and one actinic reticuloid. The CD4 count at the visit of the HIV-positive CAD group was lower than the PLE group (p = .049). The HIV-positive CAD group was more sensitive toward UVB than the PLE group (p = .020) and had a lower MED-UVB value (p = .044). There was no significant difference in UV tests among different categories of skin types. CONCLUSION: Immune-mediated photodermatoses are a manifestation of the advanced symptom of HIV infection, and sometimes also the presenting feature of HIV infection. Compared with HIV-positive PLE patients, CAD patients showed higher sensitivity to UVB radiation and had a lower MED-UVB value. The primary treatment for immune-mediated photodermatoses in HIV/AIDS patients is HAART and sun avoidance.