Effective cancer therapy with limited adverse effects is a major challenge in the medical field. This is especially complicated by the development of acquired chemoresistance. Understanding the mechanisms that underlie these processes remains a major effort in cancer research. In this review, we focus on the dual role that Bid protein plays in apoptotic cell death via the mitochondrial pathway, in oncogenesis and in cancer therapeutics. The BH3 domain in Bid and the anti-apoptotic mitochondrial proteins (Bcl-2, Bcl-XL, mitochondrial ATR) it associates with at the outer mitochondrial membrane provides us with a viable target in cancer therapy. We will discuss the roles of Bid, mitochondrial ATR, and other anti-apoptotic proteins in intrinsic apoptosis, exploring how their interaction sustains cellular viability despite the initiation of upstream death signals. The unexpected upregulation of this Bid protein in cancer cells can also be instrumental in explaining the mechanisms behind acquired chemoresistance. The stable protein associations at the mitochondria between tBid and anti-apoptotic mitochondrial ATR play a crucial role in maintaining the viability of cancer cells, suggesting a novel mechanism to induce cancer cell apoptosis by freeing tBid from the ATR associations at mitochondria.

Mitochondrial carrier homolog 2 (MTCH2) is a member of the solute carrier 25 family, located on the outer mitochondrial membrane. MTCH2 was first identified in 2000. The development in MTCH2 research is rapidly increasing. The most well-known role of MTCH2 is linking to the pro-apoptosis BID to facilitate mitochondrial apoptosis. Genetic variants in MTCH2 have been investigated for their association with metabolic and neurodegenerative diseases, however, no intervention or therapeutic suggestions were provided. Recent studies revealed the physiological and pathological function of MTCH2 in metabolic diseases, neurodegenerative diseases, cancers, embryonic development and reproduction via regulating mitochondrial apoptosis, metabolic shift between glycolysis and oxidative phosphorylation, mitochondrial fusion/fission, epithelial-mesenchymal transition, etc. This review endeavors to assess a total of 131 published articles to summarise the structure and physiological/pathological role of MTCH2, which has not previously been conducted. This review concludes that MTCH2 plays a crucial role in metabolic diseases, neurodegenerative diseases, cancers, embryonic development and reproduction, and the predominant molecular mechanism is regulation of mitochondrial function. This review gives a comprehensive state of current knowledgement on MTCH2, which will promote the therapeutic research of MTCH2.

Thyroid cancer (THCA) is one of the most common malignancies of the endocrine system. Exosomes have significant value in performing molecular treatments, evaluating the diagnosis and determining tumor prognosis. Thus, the identification of exosome-related genes could be valuable for the diagnosis and potential treatment of THCA. In this study, we examined a set of exosome-related differentially expressed genes (DEGs) (BIRC5, POSTN, TGFBR1, DUSP1, BID, and FGFR2) by taking the intersection between the DEGs of the TCGA-THCA and GeneCards datasets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the exosome-related DEGs indicated that these genes were involved in certain biological functions and pathways. Protein‒protein interaction (PPI), mRNA‒miRNA, and mRNA-TF interaction networks were constructed using the 6 exosome-related DEGs as hub genes. Furthermore, we analyzed the correlation between the 6 exosome-related DEGs and immune infiltration. The Genomics of Drug Sensitivity in Cancer (GDSC), the Cancer Cell Line Encyclopedia (CCLE), and the CellMiner database were used to elucidate the relationship between the exosome-related DEGs and drug sensitivity. In addition, we verified that both POSTN and BID were upregulated in papillary thyroid cancer (PTC) patients and that their expression was correlated with cancer progression. The POSTN and BID protein expression levels were further examined in THCA cell lines. These findings provide insights into exosome-related clinical trials and drug development.

BACKGROUND: Studies have found that BH3 interacting domain death agonist (BID) is closely related to the occurrence and development of many kinds of tumors. However, little attention has been paid to the situation of BID in clear cell renal cell carcinoma (ccRCC). So, our aim was to explore the effect of BID in ccRCC.
METHODS: Survival analysis, ROC curve, correlation analysis and Cox regression analysis were executed to analyze the prognostic value and clinical correlation of BID in ccRCC. The risk prognosis model was constructed in the training cohort and further validated in the internal testing cohort, ICGC cohort, and GEO cohort. Transcriptome sequencing and immunohistochemical staining of clinical specimens were used to validate the results of bioinformatics analysis. The GSEA, ESTIMATE algorithm, CIBERSORT algorithm, ssGSEA, TIDE score, correlation and difference analysis were used to analyze the effects of BID on immune infiltration in tumor microenvironment (TME).
RESULTS: BID was highly expressed in ccRCC tissues, which was verified by transcriptome sequencing and immunohistochemical staining of clinical specimens. Patients with high expression of BID had a worse prognosis. BID is an independent prognostic factor for ccRCC. The prognostic model based on BID can accurately predict the prognosis of patients in different cohorts. In addition, the expression levels of BID was closely related to immunomodulatory molecules such as PD-1, LAG3, and CTLA4. Enrichment analysis indicated that BID was significantly enriched in immune-related responses and cancer-related pathways. The change of BID expression mediates different characteristics of immune infiltration in TME.
CONCLUSIONS: BID is highly expressed in ccRCC, which is a reliable biomarker of ccRCC prognosis. It is closely related to TME, and may be a potential target for immunotherapy in patients with ccRCC.

Caspase-2, a highly conserved member of the caspase family, is considered an initiator caspase that triggers apoptosis in response to some cellular stresses. Previous studies suggest that an intracellular multi-protein complex PIDDosome, induced by genotoxic stress, serves as a platform for caspase-2 activation. However, due to caspase-2\'s inability to process effector caspases, the mechanism underlying caspase-2-mediated cell death upon PIDDosome activation remains unclear. Here we conducted an unbiased genome-wide genetic screen and identified that the Bcl2 family protein BID is required for PIDDosome-induced, caspase-2-mediated apoptosis. PIDDosome-activated caspase-2 directly and functionally processes BID to signal the mitochondrial pathway for apoptosis induction. Additionally, a designed chemical screen identified a compound, HUHS015, that specifically activates caspase-2-mediated apoptosis. HUHS015-stimulated apoptosis also requires BID but is independent of the PIDDosome. Through extensive structure-activity relationship efforts, we identified a derivative with a potency of ~ 60 nmol/L in activating caspase-2-mediated apoptosis. The HUHS015-series of compounds act as efficient agonists that directly target the interdomain linker in caspase-2, representing a new mode of initiator caspase activation. Human and mouse caspase-2 differ in two crucial residues in the linker, rendering a selectivity of the agonists for human caspase-2. The caspase-2 agonists are valuable tools to explore the physiological roles of caspase-2-mediated cell death and a base for developing small-molecule drugs for relevant diseases.

UNASSIGNED: Direct oral anticoagulant (DOAC) is widely used for the prevention of embolic stroke in non-valvular atrial fibrillation (NVAF) patients. However, the gastrointestinal bleeding risk in several DOAC regimens was higher than warfarin, especially in once-daily regimens.
UNASSIGNED: We conducted a single-center prospective registry of patients with NVAF treated with DOACs: the DIRECT registry (N = 2216; follow-up duration 650 [IQR 103-1574] days, UMIN000033283). All patients were divided into 2 groups: the twice-daily (BID) regimen group (dabigatran and apixaban) versus the once-daily (QD) regimen group (rivaroxaban and edoxaban). Out of 2216 patients, we successfully matched 904 patients in the QD group and 904 patients in the BID group using propensity score. The primary endpoint was gastrointestinal bleeding defined as any bleeding in the gastrointestinal tract that was identified through medical records regardless of bleeding site or severity. The BID group showed a significantly lower gastrointestinal bleeding rate than the QD group (3.5/100 person-year vs. 6.2/100 person-year, log-rank P < 0.0001). The secondary endpoints were all death, stroke, major bleeding, and any bleeding. The rate of major bleeding was significantly lower in patients with BID regimen group (log-rank P = 0.040). In contrast, all death, stroke, and any bleeding did not differ between both groups (log-rank P = 0.280, 0.520 and 0.066, respectively).
UNASSIGNED: The BID regimen as compared with the QD regimen was associated with reduced risk of gastrointestinal bleeding.

During tumorigenesis, miRNAs with unbalanced expression profiles can increase the threat of disease progression. Here, we focus on the role of miR-331-5p in the pathogenesis of thyroid cancer (TC). In vitro studies were conducted using TC cell lines after the forced expression and silencing of miR-331-5p. Cell proliferation and viability were analyzed via cell counts and colorimetric assays. Cell motility was analyzed via wound healing assays, Transwell migration and invasion assays, and Matrigel Matrix assays. The putative targets of miR-331-5p were unveiled via label-free proteomic screening and then verified using Western blot and luciferase assays. Expression studies were conducted by interrogating The Cancer Genome Atlas (TCGA). We found that ectopic miR-331-5p expression reduces TC cell motility, while miR-331-5p silencing induces the opposite phenotype. Proteomic screening revealed eight putative downregulated targets of miR-331-5p, among which BID was confirmed as a direct target. TCGA data showed the downregulation of miR-331-5p and the upregulation of BID in TC tissues. In summary, deregulation of the miR-331-5p/BID axis could enhance the aggressiveness of TC cell lines, providing new insights into the mechanisms of the progression of this disease and suggesting a potential role of the component factors as possible biomarkers in TC tissues.

Worldwide, myocardial infarction (MI) is the leading cause of death and disability-adjusted life years lost. Recent researches explored new methods of detecting biomarkers that can predict the risk of developing myocardial infarction, which includes identifying genetic markers associated with increased risk. We induced myocardial infarction in mice by occluding the left anterior descending coronary artery and performed TTC staining to assess cell death. Next, we performed ChIP assays to measure the enrichment of histone modifications at the promoter regions of key genes involved in mitochondrial fission. We used qPCR and western blot to measure expression levels of relative apoptotic indicators. We report that miR-181a inhibits myocardial ischemia-induced apoptosis and preserves left ventricular function after MI. We show that programmed cell death protein 4 (PDCD4) is the target gene involved in miR-181a-mediated anti-ischemic injury, which enhanced BID recruitment to the mitochondria. In addition, we discovered that p53 inhibits the expression of miR-181a via transcriptional regulation. Here, we discovered for the first time a mitochondrial fission and apoptosis pathway which is controlled by miR-181a and involves PDCD4 and BID. This pathway may be controlled by p53 transcriptionally, and we presume that miR-181a may lead to the discovery of new therapeutic and preventive targets for ischemic heart diseases.

In 2018, the US Congress enacted a policy permitting Medicare Advantage (MA) plans to cover telehealth services in a beneficiary\'s home and through audio-only means as part of the basic benefit package of services, where prior to the policy change such benefits were only allowed to be covered as a supplemental benefit. MA plans were afforded 2 years of lead time for strategizing, negotiating, and capital investment prior to the start date (January 1, 2020) of the new coverage option. Our data analysis found basic benefit telehealth was offered by plans comprising 71% of enrollment in 2020 and increased to 95% in 2021. At the same time, remote access telehealth was offered as a supplemental benefit for 69% of enrollees in 2020, a decrease of 23% compared to 2019. These efforts by MA plans may have enabled traditional Medicare (TM) to leverage an existing telehealth infrastructure as a solution to the access issues created by public health policies requiring sheltering in place and social distancing during the COVID-19 pandemic. The success of this MA policy prompts consideration of additional flexibility beyond the standard basic benefit package, and whether such benefits reduce costs while improving access and/or outcomes in the context of a managed care environment like MA. Subject to oversight, such flexibility could potentially improve value in MA, and facilitate future changes in TM, as appropriate.

Brain implantable wireless microsystems has potential to treat neurological diseases and maintain the quality of life. Highly efficient miniaturized antenna is the fundamental part of BID (brain implantable device) for reliable signaling of data through dissipative intracranial material. In this paper, a patch antenna with L-shaped defected ground is demonstrated. L-shaped radiator contributed to achieve the resonance at 2.45 GHz industrial scientific and medical (ISM) band. Antenna size is reduced to 10 × 10 × 0.25 mm3. The proposed L-shaped ground plane geometry is contributing in improving the radiation performance. |S11| value shifts from 15 dB to 30 dB after modifying the ground plane. Proposed structure attained the gain of -14 dBi when located between the Dura and CSF layers at the depth of 12 mm in human brain model. Full wave simulated antenna prototype is fabricated and measured for performance verification. Impedance bandwidth of 270 MHz and broadside radiation pattern (for transferring maximum electromagnetic energy away from tissue) are maintained by the proposed antenna. Brain tissue safety is ensured by specific absorption rate which is 0.709 W/kg and in compliance with the safety limits of 1.6 W/kg for 1-g averaged tissue. Proposed antenna structure is the promising candidate for medical implant technology.