SupporTive Care At Home Research (STAHR) for patients with advanced cancer: Protocol for a cluster non-randomized controlled trial.

Advancements in the treatment and management of patients with cancer have extended their survival period. To honor such patients' desire to live in their own homes, home-based supportive care programs have become an important medical practice. This study aims to investigate the effects of a multidimensional and integrated home-based supportive care program on patients with advanced cancer. SupporTive Care At Home Research is a cluster non-randomized controlled trial for patients with advanced cancer. This study tests the effects of the home-based supportive care program we developed versus standard oncology care. The home-based supportive care program is based on a specialized home-based medical team approach that includes (1) initial assessment and education for patients and their family caregivers, (2) home visits by nurses, (3) biweekly regular check-ups/evaluation and management, (4) telephone communication via a daytime access line, and (5) monthly multidisciplinary team meetings. The primary outcome measure is unplanned hospitalization within 6 months following enrollment. Healthcare service use; quality of life; pain and symptom control; emotional status; satisfaction with services; end-of-life care; advance planning; family caregivers' quality of life, care burden, and preparedness for caregiving; and medical expenses will be surveyed. We plan to recruit a total of 396 patients with advanced cancer from six institutions. Patients recruited from three institutions will constitute the intervention group, whereas those recruited from the other three institutions will comprise the control group.

Prodrug-conjugated tumor-seeking commensals for targeted cancer therapy.

Prodrugs have been explored as an alternative to conventional chemotherapy; however, their target specificity remains limited. The tumor microenvironment harbors a range of microorganisms that potentially serve as tumor-targeting vectors for delivering prodrugs. In this study, we harness bacteria-cancer interactions native to the tumor microbiome to achieve high target specificity for prodrug delivery. We identify an oral commensal strain of Lactobacillus plantarum with an intrinsic cancer-binding mechanism and engineer the strain to enable the surface loading of anticancer prodrugs, with nasopharyngeal carcinoma (NPC) as a model cancer. The engineered commensals show specific binding to NPC via OppA-mediated recognition of surface heparan sulfate, and the loaded prodrugs are activated by tumor-associated biosignals to release SN-38, a chemotherapy compound, near NPC. In vitro experiments demonstrate that the prodrug-loaded microbes significantly increase the potency of SN-38 against NPC cell lines, up to 10-fold. In a mouse xenograft model, intravenous injection of the engineered L. plantarum leads to bacterial colonization in NPC tumors and a 67% inhibition in tumor growth, enhancing the efficacy of SN-38 by 54%.

Home-based supportive care in advanced cancer: systematic review.

OBJECTIVES: This study systematically reviewed the literature on the effect of home-based supportive care (HbSC) programmes on the quality of life (QoL) of patients with advanced cancer. METHODS: The research question 'Do home-based supportive care programmes for patients with advanced cancer improve their QoL?' was addressed. After registering the plan with PROSPERO (CRD42022341237), literature published from 1 January 1990 to 30 May 2023 was searched on PubMed, Embase, Cochrane database, CINAHL and Web of Science, and reviewed for inclusion based on predefined criteria. This review only included trial studies published in English. RESULTS: Of 5,276 articles identified, 17 studies were judged suitable for inclusion in this review. The components of HbSC programmes included home visits, patient and caregiver education, home nursing, psychotherapy, exercise, telephone consultation, and multidisciplinary team meetings. Nine studies reported improvements in QoL, including social functioning, emotional functioning, and subjective QoL. CONCLUSION: HbSC programmes appear to enable the improvement of the QoL of patients with advanced cancer. The area of QoL that shows improvement could vary depending on the HbSC components. More studies that address HbSC programmes are needed to select patients at the proper time and provide suitable programmes for patients to benefit most.

Preferred versus Actual Place of Care and Factors Associated with Home Discharge among Korean Patients with Advanced Cancer: A Retrospective Cohort Study.

Respecting the preference for a place of care is essential for advance care planning in patients with advanced cancer. This retrospective study included adult patients with cancer referred to an inpatient palliative care consultation team at a tertiary acute care hospital in South Korea between April 2019 and December 2020. Patients' preference for place of care and demographic and clinical factors were recorded, and the actual discharge locations were categorized as home or non-home. Patients discharged home but with unintended hospital visits within 2 months were also investigated. Of the 891 patients referred to the palliative care consultation team, 210 (23.6%) preferred to be discharged home. Among them, 113 (53.8%) were discharged home. No significant differences were found between patients who preferred home discharge and those who did not. Home discharge was higher among female patients (p = 0.04) and lower in those with poor oral intake (p < 0.001) or dyspnea (p = 0.02). Of the 113 patients discharged home, 37 (32.8%) had unintended hospital visits within 2 months. Approximately one-quarter of hospitalized patients with advanced cancer preferred to be discharged home, but only half of them received the home discharge. To meet patients' preferences for end-of-life care, individual care planning considering relevant factors is necessary.

FELICX: A robust nucleic acid detection method using flap endonuclease and CRISPR-Cas12.

Nucleic acid detection is crucial for monitoring diseases for which rapid, sensitive, and easy-to-deploy diagnostic tools are needed. CRISPR-based technologies can potentially fulfill this need for nucleic acid detection. However, their widespread use has been restricted by the requirement of a protospacer adjacent motif in the target and extensive guide RNA optimization. In this study, we developed FELICX, a technique that can overcome these limitations and provide a useful alternative to existing technologies. FELICX comprises flap endonuclease, Taq ligase and CRISPR-Cas for diagnostics (X) and can be used for detecting nucleic acids and single-nucleotide polymorphisms. This method can be deployed as a point-of-care test, as only two temperatures are needed without thermocycling for its functionality, with the result generated on lateral flow strips. As a proof-of-concept, we showed that up to 0.6 copies/µL of DNA and RNA could be detected by FELICX in 60 min and 90 min, respectively, using simulated samples. Additionally, FELICX could be used to probe any base pair, unlike other CRISPR-based technologies. Finally, we demonstrated the versatility of FELICX by employing it for virus detection in infected human cells, the identification of antibiotic-resistant bacteria, and cancer diagnostics using simulated samples. Based on its unique advantages, we envision the use of FELICX as a next-generation CRISPR-based technology in nucleic acid diagnostics.

The Medical Needs and Characteristics of Cancer and Progressive Neurologic Disease Patients Who Use Home-Based Medical Care in Korea: A Retrospective Study for 2011-2020.

OBJECTIVES: To investigate the needs and characteristics of patients with cancer and neurologic disorders requiring home-based medical care (HBMC). DESIGN: Retrospective observational study. SETTING AND PARTICIPANTS: Patients receiving HBMC on discharge from a tertiary hospital in Korea during 2011-2020. METHODS: Patients were classified into 3 disease groups: cancer, progressive neurologic disorders (NR), and others. Characteristics and medical needs were assessed in each disease group. Medical needs were categorized based on functional items requiring support or management at the time of registration: respiratory, feeding, urinary system, drain tube, central catheter, wound, medication, and other. Patients with multiple medical needs were assigned to multiple categories. Patients who used HBMC for more than 3 months were defined as long-term users; their characteristics were evaluated in the same way. RESULTS: Of the total 655 patients, 47.0% (308) had cancer and 17.3% (113) were NR patients. Among all patients, 78.8% were partially dependent (44.0%) or completely dependent (34.8%) in daily activities, and there were more dependent patients in the NR group (80.5%) than cancer (26.6%). Patients with cancer needed central catheter management the most (43.5%), followed by wound care (36.7%), feeding support (35.1%), and drain tube management (22.1%). NR patients required feeding support the most (80.5%), followed by respiratory support (43.4%), wound care (41.6%), and urinary system support (19.5%). Of all patients, 30.2% (198) were long-term users (NR, 37.9%; cancer, 35.4%). Long-term users were common among patients who needed respiratory support (59.4%), feeding support (48.75), and urinary system support (34.6%). CONCLUSIONS AND IMPLICATIONS: Homebound patients with cancer and progressive neurologic disorders need medical services at home after discharge. Patients who need feeding and respiratory support usually use HBMC for more than 3 months. Further studies are needed to design an optimal HBMC that continuously provides medical services to patients with serious illnesses living at home.

Engineered microbial systems for advanced drug delivery.

The human body is a natural habitat for a multitude of microorganisms, with bacteria being the major constituent of the microbiota. These bacteria colonize discrete anatomical locations that provide suitable conditions for their survival. Many bacterial species, both symbiotic and pathogenic, interact with the host via biochemical signaling. Based on these attributes, commensal and attenuated pathogenic bacteria have been engineered to deliver therapeutic molecules to target specific diseases. Recent advances in synthetic biology have enabled us to perform complex genetic modifications in live bacteria and bacteria-derived particles, which simulate micron or submicron lipid-based vectors, for the targeted delivery of therapeutic agents. In this review, we highlight various examples of engineered bacteria or bacteria-derived particles that encapsulate, secrete, or surface-display therapeutic molecules for the treatment or prevention of various diseases. The review highlights recent studies on (i) the production of therapeutics by microbial cell factories, (ii) disease-triggered release of therapeutics by sense and respond systems, (iii) bacteria targeting tumor hypoxia, and (iv) bacteria-derived particles as chassis for drug delivery. In addition, we discuss the potential of such drug delivery systems to be translated into clinical therapies.

O-GlcNAcylation of Sox2 at threonine 258 regulates the self-renewal and early cell fate of embryonic stem cells.

Sox2 is a core transcription factor in embryonic stem cells (ESCs), and O-GlcNAcylation is a type of post-translational modification of nuclear-cytoplasmic proteins. Although both factors play important roles in the maintenance and differentiation of ESCs and the serine 248 (S248) and threonine 258 (T258) residues of Sox2 are modified by O-GlcNAcylation, the function of Sox2 O-GlcNAcylation is unclear. Here, we show that O-GlcNAcylation of Sox2 at T258 regulates mouse ESC self-renewal and early cell fate. ESCs in which wild-type Sox2 was replaced with the Sox2 T258A mutant exhibited reduced self-renewal, whereas ESCs with the Sox2 S248A point mutation did not. ESCs with the Sox2 T258A mutation heterologously introduced using the CRISPR/Cas9 system, designated E14-Sox2TA/WT, also exhibited reduced self-renewal. RNA sequencing analysis under self-renewal conditions showed that upregulated expression of early differentiation genes, rather than a downregulated expression of self-renewal genes, was responsible for the reduced self-renewal of E14-Sox2TA/WT cells. There was a significant decrease in ectodermal tissue and a marked increase in cartilage tissue in E14-Sox2TA/WT-derived teratomas compared with normal E14 ESC-derived teratomas. RNA sequencing of teratomas revealed that genes related to brain development had generally downregulated expression in the E14-Sox2TA/WT-derived teratomas. Our findings using the Sox2 T258A mutant suggest that Sox2 T258 O-GlcNAc has a positive effect on ESC self-renewal and plays an important role in the proper development of ectodermal lineage cells. Overall, our study directly links O-GlcNAcylation and early cell fate decisions.

Phosphorylation of OGFOD1 by Cell Cycle-Dependent Kinase 7/9 Enhances the Transcriptional Activity of RNA Polymerase II in Breast Cancer Cells.

2-oxoglutarate and iron-dependent oxygenase domain-containing protein 1 (OGFOD1) expression is upregulated in a variety of cancers and has been related to poor prognosis. However, despite this significance to cancer progression, the precise oncogenic mechanism of OGFOD1 is not understood. We demonstrated that OGFOD1 plays a role in enhancing the transcriptional activity of RNA polymerase II in breast cancer cells. OGFOD1 directly binds to the C-terminal domain of RNA polymerase II to alter phosphorylation status. The elimination of OGFOD1 resulted in decreased tumor development. Additionally, cell cycle-dependent kinase 7 and cell cycle-dependent kinase 9, critical enzymes for activating RNA polymerase II, phosphorylated serine 256 of OGFOD1, whereas a non-phosphorylated mutant OGFOD1 failed to enhance transcriptional activation and tumor growth. Consequently, OGFOD1 helps promote tumor growth by enhancing RNA polymerase II, whereas simultaneous phosphorylation of OGFOD1 by CDK enzymes is essential in stimulating RNA polymerase II-mediated transcription both in vitro and in vivo, and expression of target genes.

Biosynthesis of Commodity Chemicals From Oil Palm Empty Fruit Bunch Lignin.

Lignin is one of the most abundant natural resources that can be exploited for the bioproduction of value-added commodity chemicals. Oil palm empty fruit bunches (OPEFBs), byproducts of palm oil production, are abundant lignocellulosic biomass but largely used for energy and regarded as waste. Pretreatment of OPEFB lignin can yield a mixture of aromatic compounds that can potentially serve as substrates to produce commercially important chemicals. However, separation of the mixture into desired individual substrates is required, which involves expensive steps that undermine the utility of OPEFB lignin. Here, we report successful engineering of microbial hosts that can directly utilize heterogeneous mixtures derived from OPEFB lignin to produce commodity chemicals, adipic acid and levulinic acid. Furthermore, the corresponding bioconversion pathway was placed under a genetic controller to autonomously activate the conversion process as the cells are fed with a depolymerized OPEFB lignin mixture. This study demonstrates a simple, one-pot biosynthesis approach that directly utilizes derivatives of agricultural waste to produce commodity chemicals.

Tweak to Treat: Reprograming Bacteria for Cancer Treatment.

Recent advancements in cancer biology, microbiology, and bioengineering have spurred the development of engineered live biotherapeutics for targeted cancer therapy. In particular, natural tumor-targeting and probiotic bacteria have been engineered for controlled and sustained delivery of anticancer agents into the tumor microenvironment (TME). Here, we review the latest advancements in the development of engineered bacteria for cancer therapy and additional engineering strategies to potentiate the delivery of therapeutic payloads. We also explore the use of combination therapies comprising both engineered bacteria and conventional anticancer therapies for addressing intratumor heterogeneity. Finally, we discuss prospects for the development and clinical translation of engineered bacteria for cancer prevention and treatment.

Engineering probiotics for therapeutic applications: recent examples and translational outlook.

Engineered probiotics are the next generation of live biotherapeutics that have been genetically modified to target specific diseases. With the advancements in synthetic biology, the engineering of probiotics has become increasingly sophisticated which has led to the development of therapies for treating cancer, infection, metabolic disorders and inflammation, as well as for diagnosing and preventing them. Herein, we review some of the recent examples of probiotics which have been engineered to target such diseases. Although there are numerous examples of engineered probiotics showing efficacy in animal models, there are no approved products on the market with very few in clinical trials. Therefore, we also discuss a set of features that may be incorporated into engineered probiotics to aid in clinical translation and ultimately, realizing the potential of these biotherapeutics.

Engineering commensal bacteria to rewire host-microbiome interactions.

There has been a growing emphasis on understanding the important relationship between human-associated microbial communities and disease development. With technological advancements, we are able to gain further insights into host-microbiome interactions at a deeper level. In order to fully leverage the close associations between microbes and their host, development of therapeutics targeting the microbiome has surged in recent years. In this review, we discuss advances made in engineering gut bacteria to develop novel therapeutic modalities that aim to rewire host-microbiome interactions such as host metabolism and immune functions for prevention and treatment of various diseases. In particular, applications of these engineered bacteria against diseases such as metabolic, immune disorders and cancer are covered.

Protective Effects of Genipin on Gastrointestinal Disorders.

Genipin, an aglycone of geniposide, is a major component of gardeniae fructus, and has been used to treat jaundice, various inflammatory disorders, and liver disease, and has also been used as a natural cross-linking agent. The authors conducted several experiments to evaluate the protective effects of genipin on gastrointestinal disorders, such as, gastritis and gastric ulcers. Genipin showed inhibitory effects against HCl·ethanol-induced acute gastritis and indomethacin-induced gastric ulcers in rats and increased prostaglandin E2 (PGE2) in AGS gastric cancer cell. Genipin had significant effects on aggressive factors, acid-neutralization, and gastric secretion, and inhibited H+/K+-ATPase (a proton pump), which secretes gastric acid. The results obtained indicate that genipin has significant gastroprotective effects and might be useful for treating and preventing gastric lesions.

Psat1-Dependent Fluctuations in α-Ketoglutarate Affect the Timing of ESC Differentiation.

Embryonic stem cells (ESCs) undergo coordinated epigenetic and metabolic changes to differentiate properly. However, the precise mechanisms by which these alterations are fine-tuned in the early stages of differentiation have not been identified. In this study, we demonstrate that phosphoserine aminotransferase 1 (Psat1), an Oct4/Sox2/Nanog (OSN) target protein, regulates changes in α-ketoglutarate (α-KG), determining the fate of mouse ESCs (mESCs). Maintaining Psat1 levels was essential for mESC self-renewal and pluripotency. Moderate knockdown (KD) of Psat1 in mESCs lowered DNA 5'-hydroxymethylcytosine (5'-hmC) and increased histone methylation levels by downregulating permissive amounts of α-KG, ultimately accelerating differentiation. We found that intracellular α-KG declined transiently during differentiation and that its dysregulation by treatment with dimethyl-α-KG impeded differentiation. Further, by in vivo teratoma formation assay, pluripotency of Psat1 KD mESCs was impaired, especially into the ectodermal lineage. Thus, we have established how Psat1 is regulated in maintaining intracellular α-KG levels and determining the fate of mESCs.

Reprogrammable microbial cell-based therapeutics against antibiotic-resistant bacteria.

The discovery of antimicrobial drugs and their subsequent use has offered an effective treatment option for bacterial infections, reducing morbidity and mortality over the past 60 years. However, the indiscriminate use of antimicrobials in the clinical, community and agricultural settings has resulted in selection for multidrug-resistant bacteria, which has led to the prediction of possible re-entrance to the pre-antibiotic era. The situation is further exacerbated by significantly reduced antimicrobial drug discovery efforts by large pharmaceutical companies, resulting in a steady decline in the number of new antimicrobial agents brought to the market in the past several decades. Consequently, there is a pressing need for new antimicrobial therapies that can be readily designed and implemented. Recently, it has become clear that the administration of broad-spectrum antibiotics can lead to collateral damage to the human commensal microbiota, which plays several key roles in host health. Advances in genetic engineering have opened the possibility of reprogramming commensal bacteria that are in symbiotic existence throughout the human body to implement antimicrobial drugs with high versatility and efficacy against pathogenic bacteria. In this review, we discuss recent advances and potentialities of engineered bacteria in providing a novel antimicrobial strategy against antibiotic resistance.

Protective Effect of Liriodendrin Isolated from Kalopanax pictus against Gastric Injury.

In this study, we investigated the inhibitory activities on gastritis and gastric ulcer using liriodendrin which is a constituent isolated from Kalopanax pictus. To elucidate its abilities to prevent gastric injury, we measured the quantity of prostaglandin E2 (PGE2) as the protective factor, and we assessed inhibition of activities related to excessive gastric acid be notorious for aggressive factor and inhibition of Helicobacter pylori (H. pylori) colonization known as a cause of chronic gastritis, gastric ulcer, and gastric cancer. Liriodendrin exhibited higher PGE2 level than rebamipide used as a positive control group at the dose of 500 µM. It was also exhibited acid-neutralizing capacity (10.3%) and H(+)/K(+)-ATPase inhibition of 42.6% (500 µM). In pylorus-ligated rats, liriodendrin showed lower volume of gastric juice (4.38 ± 2.14 ml), slightly higher pH (1.53 ± 0.41), and smaller total acid output (0.47 ± 0.3 mEq/4 hrs) than the control group. Furthermore liriodendrin inhibited colonization of H. pylori effectively. In vivo test, liriodendrin significantly inhibited both of HCl/EtOH-induced gastritis (46.9 %) and indomethacin-induced gastric ulcer (46.1%). From these results, we suggest that liriodendrin could be utilized for the treatment and/or protection of gastritis and gastric ulcer.

Mobility of older palliative care patients with advanced cancer: a Korean study.

PURPOSE: to describe the levels of mobility in older cancer patients receiving palliative care in Korea, and to examine the associations of their mobility with lifestyle factors (sleep disturbance, physical activity) and physical symptoms (pain, fatigue). METHODS: In this cross-sectional descriptive study, 91 older cancer patients receiving palliative care were interviewed using a semi-structured survey questionnaire. Mobility was measured using the 6MWT. Physical activity behavior was measured using the classification of the ACSM. Sleep disturbance was assessed using the frequency sub-category of the SHQ. Both pain and fatigue were measured using a VAS. RESULTS: The mean 6MWT distance was 220.38 m. Participants in their 60 s, 70 s, and 80 s walked, on average, 260.93 m, 205.31 m, and 157.05 m, respectively. Approximately 73% of the participants engaged in regular physical activity. Those engaged in regular physical activity were significantly more mobile than those who were not (t = 2.44; p = .017). Higher levels of mobility were correlated with lower levels of sleep disturbance (r = -.37), fatigue (r = -.23), and pain (r = -.27). Significant predictors for mobility included levels of sleep disturbance, medication status, age, number of family members and monthly income, accounting for 34.7% of the variance in mobility. CONCLUSIONS: Korean cancer patients have relatively low levels of mobility. Cancer patients aged over 80 years are a vulnerable group at risk for impaired mobility. Older palliative care patients are more active than one might expect. Levels of mobility are inversely associated with pain, fatigue, and sleep-related symptoms.

A p53-inducible microRNA-34a downregulates Ras signaling by targeting IMPDH.

p53 is a well-known transcription factor that controls cell cycle arrest and cell death in response to a wide range of stresses. Moreover, p53 regulates glucose metabolism and its mutation results in the metabolic switch to the Warburg effect found in cancer cells. Nucleotide biosynthesis is also critical for cell proliferation and the cell division cycle. Nonetheless, little is known about whether p53 regulates nucleotide biosynthesis. Here we demonstrated that p53-inducible microRNA-34a (miR-34a) repressed inosine 5'-monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme of de novo GTP biosynthesis. Treatment with anti-miR-34a inhibitor relieved the expression of IMPDH upon DNA damage. Ultimately, miR-34a-mediated inhibition of IMPDH resulted in repressed activation of the GTP-dependent Ras signaling pathway. In summary, we suggest that p53 has a novel function in regulating purine biosynthesis, aided by miR-34a-dependent IMPDH repression.