ABSTRACT We re-analyzed the data from a recent large-scale study that reported strong correlations between DNA signatures of microbial organisms and 33 different cancer types and that created machine-learning predictors with near-perfect accuracy at distinguishing among cancers. We found at least two fundamental flaws in the reported data and in the methods: (i) errors in the genome database and the associated computational methods led to millions of false-positive findings of bacterial reads across all samples, largely because most of the sequences identified as bacteria were instead human; and (ii) errors in the transformation of the raw data created an artificial signature, even for microbes with no reads detected, tagging each tumor type with a distinct signal that the machine-learning programs then used to create an apparently accurate classifier. Each of these problems invalidates the results, leading to the conclusion that the microbiome-based classifiers for identifying cancer presented in the study are entirely wrong. These flaws have subsequently affected more than a dozen additional published studies that used the same data and whose results are likely invalid as well. IMPORTANCE Recent reports showing that human cancers have a distinctive microbiome have led to a flurry of papers describing microbial signatures of different cancer types. Many of these reports are based on flawed data that, upon re-analysis, completely overturns the original findings. The re-analysis conducted here shows that most of the microbes originally reported as associated with cancer were not present at all in the samples. The original report of a cancer microbiome and more than a dozen follow-up studies are, therefore, likely to be invalid. Recent reports showing that human cancers have a distinctive microbiome have led to a flurry of papers describing microbial signatures of different cancer types. Many of these reports are based on flawed data that, upon re-analysis, completely overturns the original findings. The re-analysis conducted here shows that most of the microbes originally reported as associated with cancer were not present at all in the samples. The original report of a cancer microbiome and more than a dozen follow-up studies are, therefore, likely to be invalid.

Major data analysis errors invalidate cancer microbiome findings

Patients with long COVID suffer from many neurological manifestations that persist for 3 months following infection by SARS-CoV-2. Autonomic dysfunction (AD) or dysautonomia is one complication of long COVID that causes patients to experience fatigue, dizziness, syncope, dyspnea, orthostatic intolerance, nausea, vomiting, and heart palpitations. The pathophysiology behind AD onset post-COVID is largely unknown. As such, this review aims to highlight the potential mechanisms by which AD occurs in patients with long COVID. The first proposed mechanism includes the direct invasion of the hypothalamus or the medulla by SARS-CoV-2. Entry to these autonomic centers may occur through the neuronal or hematogenous routes. However, evidence so far indicates that neurological manifestations such as AD are caused indirectly. Another mechanism is autoimmunity whereby autoantibodies against different receptors and glycoproteins expressed on cellular membranes are produced. Additionally, persistent inflammation and hypoxia can work separately or together to promote sympathetic overactivation in a bidirectional interaction. Renin-angiotensin system imbalance can also drive AD in long COVID through the downregulation of relevant receptors and formation of autoantibodies. Understanding the pathophysiology of AD post-COVID-19 may help provide early diagnosis and better therapy for patients. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9789535

Investigating the possible mechanisms of autonomic dysfunction post-COVID-19

We re-analyzed the data from a recent large-scale study that reported strong correlations between microbial organisms and 33 different cancer types, and that created machine learning predictors with near-perfect accuracy at distinguishing among cancers. We found at least two fundamental flaws in the reported data and in the methods: (1) errors in the genome database and the associated computational methods led to millions of false positive findings of bacterial reads across all samples, largely because most of the sequences identified as bacteria were instead human; and (2) errors in transformation of the raw data created an artificial signature, even for microbes with no reads detected, tagging each tumor type with a distinct signal that the machine learning programs then used to create an apparently accurate classifier. Each of these problems invalidates the results, leading to the conclusion that the microbiome-based classifiers for identifying cancer presented in the study are entirely wrong. These flaws have subsequently affected more than a dozen additional published studies that used the same data and whose results are likely invalid as well.

SARS-CoV-2, a single-stranded RNA coronavirus, causes an illness known as coronavirus disease 2019 (COVID-19). Long-term complications are an increasing issue in patients who have been infected with COVID-19 and may be a result of viral-associated systemic and central nervous system inflammation or may arise from a virus-induced hypercoagulable state. COVID-19 may incite changes in brain function with a wide range of lingering symptoms. Patients often experience fatigue and may note brain fog, sensorimotor symptoms, and sleep disturbances. Prolonged neurological and neuropsychiatric symptoms are prevalent and can interfere substantially in everyday life, leading to a massive public health concern. The mechanistic pathways by which SARS-CoV-2 infection causes neurological sequelae are an important subject of ongoing research. Inflammation- induced blood-brain barrier permeability or viral neuro-invasion and direct nerve damage may be involved. Though the mechanisms are uncertain, the resulting symptoms have been documented from numerous patient reports and studies. This review examines the constellation and spectrum of nervous system symptoms seen in long COVID and incorporates information on the prevalence of these symptoms, contributing factors, and typical course. Although treatment options are generally lacking, potential therapeutic approaches for alleviating symptoms and improving quality of life are explored.

https://www.mdpi.com/2035-8377/15/3/52/pdf?version=1688631861

Long COVID, the Brain, Nerves, and Cognitive Function

Olfactory dysfunction is a hallmark symptom of COVID-19 disease resulting from the SARS-CoV-2 virus. The cause of the sudden and usually temporary anosmia that most people suffer from COVID-19 is likely entirely peripheral - inflammation and other damage caused by the virus in the sensory epithelium inside the upper recesses of the nasal cavity can damage or prevent chemicals from properly activating the olfactory sensory neurons. However, persistent olfactory dysfunction from COVID-19, in the form of hyposmia and parosmia (decreased or altered smell) may affect as many as 15 million people worldwide. This epidemic of olfactory dysfunction is thus a continuing public health concern. Mounting evidence suggests that the SARS-CoV-2 virus itself or inflammation from the immune response in the nasal sensory epithelium may invade the olfactory bulb, likely via non-neuronal transmission. COVID-19 related long term olfactory dysfunction and early damage to olfactory and limbic brain regions suggests a pattern of degeneration similar to that seen in early stages of Alzheimer's, Parkinson's and Lewy Body dementias. Thus, long term olfactory dysfunction coupled with cognitive and emotional disturbance from COVID-19 may be the first signs of delayed onset dementia from neurodegeneration. Few treatments are known to be effective to prevent further degeneration, but the first line of defense against degeneration may be olfactory and environmental enrichment. There is a pressing need for more research on treatments for olfactory dysfunction and longitudinal studies including cognitive and olfactory function from patients who have recovered from even mild COVID-19.

COVID-19 and olfactory dysfunction: a looming wave of dementia?

Microbiome has been shown to substantially contribute to some cancers. However, the diagnostic implications of microbiome in head and neck squamous cell carcinoma (HNSCC) remain unknown.To identify the molecular difference in the microbiome of oral and non-oral HNSCC, primary data was downloaded from the Kraken-TCGA dataset. The molecular differences in the microbiome of oral and non-oral HNSCC were identified using the linear discriminant analysis effect size method.In the study, the common microbiomes in oral and non-oral cancers were Fusobacterium, Leptotrichia, Selenomonas and Treponema and Clostridium and Pseudoalteromonas, respectively. We found unique microbial signatures that positively correlated with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in oral cancer and positively and negatively correlated KEGG pathways in non-oral cancer. In oral cancer, positively correlated genes were mostly found in prion diseases, Alzheimer disease, Parkinson disease, Salmonella infection, and Pathogenic Escherichia coli infection. In non-oral cancer, positively correlated genes showed Herpes simplex virus 1 infection and Spliceosome and negatively correlated genes showed results from PI3K-Akt signaling pathway, Focal adhesion, Regulation of actin cytoskeleton, ECM-receptor interaction and Dilated cardiomyopathy.These results could help in understanding the underlying biological mechanisms of the microbiome of oral and non-oral HNSCC. Microbiome-based oncology diagnostic tool warrants further exploration. 

/pdf/microbial-and-molecular-differences-according-to-the-1s0nrmpk.pdf

Microbial and molecular differences according to the location of head and neck cancers

OBJECTIVES
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into the host cells depends on the expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). We investigated the distribution of ACE2- and TMPRSS2-expressing cells in various oral tissues to identify the underlying mechanism of oral manifestations in patients with coronavirus disease 2019. Subjects We analysed the expression patterns of ACE2 and TMPRSS2 in the oral mucosa (tongue, palate, and buccal mucosa), trigeminal ganglion, vessels, and salivary glands of 9 Sprague-Dawley rats using immunohistochemistry and immunofluorescence.


RESULTS
ACE2 and TMPRSS2 were strongly expressed in the intermediate layer of the squamous epithelia of tongue papillae and buccal mucosa. ACE2- and TMPRSS2-positive cells were observed in the taste buds of the tongue. Additionally, ACE2 and TMPRSS2 were co-expressed in the ductal epithelium and acinar cells of salivary glands. Furthermore, both ACE2 and TMPRSS2 were stained in the neuronal cell body of trigeminal ganglia, but not in Schwann cells. Moreover, ACE2 and TMPRSS2 were expressed in capillaries, but not in venules/arterioles.


CONCLUSIONS
SARS-CoV-2 can spread the suprabasal area of squamous epithelia of the oral mucosa, invades taste bud, trigeminal nerve, parotid gland, and microvessel, resulting in oral manifestations.

ACE2 and TMPRSS2 immunolocalization and oral manifestations of COVID-19.

Oxysterols are oxygenated derivatives of cholesterol that contain an additional hydroxy, epoxide, or ketone group in the sterol nucleus and/or a hydroxyl group in the side chain of the cholesterol molecule. 27-Hydroxycholesterol (27HC) is a side-chain oxysterol that is oxygenated at the 27th carbon atom of cholesterol. The oxysterol (27HC) is produced via oxidation by sterol 27-hydroxylase (CYP27A1) and metabolized via oxysterol 7a-hydroxylase (CYP7B1) for bile acid synthesis in the liver. A previous study has demonstrated that treatment with the alternative Estrogen receptor alpha (ERα) ligand 27HC induces ERα-dependent hematopoietic stem cell (HSC) mobilization. In addition, Cyp27a1-deficient mice demonstrate significantly reduced 27HC levels and HSC mobilization. Here, we report that exogenous 27HC treatment leads to a substantial reduction in the hematopoietic stem and progenitor cell (HSPC) population owing to significantly increased reactive oxygen species (ROS) levels and apoptosis in the bone marrow (BM). However, 27HC does not influence the population of mature hematopoietic cells in the BM. Furthermore, exogenous 27HC treatment suppresses cell growth and promotes ROS production and apoptosis in leukemic cells. Moreover, acute myeloid leukemia (AML) patients with high CYP7B1 expression (expected to have inhibition of 27HC) had significantly shorter survival than those with low CYP7B1 expression (expected to have an elevation of 27HC). Single-cell RNA-sequencing (scRNA seq) analysis revealed that the expression of CYP7B1 was significantly increased in AML patients. Thus, our study suggests that 27HC may serve as a potent agent for regulating pools of HSPCs and may have an application as a novel therapeutic target for hematological malignancies. Collectively, pharmacological inhibition of CYP7B1 (expected to have an elevation of 27HC) would potentially have fewer long-term hematological side effects, particularly when used in combination with chemotherapy or radiation for the treatment of leukemia patients. 

https://www.nature.com/articles/s41419-022-05360-0.pdf

Role of reactive oxygen species in regulating 27-hydroxycholesterol-induced apoptosis of hematopoietic progenitor cells and myeloid cell lines

The mechanism underlying xerostomia after menopause has not yet been fully elucidated. This study aimed to investigate the mechanism of xerostomia and the effect of the ferroptosis inhibitors deferoxamine (DFO) and ferrostatin-1 (FER) on salivary gland dysfunction in a postmenopausal animal model. Twenty-four female Sprague–Dawley rats were randomly divided into four groups: a SHAM group (n = 6, sham-operated rats), an OVX group (n = 6, ovariectomized rats), an FER group (n = 6, ovariectomized rats injected intraperitoneally with FER), and a DFO group (n = 6, ovariectomized rats injected intraperitoneally with DFO). GPX4 activity, iron accumulation, lipid peroxidation, inflammation, fibrosis, and salivary gland function were analyzed. Recovery of GPX4 activity and a decrease in iron accumulation and cytosolic MDA + HAE were observed in the DFO group. In addition, collagen I, collagen III, TGF-β, IL-6, TNF-α, and TGF-β levels were decreased in the DFO group compared to the OVX group. Recovery of GPX4 activity and the morphology of mitochondria, and reduction of cytosolic MDA + HAE were also observed in the FER group. In addition, decreased expression of inflammatory cytokines and fibrosis markers and increased expression of AQP5 were observed in both the DFO and FER groups. Postmenopausal salivary gland dysfunction is associated with ferroptosis, and DFO and FER may reverse the postmenopausal salivary gland dysfunction after menopause. DFO and FER are hence considered promising treatments for postmenopausal xerostomia.

/pdf/effect-of-deferoxamine-and-ferrostatin-1-on-salivary-gland-uf1v4t4t.pdf

Effect of deferoxamine and ferrostatin-1 on salivary gland dysfunction in ovariectomized rats

Post-menopausal dry mouth or xerostomia is caused by reduced salivary secretion. This study aimed to investigate the efficacy of echinochrome A (Ech A) in alleviating submandibular gland dysfunctions in ovariectomized rats that mimic menopause. Female rats that were eight-weeks-old were randomly divided into SHAM-6, -12; OVX-6, -12; and ECH-6, -12 groups (consisting of 6- and 12-weeks post-sham-operated, ovariectomized, and Ech A-treated ovariectomized rats, respectively). The ECH groups had lower body weight than OVX but similar food intake and estradiol or estrogen receptor β expression. However, the ECH groups had lower mRNA expression of sterol-regulatory element binding protein-1c (Srebp-1c), acetyl-CoA carboxylase (Acc), fatty acid synthase (Fasn), cluster of differentiation 36 (Cd36), and lipid vacuole deposition than OVX mice. Moreover, reactive oxygen species (ROS), malondialdehyde (MDA), and iron accumulation were lower in the ECH than in the OVX groups. Fibrosis markers, transforming growth factor β (Tgf-βI and Tgf-βII mRNA) increased in the OVX than SHAM groups but decreased in the ECH groups. Aquaporin (Aqp-1 and Aqp-5 mRNA) and mucin expressions were downregulated in the OVX groups but improved with Ech A. In addition, Ech A prevented post-menopausal salivary gland dysfunction by inhibiting lipogenesis and ferroptosis. These findings suggest Ech A as an effective remedy for treating menopausal dry mouth.

/pdf/effect-of-echinochrome-a-on-submandibular-gland-dysfunction-11npg9zl.pdf

Effect of Echinochrome A on Submandibular Gland Dysfunction in Ovariectomized Rats

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