Methotrimeprazine is a neuroprotective antiviral in JEV infection via adaptive ER stress and autophagy.

Japanese encephalitis virus (JEV) pathogenesis is driven by a combination of neuronal death and neuroinflammation. We tested 42 FDA-approved drugs that were shown to induce autophagy for antiviral effects. Four drugs were tested in the JE mouse model based on in vitro protective effects on neuronal cell death, inhibition of viral replication, and anti-inflammatory effects. The antipsychotic phenothiazines Methotrimeprazine (MTP) & Trifluoperazine showed a significant survival benefit with reduced virus titers in the brain, prevention of BBB breach, and inhibition of neuroinflammation. Both drugs were potent mTOR-independent autophagy flux inducers. MTP inhibited SERCA channel functioning, and induced an adaptive ER stress response in diverse cell types. Pharmacological rescue of ER stress blocked autophagy and antiviral effect. MTP did not alter translation of viral RNA, but exerted autophagy-dependent antiviral effect by inhibiting JEV replication complexes. Drug-induced autophagy resulted in reduced NLRP3 protein levels, and attenuation of inflammatory cytokine/chemokine release from infected microglial cells. Our study suggests that MTP exerts a combined antiviral and anti-inflammatory effect in JEV infection, and has therapeutic potential for JE treatment.

Opportunities and Challenges for a Histology-Agnostic Utilization of Trastuzumab Deruxtecan.

PURPOSE OF REVIEW: This review delves into the prospects and challenges offered by a potential pan-histological utilization of trastuzumab deruxtecan (T-DXd) in patients with advanced solid tumors. RECENT FINDINGS: The HER2-targeted antibody-drug conjugate (ADC) T-DXd has shown broad activity across cancer types, with current indications for patients with biomarker-selected breast, gastric, and non-small-cell lung cancer and relevant activity observed in multiple histology-specific trials. Moreover, two recently reported phase 2 trials (DESTINY-Pantumor02 and HERALD) have supported the potential for a pan-cancer utilization of this ADC in patients with advanced cancers expressing HER2 or with HER2 amplifications. By improving the delivery of cytotoxic chemotherapy, ADCs have allowed for meaningful clinical advantages in broad populations of cancer patients, often leading to survival advantages over conventional chemotherapy. Notably, the broad spectrum of activity of certain ADCs has led to the hypothesis of a histology-agnostic utilization based on detecting specific biomarkers, similar to what is already established for certain targeted treatments and immunotherapy. To date, T-DXd has shown the broadest activity across cancer types, with current approvals in breast, gastric, and lung cancer, and relevant antitumor activity observed in a multiplicity of additional cancer types. The optimization of the drug dose, identification of predictive biomarkers, and clarification of mechanisms of resistance will be critical steps in view of a pan-histological expansion in the use of T-DXd.

Mitochondrial calcium signaling mediated transcriptional regulation of keratin filaments is a critical determinant of melanogenesis.

Mitochondria are versatile organelles that regulate several physiological functions. Many mitochondria-controlled processes are driven by mitochondrial Ca2+ signaling. However, role of mitochondrial Ca2+ signaling in melanosome biology remains unknown. Here, we show that pigmentation requires mitochondrial Ca2+ uptake. In vitro gain and loss of function studies demonstrated that Mitochondrial Ca2+ Uniporter (MCU) is crucial for melanogenesis while the MCU rheostats, MCUb and MICU1 negatively control melanogenesis. Zebrafish and mouse models showed that MCU plays a vital role in pigmentation in vivo. Mechanistically, MCU controls activation of transcription factor NFAT2 to induce expression of three keratins (keratin 5, 7 and 8), which we report as positive regulators of melanogenesis. Interestingly, keratin 5 in turn modulates mitochondrial Ca2+ uptake thereby this signaling module acts as a negative feedback loop that fine-tunes both mitochondrial Ca2+ signaling and melanogenesis. Mitoxantrone, an FDA approved drug that inhibits MCU, decreases physiological melanogenesis. Collectively, our data demonstrates a critical role for mitochondrial Ca2+ signaling in vertebrate pigmentation and reveal the therapeutic potential of targeting MCU for clinical management of pigmentary disorders. Given the centrality of mitochondrial Ca2+ signaling and keratin filaments in cellular physiology, this feedback loop may be functional in a variety of other pathophysiological conditions.

Transient suppression of Wnt signaling in poor-quality buffalo oocytes improves their developmental competence.

Introduction: One of the most evolutionary conserved communication systems, the Wnt signaling pathway is a major gene regulatory pathway that affects the developmental competence of oocytes and regulates most embryonic developmental processes. The present study was undertaken to modulate the canonical Wnt (Wingless/integration) signaling pathway in the poor-quality (colorless cytoplasm after Brilliant Cresyl Blue staining, BCB-) buffalo cumulus-oocyte complexes (COCs) to improve their in vitro maturation (IVM) and embryo production (IVEP) rates. Methods: The expression of key Wnt pathway genes was initially assessed in the good (blue cytoplasm after Brilliant Cresyl Blue staining, BCB+) and poor quality (BCB-) buffalo COCs to establish a differential activity of the Wnt pathway. The BCB- COCs were supplemented with the Wnt pathway inhibitor, Dickkopf-related protein 1 (DKK1) and later subjected to IVM and IVEP along with the BCB+ and BCB- controls. The cumulus expansion index (CEI), rate of nuclear maturation (mean percentage of oocytes in the MII stage) and embryo production, and the expression of developmentally important genes were evaluated to assess the effect of Wnt pathway inhibition on the development competence of these poor-quality oocytes. Results: The Wnt pathway genes exhibited a significantly higher expression (p < 0.05) in the poor-quality BCB- oocytes compared to the good-quality BCB+ oocytes during the early maturation stages. The supplementation of BCB- COCs with 100 ng/mL DKK1 effectively inhibited the expression of the key mediators of the Wnt pathway (ß-catenin and dishevelled homolog 1, DVL1). DKK1 supplemented BCB- COCs exhibited significantly improved cytoplasmic and nuclear maturation indices, development rates and significantly elevated expression (p < 0.05) of genes implicated in germinal vesicle breakdown (GVBD) and embryonic genome activation (EGA) vis-à-vis BCB- control COCs. Conclusion: These data indicate that inhibition of the Wnt pathway during the initial course of oocyte maturation can improve the development competence of poor-quality buffalo oocytes.

Potential of targeting host cell calcium dynamics to curtail SARS-CoV-2 infection and COVID-19 pathogenesis.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection and associated coronavirus disease 2019 (COVID-19) has severely impacted human well-being. Although vaccination programs have helped in reducing the severity of the disease, drug regimens for clinical management of COVID-19 are not well recognized yet. It is therefore important to identify and characterize the molecular pathways that could be therapeutically targeted to halt SARS-CoV-2 infection and COVID-19 pathogenesis. SARS-CoV-2 hijacks host cell molecular machinery for its entry, replication and egress. Interestingly, SARS-CoV-2 interacts with host cell Calcium (Ca2+) handling proteins and perturbs Ca2+ homeostasis. We here systematically review the literature that demonstrates a critical role of host cell Ca2+ dynamics in regulating SARS-CoV-2 infection and COVID-19 pathogenesis. Further, we discuss recent studies, which have reported that SARS-CoV-2 acts on several organelle-specific Ca2+ transport mechanisms. Moreover, we deliberate upon the possibility of curtailing SARS-CoV-2 infection by targeting host cell Ca2+ handling machinery. Importantly, we delve into the clinical trials that are examining the efficacy of FDA-approved small molecules acting on Ca2+ handling machinery for the management of COVID-19. Although an important role of host cell Ca2+ signaling in driving SARS-CoV-2 infection has emerged, the underlying molecular mechanisms remain poorly understood. In future, it would be important to investigate in detail the signaling cascades that connect perturbed Ca2+ dynamics to SARS-CoV-2 infection.

Optic Nerve Infiltration in Systemic Lymphoma in an HIV Patient.

Different mechanisms have been proposed in lymphomatous involvement of the optic nerve. They include isolated optic nerve lymphoma, optic nerve lymphoma associated with primary central nervous system (CNS) lymphoma, or with systemic lymphoma. We present one case of non-Hodgkin lymphoma of the optic nerve in a Human Immunodeficiency Virus (HIV) patient and discuss the mechanism of metastasis, classification of optic nerve involvement with clinical and radiologic features as well as treatment options. Despite the uncommon nature of optic nerve infiltration by lymphoma, prompt evaluation should be considered in patients with a history of lymphoma and visual symptoms as delays in treatment can result in permanent vision loss. The recommended initial workup includes neuroimaging and cerebrospinal fluid evaluation. Treatment options are not standardized but include intravenous and intrathecal chemotherapy, corticosteroids, and radiation.

Life-Threatening Fungal Infection in Richter Transformation of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Case Report and Brief Review of Literature.

Chronic lymphocytic leukemia/small lymphocytic lymphoma is an indolent B cell lymphoproliferative malignancy typically affecting the elderly. Clinical outcomes of this condition have steadily improved as a result of advances in therapy. However, an increase in survival is accompanied by increased incidence of Richter transformation into an aggressive lymphoma. We present one such case and delve into its risk factors and associated complications. Exposure to increased lines of treatment appears to be a contributing factor in transformation, such that those with fewer than two lines of treatment are considered to have a lower risk of transformation. Fever, rapid lymph node involvement and drastic increases in lactate dehydrogenase, as seen in our patient, are concerning for transformation and treatment options include chemotherapy versus novel agent therapy. However, patients receiving therapy are at risk for adverse outcomes such as invasive infections, particularly in those receiving consolidation chemotherapy. Fungal infections such as Aspergillus and Candida are gaining prominence in the setting of neutropenia which adversely impact survival, but are underreported. Efforts to improve outcomes may include consideration of growth factor therapy in neutropenic patients and continuing to be vigilant for early signs of infection.

Dysregulation of host cell calcium signaling during viral infections: Emerging paradigm with high clinical relevance.

Viral infections are one of the leading causes of human illness. Viruses take over host cell signaling cascades for their replication and infection. Calcium (Ca2+) is a versatile and ubiquitous second messenger that modulates plethora of cellular functions. In last two decades, a critical role of host cell Ca2+ signaling in modulating viral infections has emerged. Furthermore, recent literature clearly implicates a vital role for the organellar Ca2+ dynamics (influx and efflux across organelles) in regulating virus entry, replication and severity of the infection. Therefore, it is not surprising that a number of viral infections including current SARS-CoV-2 driven COVID-19 pandemic are associated with dysregulated Ca2+ homeostasis. The focus of this review is to first discuss the role of host cell Ca2+ signaling in viral entry, replication and egress. We further deliberate on emerging literature demonstrating hijacking of the host cell Ca2+ dynamics by viruses. In particular, a variety of viruses including SARS-CoV-2 modulate lysosomal and cytosolic Ca2+ signaling for host cell entry and replication. Moreover, we delve into the recent studies, which have demonstrated the potential of several FDA-approved drugs targeting Ca2+ handling machinery in inhibiting viral infections. Importantly, we discuss the prospective of targeting intracellular Ca2+ signaling for better management and treatment of viral pathogenesis including COVID-19. Finally, we highlight the key outstanding questions in the field that demand critical and timely attention.

A case report of mesenchymal scapular FGF secreting tumor: Importance of follow up in tumor induced osteomalacia.

A 46-year-old Asian male with history of atraumatic fracture of femur (requiring the use of a walker), muscle cramps and loosening teeth presents to Endocrine clinic. He had elevated parathyroid hormone, severely low phosphorus, elevated bone-specific ALP, with normal serum and urine calcium. He was found to have elevated FGF 23 levels, but initial functional and anatomic imaging was negative for any localizing tumor. With persistent follow-up and serial imaging, after 3 years, a 2.2 cm right scapular mass was found on MRI. Since it was also visualized on PET/CT, this was suspected to be the cause of his severe hypophosphatemia. He underwent surgical excision and pathology revealed a phosphaturic mesenchymal tumor after excision. Tumor induced osteomalacia is a rare, acquired paraneoplastic syndrome in which a tumor that secretes FGF23 leads to decreased renal phosphate reabsorption, resulting in hypophosphatemia, and bone demineralization. Diagnosis is challenging as common presenting symptoms are nonspecific, but when followed up closely with proper diagnostic modalities, identification & removal of the culprit lesion is usually curative.

A review of commonly performed bariatric surgeries: Imaging features and its complications.

Obesity is a disease that has achieved the level that can be considered an epidemic. According to the National Center for Health Statistics data, the prevalence of obesity has increased from 30.5% in 1999-2000 to 42.4% in 2017-2018. During the same period, severe obesity has increased from 4.7% to 9.2%. With the growing prevalence of obesity, related conditions such as coronary artery disease, diabetes, and strokes have also become more prevalent. In the past few years, the need for bariatric surgeries such as laparoscopic Roux-en-Y gastric bypass, sleeve gastrectomy, and laparoscopic adjustable gastric banding has increased considerably. With an increasing number of bariatric surgeries, multiple postoperative complications have become common. In this review, we have attempted to describe normal postsurgical anatomical findings after bariatric surgeries and pictorial review of a few common postoperative complications.

Abdominal aortic aneurysm and its association with duodenal obstruction: aortoduodenal syndrome.

Proximal small bowel obstruction in the region of the duodenum is an uncommon clinical entity. Our case, which involves obstruction of the third portion of the duodenum due to an abdominal aortic aneurysm (AAA), is even more unusual. A review of the relevant literature regarding duodenal obstruction due to extrinsic compression includes features that differentiate aortoduodenal syndrome from superior mesenteric artery syndrome. Management of these conditions range from conservative to surgical, of which now includes a more recent role of metallic stents in some instances.

Kratom induced severe cholestatic liver injury histologically mimicking primary biliary cholangitis: A case report.

BACKGROUND: Kratom is a psychoactive substance that is isolated from the plant Mitragyna speciosa. The leaves can be chewed fresh or dried, smoked, or infused similar to herbal teas. The plant leaves have been used by natives of Southeast Asia for centuries. The substance has been used for its stimulant activity at low doses, and as an opium substitute at higher doses due to a morphine like effect. CASE SUMMARY: A 37-year-old female with a history of depression and obesity (body mass index: 32) presented to emergency room with a week-long history of nausea, decreased appetite, fatigue, and two days of jaundice. On admission bilirubin was markedly elevated. Her condition was thought to be due to consumption of Kratom 2 wk before onset of symptoms. Liver biopsy showed changes mimicking primary biliary cholangitis. Patient's symptoms and jaundice improved quickly. CONCLUSION: The use of Kratom has been on the rise in recent years across the United States and Europe. Several case reports have associated adverse health impact of Kratom-containing products including death due to its ability to alter levels of consciousness. Only a few case reports have highlighted the hepatotoxic effects of Kratom. Even fewer reports exist describing the detailed histopathological changes.

Review of X-ray and computed tomography scan findings with a promising role of point of care ultrasound in COVID-19 pandemic.

As healthcare professionals continue to combat the coronavirus disease 2019 (COVID-19) infection worldwide, there is an increasing interest in the role of imaging and the relevance of various modalities. Since imaging not only helps assess the disease at the time of diagnosis but also aids evaluation of response to management, it is critical to examine the role of different modalities currently in use, such as baseline X-rays and computed tomography scans carefully. In this article, we will draw attention to the critical findings for the radiologist. Further, we will look at point of care ultrasound, an increasingly a popular tool in diagnostic medicine, as a component of COVID-19 management.

Roca disease: An osteochondrosis of the inferior pole of the scapula with review of the literature.

Osteochondrosis is a developmental condition affecting the endochondral ossification. It is commonly idiopathic however can be due to vascular anomalies, dietary conditions, hormonal irregularity, or overuse trauma. Osteochondrosis occurring in the inferior pole of the scapula is an extremely rare condition and is referred to as roca disease. A higher degree of suspicion is required especially in a young patient with atraumatic shoulder pain and additional unconventional MRI sequences focusing on the inferior pole of scapula can be taken to rule out such conditions. We report a case of Roca disease in a 16-year male who presented with right shoulder pain. This is the third case report of roca disease in the English literature according to our knowledge and the first case report to demonstrate extensive MRI imaging features with a normal radiograph. Imaging, particularly MRI, plays a pivotal role in the diagnosis of this extremely rare entity. Also, the inferior pole of the scapula is usually not included in routine shoulder MRI imaging thus close scrutiny with additional MRI sequences should be done to diagnose such a rare entity.

Osteochondroses of the bilateral metacarpal heads: Dieterich disease. A case report with review of the literature.

Osteochondroses is a well-known entity and typically affecting immature skeleton with few common locations involved are femoral head epiphysis, tibial tubercle apophysis, calcaneal apophysis, humeral capitellum and anterior vertebral end plates. We report a rare case of osteochondroses showing avascular necrosis involving metacarpal heads known as Dieterich disease, involving the head of the third metacarpal and probably the first case with a history of rock climbing as an etiology. Chronic repetitive microtrauma plays a significant role in the disease, as is seen in our patient. Imaging plays a crucial role in diagnosing, as well as monitoring progress, with MRI being a critical modality. The fact that this entity is rare does not necessarily make it difficult to detect. It may be clinical underdiagnosed due to lack of familiarity with this entity and radiographic findings may be subtle or inapparent. Bone scan is likely sensitive but not specific. MRI also likely has a role for early detection. This article is written with educational intent for the reader for the benefit of the patients with this rare disease.

Solid pseudopapillary Tumor of the Pancreas: Radiological and surgical review.

Solid Pseudopapillary Neoplasms of the pancreas are rare pancreatic tumors with low-grade malignant potential, typically affecting young females. In this review, we discuss the surgical anatomy; the imaging characteristics, and image reporting essentials for proper surgical planning along with the atypical features which should caution the physician regarding the risk of malignancy. We also discuss the common surgical procedures and organ preservation surgeries along with a comprehensive review of the literature.

18F-Sodium Fluoride PET: History, Technical Feasibility, Mechanism of Action, Normal Biodistribution, and Diagnostic Performance in Bone Metastasis Detection Compared with Other Imaging Modalities.

The skeleton is the third most common site for metastasis overall, after the lungs and liver. Accurate diagnosis of osseous metastasis is critical for initial staging, treatment planning, restaging, treatment monitoring, and survival prediction. Currently, 99mTc-methylene diphosphonate whole-body scanning is the cornerstone of imaging to detect osseous metastasis. Although 18F-sodium fluoride (18F-NaF) was one of the oldest medical tracers for this purpose, it was replaced by other tracers because of their better physical properties, until recently. Continued development of PET scanners has opened a new era for 18F-NaF, and given its higher sensitivity, there have been increasing applications in imaging. In this review, we will discuss the history, technical aspects, radiobiology, and biodistribution of this tracer. Finally, we compare the accuracy of 18F-NaF PET with other conventional imaging methods for detection of osseous metastasis.

Bilateral persistent primitive hypoglossal artery presenting with hemiplegia✰.

The manuscript describes an unusual vascular anomaly. Persistence of carotid-vertebrobasilar anastomosis is a rare occurrence with presence of bilateral hypoglossal arteries (HAs) rarer still. We present a case of bilateral persistent HAs with hypoplastic vertebral arteries which end into posterior inferior cerebellar arteries. The computed tomography and magnetic resonance imaging appearance, course, and other associations are discussed. A review of 6 cases of bilateral HA published in the world literature is also discussed.

Incidentally detected ectopic thyroid in juxta cardiac location-Imaging and pathology.

Ectopic thyroid gland is a developmental anomaly that results from the arrest of thyroid tissue along its path of descent from the floor of mouth to the pre tracheal position in the lower neck. It is typically found along the thyroglossal duct with the base of the tongue being the most common site. Apart from mediastinal extension of goiter, the incidence of true intrathoracic ectopic thyroid tissue is rare. Presence of ectopic thyroid has been reported not only in the chest but also in the abdomen and pelvis. Pericardial and intracardiac locations are extremely uncommon and right ventricle location is predominant among the described cases. We describe a case of incidentally detected ectopic thyroid tissue in a rarer location-adjacent to the left atrium. The patient, who had undergone a nephrectomy for renal oncocytoma 5 years ago, presented with unintentional weight loss and left sided flank pain, prompting a workup to rule out abdominal malignancy. Findings on the computed tomography (CT) scan of the abdomen and pelvis prompted further investigation including a chest CT which showed a heterogeneously enhancing mass near the left atrium. Given its location, further radiological investigations played an important role in eliminating the differential diagnosis of paraganglioma. The mass was surgically resected and discovered to be a hyperplastic thyroid nodule on histologic examination.