The impact of cancer metastases on COVID-19 outcomes: A COVID-19 and Cancer Consortium registry-based retrospective cohort study.

BACKGROUND: COVID-19 can have a particularly detrimental effect on patients with cancer, but no studies to date have examined if the presence, or site, of metastatic cancer is related to COVID-19 outcomes. METHODS: Using the COVID-19 and Cancer Consortium (CCC19) registry, the authors identified 10,065 patients with COVID-19 and cancer (2325 with and 7740 without metastasis at the time of COVID-19 diagnosis). The primary ordinal outcome was COVID-19 severity: not hospitalized, hospitalized but did not receive supplemental O2, hospitalized and received supplemental O2, admitted to an intensive care unit, received mechanical ventilation, or died from any cause. The authors used ordinal logistic regression models to compare COVID-19 severity by presence and specific site of metastatic cancer. They used logistic regression models to assess 30-day all-cause mortality. RESULTS: Compared to patients without metastasis, patients with metastases have increased hospitalization rates (59% vs. 49%) and higher 30 day mortality (18% vs. 9%). Patients with metastasis to bone, lung, liver, lymph nodes, and brain have significantly higher COVID-19 severity (adjusted odds ratios [ORs], 1.38, 1.59, 1.38, 1.00, and 2.21) compared to patients without metastases at those sites. Patients with metastasis to the lung have significantly higher odds of 30-day mortality (adjusted OR, 1.53; 95% confidence interval, 1.17-2.00) when adjusting for COVID-19 severity. CONCLUSIONS: Patients with metastatic cancer, especially with metastasis to the brain, are more likely to have severe outcomes after COVID-19 whereas patients with metastasis to the lung, compared to patients with cancer metastasis to other sites, have the highest 30-day mortality after COVID-19.

Mechanisms of persistent hemolysis-induced middle kidney injury in grass carp (Ctenopharyngodon idella).

Infection-induced hemolysis results in intravascular hemolysis, which releases hemoglobin (Hb) into the tissues. Free Hb exhibits cytotoxic, oxidative, and pro-inflammatory effects, leading to systemic inflammation, vascular constriction dysfunction, thrombosis, and proliferative vascular lesions. Currently, the impact of intravascular hemolysis on the middle kidney in fish is unclear. Here, the injection of phenylhydrazine (PHZ) was used to establish a persistent hemolysis model in grass carp. The determination results revealed that the PHZ-induced hemolysis caused conspicuous tissue damage in the kidneys of grass carp, increased the levels of Cr in the serum and the expression indicators of kidney injury-related genes in the middle kidney. Prussian blue staining indicated that PHZ-induced hemolysis significantly increased the deposition of iron ions in the kidneys of grass carp, and activated the expression levels of iron metabolism-related genes. The results of oxidative damage-related experiments indicate that under PHZ treatment, the activity of middle kidney cells decreases, and the production of oxidative damage markers malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) increases, simultaneously inhibiting the activity of antioxidant enzymes and upregulating the transcription levels of antioxidant enzyme-related genes. Additionally, the analysis of inflammatory factors revealed a significant upregulation of genes associated with inflammation induced by PHZ-induced hemolysis. The transcriptome analysis was performed to further explore the molecular regulatory effects of hemolysis on tissues, the analysis revealed the treatment of PHZ activated various of programmed cell death (PCD) pathways, including ferroptosis, apoptosis, and autophagy. In summary, this study found that sustained hemolysis in fish results in Hb and iron ion deposition in middle kidney, promoting oxidative damage, ultimately inducing various forms of PCD.

De novo design of a nanoregulator for the dynamic restoration of ovarian tissue in cryopreservation and transplantation.

The cryopreservation and transplantation of ovarian tissue underscore its paramount importance in safeguarding reproductive capacity and ameliorating reproductive disorders. However, challenges persist in ovarian tissue cryopreservation and transplantation (OTC-T), including the risk of tissue damage and dysfunction. Consequently, there has been a compelling exploration into the realm of nanoregulators to refine and enhance these procedures. This review embarks on a meticulous examination of the intricate anatomical structure of the ovary and its microenvironment, thereby establishing a robust groundwork for the development of nanomodulators. It systematically categorizes nanoregulators and delves deeply into their functions and mechanisms, meticulously tailored for optimizing ovarian tissue cryopreservation and transplantation. Furthermore, the review imparts valuable insights into the practical applications and obstacles encountered in clinical settings associated with OTC-T. Moreover, the review advocates for the utilization of microbially derived nanomodulators as a potent therapeutic intervention in ovarian tissue cryopreservation. The progression of these approaches holds the promise of seamlessly integrating nanoregulators into OTC-T practices, thereby heralding a new era of expansive applications and auspicious prospects in this pivotal domain.

Current state of the art: immunotherapy in esophageal cancer and gastroesophageal junction cancer.

Esophageal cancers have a high mortality rate and limited treatment options especially in the advanced/metastatic setting. Squamous cell carcinoma (SCC) and adenocarcinoma are two distinct types of esophageal cancer. Esophageal SCC is more common in nonindustrialized countries with risk factors including smoking, alcohol use, and achalasia. Adenocarcinoma is the predominant esophageal cancer in developed nations, and risk factors include chronic gastroesophageal reflux disease, obesity, and smoking. Chemotherapy has been the mainstay of therapy for decades until immunotherapy made its debut in the past few years. Immune checkpoint inhibitors have been tested in many studies now and are becoming an essential component of esophageal cancer treatment. Monoclonal antibodies that selectively inhibit programmed cell death-1 (PD-1) activity such as pembrolizumab and nivolumab, have become standard of care in the treatment of esophageal cancer. Several other anti-PD-1 antibodies like camrelizumab, toripalimab, sintilimab, trislelizumab are under investigation in different stages of clinical trials. Here we provide a comprehensive review of extant literature as well as ongoing trials with various combinations of chemotherapy or other targeted therapy with a focus on different histological subgroups of esophageal cancer and in different clinical settings.

Belzutifan, HIF-2α Inhibitor, and Clear Cell Renal Cell Carcinoma With Somatic Von-Hippel-Lindau Loss-of-Function Mutation.

The Von-Hippel-Lindau (VHL) gene, acting as a tumor suppressor, plays a crucial role in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). Approximately 90% of individuals with advanced ccRCC exhibit somatic mutations in the VHL gene. Belzutifan, orally administered small-molecule inhibitor of hypoxia-induced factor-2α, has demonstrated promising efficacy in solid tumors associated with germline loss-of-function mutations in VHL, including ccRCC. However, its impact on cases with somatic or sporadic VHL mutations remains unclear. Here, we present 2 cases where belzutifan monotherapy was employed in patients with advanced ccRCC and somatic loss-of-function mutations in VHL. Both patients exhibited a swift and sustained response, underscoring the potential role of belzutifan as a viable option in second or subsequent lines of therapy for individuals with somatic VHL mutations. Despite both patients experiencing a pulmonary crisis with respiratory compromise, their rapid response to belzutifan further emphasizes its potential utility in cases involving pulmonary or visceral crises. This report contributes valuable insights into the treatment landscape for advanced ccRCC with somatic VHL mutations.

A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas.

PURPOSE: High-grade gliomas (HGG) carry a poor prognosis, with glioblastoma accounting for almost 50% of primary brain malignancies in the elderly. Unfortunately, despite the use of multiple treatment modalities, the prognosis remains poor in this population. Our preclinical studies suggest that the presence of aromatase expression, encoded by CYP19A1, is significantly upregulated in HGGs. Remarkably, we find that letrozole (LTZ), an FDA-approved aromatase inhibitor, has marked activity against HGGs. PATIENTS AND METHODS: We conducted a phase 0/I single-center clinical trial (NCT03122197) to assess the tumoral availability, pharmacokinetics (PK), safety, and tolerability of LTZ in recurrent patients with HGG. Planned dose cohorts included 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and postsurgery or biopsy. Tumor samples were assayed for LTZ content and relevant biomarkers. The recommended phase 2 dose (R2PD) was determined as the dose that resulted in predicted steady-state tumoral extracellular fluid (ECF; Css,ecf) >2 µmol/L and did not result in ≥33% dose-limiting adverse events (AE) assessed using CTCAE v5.0. RESULTS: Twenty-one patients were enrolled. Common LTZ-related AEs included fatigue, nausea, musculoskeletal, anxiety, and dysphoric mood. No DLTs were observed. The 15 mg dose achieved a Css,ecf of 3.6 ± 0.59 µmol/L. LTZ caused dose-dependent inhibition of estradiol synthesis and modulated DNA damage pathways in tumor tissues as evident using RNA-sequencing analysis. CONCLUSIONS: On the basis of safety, brain tumoral PK, and mechanistic data, 15 mg daily is identified as the RP2D for future trials.

Differences of functionalized graphene materials on inducing chronic aquatic toxicity through the regulation of DNA damage, metabolism and oxidative stress in Daphnia magna.

Graphene can be modified with functional groups when released into the environment. However, very little is known about molecular mechanisms of chronic aquatic toxicity induced by graphene nanomaterials with different surface functional groups. By using RNA sequencing, we investigated the toxic mechanisms of unfunctionalized graphene (u-G), carboxylated graphene (G-COOH), aminated graphene (G-NH2), hydroxylated graphene (G-OH) and thiolated graphene (G-SH) to Daphnia magna during 21-day exposure. We revealed that alteration of ferritin transcription levels in the "mineral absorption" signaling pathway is a molecular initiating event leading to potential of oxidative stress in Daphnia magna by u-G, while toxic effects of four functionalized graphenes are related to several metabolic pathways including the "protein digestion and absorption" pathway and "carbohydrate digestion and absorption" pathway. The transcription and translation related pathways were inhibited by G-NH2 and G-OH, which further affected the functions of proteins and normal life activities. Noticeably, detoxifications of graphene and its surface functional derivatives were promoted by increasing the gene expressions related to chitin and glucose metabolism as well as cuticle structure components. These findings demonstrate important mechanistic insights that can potentially be employed for safety assessment of graphene nanomaterials.

Somatic BRCA2 Mutation-Positive Concurrent Accessory Male Breast Cancer (BC) and Non-Small Cell Lung Cancer (NSCLC): Excellent Efficacy of Palbociclib, Fulvestrant and Leuprolide in Platinum-Exposed and Endocrine-Refractory BC Associated with Cyclin D1 and FGFR1 Amplification and of Carboplatin, Paclitaxel and Radiation in NSCLC.

Accessory male breast cancer (BC) is a rare entity and is associated with poor outcome. We report a 76-year-old patient who was diagnosed with concurrent accessory breast and primary lung cancer, both were positive for somatic BRCA-2 (E1593D) mutation. He received concurrent radiation and platinum-based chemotherapy for lung cancer with good response, but breast cancer progressed in about 8 months, and further progressed after single agent anastrozole in 10 months. Next Generation Sequencing (NGS) of breast cancer was also positive for CCND1 (Cyclin D1) and FGFR1 amplifications. Despite a poor molecular profile of breast cancer, and progression following platinum-based chemotherapy and anastrozole, he was successfully treated with the Cyclin-dependent kinase (CKD) 4/6 inhibitor palbociclib, estrogen-receptor down-regulator fulvestrant and luteinizing hormone-releasing hormone (LHRH) agonist leuprolide with the duration of response of 21 months which has exceeded duration of response to prior treatments. This case is of interest given FDA expanded the approval of palbociclib in combination with AI or fulvestrant for male patients with HR-positive, HER2-negative metastatic breast cancer in Apr. 2019 based on real-world data from electronic health records.

The role of melanin concentrating hormone (MCH) in the central chemoreflex: a knockdown study by siRNA in the lateral hypothalamus in rats.

Melanin concentrating hormone (MCH), a neuropeptide produced mainly in neurons localized to the lateral hypothalamic area (LHA), has been implicated in the regulation of food intake, energy balance, sleep state, and the cardiovascular system. Hypothalamic MCH neurons also have multisynaptic connections with diaphragmatic motoneurons and project to many central chemoreceptor sites. However, there are few studies of MCH involvement in central respiratory control. To test the hypothesis that MCH plays a role in the central chemoreflex, we induced a down regulation of MCH in the central nervous system by knocking down the MCH precursor (pMCH) mRNA in the LHA using a pool of small interfering RNA (siRNA), and measured the resultant changes in breathing, metabolic rate, body weight, and blood glucose levels in conscious rats. The injections of pMCH-siRNA into the LHA successfully produced a ∼ 62% reduction of pMCH mRNA expression in the LHA and a ∼ 43% decrease of MCH levels in the cerebrospinal fluid relative to scrambled-siRNA treatment (P = 0.006 and P = 0.02 respectively). Compared to the pretreatment baseline and the scrambled-siRNA treated control rats, knockdown of MCH resulted in: 1) an enhanced hypercapnic chemoreflex (∼ 42 & 47% respectively; P < 0.05) only in wakefulness; 2) a decrease in body weight and basal glucose levels; and 3) an unchanged metabolic rate. Our results indicate that MCH participates not only in the regulation of glucose and sleep-wake homeostasis but also the vigilance-state dependent regulation of the central hypercapnic chemoreflex and respiratory control.

Focal microdialysis of CO2 in the perifornical-hypothalamic area increases ventilation during wakefulness but not NREM sleep.

We investigated whether the perifornical-lateral hypothalamic area (PF-LHA), where the orexin neurons reside, is a central chemoreceptor site by microdialysis of artificial cerebrospinal fluid (aCSF) equilibrated with 25% CO(2) into PF-LHA in conscious rats. This treatment is known to produce a focal tissue acidification like that associated with a 6-7 mm Hg increase in arterial [Formula: see text] . Such focal acidification in the PF-LHA significantly increased ventilation up to 15% compared with microdialysis of normal aCSF equilibrated with 5% CO(2) only in wakefulness but not in sleep in both the dark (P=0.004) and light (P<0.001) phases of the diurnal cycle. This response was predominantly due to a significant increase in respiratory frequency (11%, P<0.001). There were no significant effects on ventilation in the group with probes misplaced outside the PF-LHA. These results suggest that PF-LHA functions as a central chemoreceptor site in the central nervous system in a vigilant state dependent manner with predominant effects in wakefulness.