Combination approach for CDC73-related parathyroid carcinoma in an adolescent female patient: a case report and literature review.

Parathyroid carcinoma (PC) is extremely rare in children and adolescent. PC is more often sporadic, but also it could be associated with germline mutations. The clinical features of primary hyperparathyroidism (PHPT) are nonspecific in children and adolescent, which delays the diagnosis for years. This case of PC in a pediatric patient, caused by germline heterozygous pathogenic variant in exon 1 of the CDC73 gene (c.70 G > T, p. Glu24Ter) is the first to be reported in Russia. Due to the rarity of pediatric parathyroid malignancy, the diagnosis of this endocrine neoplasm remains a challenge. The main difficulties that we faced in the management of the patient were the morphological confirmation of diagnosis, multiple surgical interventions, and disseminated PC metastases. We describe a 13-year-old girl with delayed diagnosis of PC and subsequent local recurrence after several surgeries, who underwent specific radiation therapy that allowed controlling hypercalcemia.

Treatment of Multi-Walled Carbon Nanotubes with Dichromic Acid: Oxidation and Appearance of Intercalation.

This work is dedicated to the study of the treatment of multi-walled carbon nanotubes (MWCNTs) with dichromic acid. The dichromic acid was formed by dissolving different concentrations of CrO3 in water. The effect of the concentration of dichromic acid on the change in texture characteristics, elemental composition, defectiveness, graphitization degree, and surface chemistry of MWCNTs was investigated using various analytical techniques, such as transmission electron microscopy, energy-dispersive X-ray spectroscopy (EDX), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction, and X-ray photoelectron spectroscopy (XPS). Testing of MWCNTs as electrodes for supercapacitors in 3.5 M H2SO4 solution was carried out using cyclic voltammetry. A decrease in the average diameter of CNTs after treatment was found. The EDX and XPS showed that the oxygen content on the surface of MWCNTs increased after treatment with dichromic acid. The formation of Cr2O3 after treatment with dichromic acid was detected by XPS. High angle annular dark field scanning transmission electron microscopy was used to confirm the intercalation of the chromium-containing compound between graphene layers of MWCNTs after treatment with dichromic acid. It was found that two different types of MWCNTs showed diverse behavior after treatment. The highest specific capacitance of the MWCNTs after treatment was 141 F g-1 (at 2 mV s-1) compared to 0.3 F g-1 for the untreated sample.

Adsorption Kinetics of Type-III Antifreeze Protein on Ice Crystal Surfaces.

The spatio-temporal distribution of type-III antifreeze protein (AFP-III) molecules labeled with fluorescent isocyanate (FITC) was visualized at the interfaces between ice and solutions with an FITC-labeled AFP-III (F-AFP-III) concentration of 20-800 µg/mL by fluorescence microscopy. The number density of F-AFP-III on the surface of ice microcrystals was calculated from the calibrated fluorescence intensity. The adsorption of F-AFP-III molecules on the ice crystal surfaces proceeded at a finite rate and then reached the saturation level. The time course of the number density of adsorbed F-AFP-III molecules could be well represented by Langmuir's model. The characteristic adsorption time of F-AFP-III, the adsorption coefficient k1 = (0.5 ± 0.05) × 10-4 (µg/mL)-1 s-1, and the desorption coefficient k2 = 0.005 ± 0.002 s-1 were determined using the Langmuir's model and obtained experimental data. We found that the adsorption of F-AFP-III could have different kinetics depending on the solution conditions and the type of fluorescence molecules conjugated with AFP-III.

Silent intrathyroid parathyroid carcinoma.

Summary: A 59-year-old male presented with an accidental thyroid mass in 2022. Ultrasound and CT scan showed a nodule 5.2 × 4.9 × 2.8 cm (EU-TIRADS 4) in the right lobe of the thyroid gland. Taking into account the results of the fine needle aspiration biopsy (Bethesda V), intrathyroid localization, and absence of clinical symptoms, a malignant tumor of the thyroid gland was suspected. The patient underwent total thyroidectomy using fluorescence angiography with indocyanine green, and two pairs of intact parathyroid glands were visualized in typical localization. Unexpected histological and immunohistochemistry examinations revealed parathyroid carcinoma. Due to the asymptomatic course of the disease and atypical localization of parathyroid tumor, primary hyperparathyroidism was not suspected before the surgery. The diagnosis of asymptomatic intrathyroid parathyroid cancer is a serious diagnostic challenge for a wide range of specialists. Learning points: Parathyroid cancer is a rare disease that may be asymptomatic. Intrathyroidal localization of parathyroid carcinoma is casuistic and challenging for diagnosis, and the treatment strategy is not well defined. Preoperative parathyroid hormone and serum calcium testing are recommended for patients with solid thyroid nodules (Bethesda IV-V).

Multiple Metastases of Parathyroid and Papillary Thyroid Carcinoma in a Female Patient Treated with Long-Term Hemodialysis.

Parathyroid cancer is a rare, clinically aggressive malignancy with a prevalence of approximately 0.005% relative to all carcinoma cases and 1-5% among patients with primary hyperparathyroidism. Prognosis largely depends on the extent of the primary surgery. Non-radical surgical treatment increases the risk of local and distant metastases of the parathyroid cancer associated with limited treatment options. The combination of thyroid and parathyroid disorders has been described rather well for the general population; however, cases of parathyroid and thyroid carcinoma in the same patient are extremely rare (1 case per 3000 patients with parathyroid disorders). We present a rare clinical case of combination of parathyroid and thyroid cancers with metastases of both tumors to the neck lymph nodes in a woman with a mutation in the MEN1 gene (NM_130799.2): c.658T > C p.Trp220Arg (W220R), who has been exposed to radiation for 20 years before diagnosis of thyroid cancer and received renal replacement therapy with long-term hemodialysis before the diagnosis of parathyroid cancer. The patient underwent several surgeries because of metastases of the parathyroid cancer in the neck lymph nodes. Surgeons used intraoperative navigation methods (single-channel gamma detection probe, Gamma Probe 2, and fluorescence angiography with indocyanine green (ICG)) to clarify the volume of surgery. Currently, the patient is still in laboratory remission, despite the structural recurrence of tumors.

Case report: Sagliker syndrome in the patient with recurrent tertiary hyperparathyroidism due to intrathyroidal parathyroid carcinoma.

Sagliker syndrome (SS) is an extremely rare disorder that manifests in patients with advanced chronic kidney disease (CKD) undergoing programmed hemodialysis as a renal replacement therapy. Treatment of secondary hyperparathyroidism (SHPT) in these patients is still challenging. The main clinical manifestations of SS include craniofacial and fingertip deformities, dental anomalies, gingival hyperplasia, short stature, hearing loss, neurological and psychiatric impairment. The etiology and pathogenesis of SS in patients with SHPT require further clarification. However, mutations in the GNAS1, FGF23, and FGFR3 genes were described in some patients, suggesting a possible role of genetic predisposition to the syndrome. The preferred therapeutic approach for SS is surgery, but the volume of the operation is debated. The main surgical strategies include total, subtotal parathyroidectomy, or total parathyroidectomy with autotransplantation of the parathyroid gland (PG). Unfortunately, parathyroidectomy does not contribute to the regression of significant skeletal deformities. We present a unique clinical case of a patient with classical features of SS, recurrent tertiary hyperparathyroidism (THPT) after total parathyroidectomy due to intrathyroidal parathyroid carcinoma (PC).

NO2 Sensing Behavior of Compacted Chemically Treated Multi-Walled Carbon Nanotubes.

This article is devoted to the investigation of the sensing behavior of chemically treated multi-walled carbon nanotubes (MWNTs) at room temperature. Chemical treatment of MWNTs was carried out with a solution of either sulfuric or chromic acids. The materials obtained were investigated by transmission electron microscopy, scanning electron microscopy, Raman-spectroscopy, X-ray diffraction, and Fourier transform infrared spectroscopy. The active layer of chemiresistive gas sensors was obtained by cold pressing (compaction) at 11 MPa of powders of bare and treated multi-walled carbon nanotubes. The sensing properties of pellets were investigated using a custom dynamic type of station at room temperature (25 ± 2 °C). Detection of NO2 was performed in synthetic air (79 vol% N2, 21 vol% O2). It was found that the chemical treatment significantly affects the sensing properties of multi-walled carbon nanotubes, which is indicated by increasing the response of the sensors toward 100-500 ppm NO2 and lower concentrations.

Targeting XPO1-Dependent Nuclear Export in Cancer.

Nucleocytoplasmic transport of macromolecules is tightly regulated in eukaryotic cells. XPO1 is a transport factor responsible for the nuclear export of several hundred protein and RNA substrates. Elevated levels of XPO1 and recurrent mutations have been reported in multiple cancers and linked to advanced disease stage and poor survival. In recent years, several novel small-molecule inhibitors of XPO1 were developed and extensively tested in preclinical cancer models and eventually in clinical trials. In this brief review, we summarize the functions of XPO1, its role in cancer, and the latest results of clinical trials of XPO1 inhibitors.

Activation and expansion of T-follicular helper cells in chronic lymphocytic leukemia nurselike cell co-cultures.

Interactions between chronic lymphocytic leukemia (CLL) cells and T-cell subsets in the lymph node microenvironment are thought to play a central role in disease biology. To study these interactions in a model of the CLL lymph node microenvironment, we characterized T-cell subsets in CLL nurselike cell (NLC) co-cultures. We focused on T-follicular helper (Tfh) cells, which are characterized by CXCR5 expression and localization to B-cell follicles. In co-cultures from 28 different CLL patients, we detected an expansion of Tfh cells based on PD-1, BCL6, and ICOS expression, with increased IL-21 and downmodulated CD40L surface expression. Regulatory T cells (Treg), which promote immune tolerance, also expanded in NLC co-cultures. T-cell receptor (TR) gene repertoire analyses confirmed the clonal expansion of CD4+ T cells, with an enrichment of TR clonotypes commonly expanded also in primary CLL samples. Multicolor confocal microscopy revealed that Tfh, but not Treg co-localize with proliferating CLL cells in CLL lymph node sections. Collectively, these data provide new insight into the cellular and molecular cross-talk between CLL and T-cell subsets, resulting in clonal expansion of T-helper cells and interaction of Tfh cells with proliferating CLL cells which may open new avenues for therapeutic targeting.

A retrospective study of Uncinaria stenocephala in domestic dogs: Age, sex distribution, and risk factors.

BACKGROUND AND AIM: Uncinaria infection often appears in domestic dogs. In the present study, parasitological examination of fecal samples from 782 dogs were analyzed for the presence of Uncinaria stenocephala. MATERIALS AND METHODS: Fecal samples were analyzed by means of a standardized flotation method using a saturated salt solution containing NaNO3 (specific gravity 1.38), with a centrifugation step. RESULTS: The highest prevalence rates were found among young adult dogs (8.3%), followed by puppies (5.4%); the lowest prevalence rates were found in dogs older than 3 years (4.3%). The prevalence was 5.8% among female dogs and 7.2% in male dogs. Coinfections with roundworms and protozoan parasites were frequently observed in U. stenocephala-positive dogs (15%). In total, three types of coinfections were registered. Coinfection of U. stenocephala + Sarcocystids oocysts was recorded in 19.1% of the dogs (n=10). This may relate to higher prevalence of S. oocysts in dogs (n=153; 19.5%). There were two cases of coinfection of U. stenocephala + Toxocara canis (3.9%), which may relate to low prevalence of T. canis (3.9 %). One case of coinfection of Dipylidium caninum + U. stenocephala (0.1%) also appeared. CONCLUSION: The present study showed that male dogs and young dogs were most susceptible to U. stenocephala infection.

A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation.

Hotspot mutation of IKZF3 (IKZF3-L162R) has been identified as a putative driver of chronic lymphocytic leukemia (CLL), but its function remains unknown. Here, we demonstrate its driving role in CLL through a B cell-restricted conditional knockin mouse model. Mutant Ikzf3 alters DNA binding specificity and target selection, leading to hyperactivation of B cell receptor (BCR) signaling, overexpression of nuclear factor κB (NF-κB) target genes, and development of CLL-like disease in elderly mice with a penetrance of ~40%. Human CLL carrying either IKZF3 mutation or high IKZF3 expression was associated with overexpression of BCR/NF-κB pathway members and reduced sensitivity to BCR signaling inhibition by ibrutinib. Our results thus highlight IKZF3 oncogenic function in CLL via transcriptional dysregulation and demonstrate that this pro-survival function can be achieved by either somatic mutation or overexpression of this CLL driver. This emphasizes the need for combinatorial approaches to overcome IKZF3-mediated BCR inhibitor resistance.

YB-1 Phosphorylation at Serine 209 Inhibits Its Nuclear Translocation.

YB-1 is a multifunctional DNA- and RNA-binding protein involved in cell proliferation, differentiation, and migration. YB-1 is a predominantly cytoplasmic protein that is transported to the nucleus in certain conditions, including DNA-damaging stress, transcription inhibition, and viral infection. In tumors, YB-1 nuclear localization correlates with high aggressiveness, multidrug resistance, and a poor prognosis. It is known that posttranslational modifications can regulate the nuclear translocation of YB-1. In particular, well-studied phosphorylation at serine 102 (S102) activates YB-1 nuclear import. Here, we report that Akt kinase phosphorylates YB-1 in vitro at serine 209 (S209), which is located in the vicinity of the YB-1 nuclear localization signal. Using phosphomimetic substitutions, we showed that S209 phosphorylation inhibits YB-1 nuclear translocation and prevents p-S102-mediated YB-1 nuclear import.

CXCL13 plasma levels function as a biomarker for disease activity in patients with chronic lymphocytic leukemia.

The chemoattractant CXCL13 organizes the cellular architecture of B-cell follicles and germinal centers. During adaptive immune responses, CXCL13 plasma concentrations transiently increase and function as a biomarker for normal germinal center activity. Chronic lymphocytic leukemia (CLL) cells express high levels of CXCR5, the receptor for CXCL13, and proliferate in pseudofollicles within secondary lymphoid organs (SLO). Given the morphologic and functional similarities between normal and CLL B-cell expansion in SLO, we hypothesized that CXCL13 plasma concentrations would correlate with CLL disease activity and progression. We analyzed CXCL13 plasma concentrations in 400 CLL patients and correlated the findings with other prognostic markers, time to treatment (TTT), CCL3 and CCL4 plasma concentrations, and in vivo CLL cell proliferation. We found that CXCL13 plasma concentrations were higher in CLL patients with active and advanced stage disease, resulting in a significantly shorter TTT. Accordingly, high CXCL13 levels correlated with other markers of disease activity and CCL3 levels. Higher CLL cell birth rates in vivo also associated with higher CXCL13 plasma concentrations. Interestingly, elevated CXCL13 plasma levels normalized during ibrutinib therapy, and increased in ibrutinib resistance patients. Collectively, these studies emphasize the importance of CXCL13 in crosstalk between CLL cells and the SLO microenvironment.

[Cushing's syndrome due to bilateral oncocytic adrenal tumor].

Cushing’s syndrome accounts for approximately 20–30% of endogenous hypercortisolism cases, and adrenal involvement can be either unilateral or bilateral. Cushing’s syndrome due to bilateral adrenal tumors is extremely rare. Adrenal oncocytomas are another rare cause of endogenous hypercortisolism: about 13 cases are described in the literature. Oncocytomas are rare epithelial neoplasms, characterized by abnormally excessive accumulation of defective mitochondria in the cytoplasm of cells, and make up 1.8% of all adrenal neoplasms. We describe a 58-year old patient with Cushing’s syndrome and bilateral adrenal tumors. Multispiral computed tomography of the adrenals showed signs suspicious of lipid-poor atypical adenomas or malignant tumors. Surgical treatment was the method of choice, and the larger tumor was excised first. Due to the absence of remission of endogenous hypercortisolism the excision of the second tumor was performed. Morphological and immunohistochemical examination confirmed the diagnosis of bilateral oncocytic adrenocortical tumors with uncertain malignant potential. Cases of bilateral hormone-producing adrenal oncocytomas have not been described in the literature.

Rapid Mass Spectrometric Study of a Supercritical CO2-extract from Woody Liana Schisandra chinensis by HPLC-SPD-ESI-MS/MS.

Woody liana Schisandra chinensis contains valuable lignans, which are phenylpropanoids with valuable biological activity. Among green and selective extraction methods, supercritical carbon dioxide (SC-CO2) was shown to be the method of choice for the recovery of these naturally occurring compounds. Carbon dioxide (CO2) was the solvent with the flow rate (10-25 g/min) with 2% ethanol as co-solvent. In this piece of work operative parameters and working conditions were optimized by experimenting with different pressures (200-400 bars) and temperatures (40-60 °C). The extraction time varied from 60 to 120 min. HPLC-SPD-ESI -MS/MS techniques were applied to detect target analytes. Twenty-six different lignans were identified in the S. chinensis SC-CO2 extracts.

The BET inhibitor GS-5829 targets chronic lymphocytic leukemia cells and their supportive microenvironment.

Despite major improvements in treatment outcome with novel targeted therapies, such as the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, chronic lymphocytic leukemia (CLL) remains incurable in the majority of patients. Activation of PI3K, NF-κB, and/or MYC has been linked to residual disease and/or resistance in ibrutinib-treated patients. These pathways can be targeted by inhibitors of bromodomain and extra-terminal (BET) proteins. Here we report about the preclinical activity of GS-5829, a novel BET inhibitor, in CLL. GS-5829 inhibited CLL cell proliferation and induced leukemia cell apoptosis through deregulation of key signaling pathways, such as BLK, AKT, ERK1/2, and MYC. IκBα modulation indicates that GS-5829 also inhibited NF-κB signaling. GS-5829-induced apoptosis resulted from an imbalance between positive (BIM) and negative regulators (BCL-XL) of the intrinsic apoptosis pathway. The antileukemia activity of GS-5829 increased synergistically in combinations with B-cell receptor signaling inhibitors, the BTK inhibitor ibrutinib, the PI3Kδ inhibitor idelalisib, and the SYK inhibitor entospletinib. In cocultures that mimic the lymph node microenvironment, GS-5829 inhibited signaling pathways within nurselike cells and their growth, indicating that BET inhibitors also can target the supportive CLL microenvironment. Collectively, these data provide a rationale for the clinical evaluation of BET inhibitors in CLL.

Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia.

Ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase, is an effective therapy for patients with chronic lymphocytic leukemia (CLL). To determine whether rituximab provides added benefit to ibrutinib, we conducted a randomized single-center trial of ibrutinib vs ibrutinib plus rituximab. Patients with CLL requiring therapy were randomized to receive 28-day cycles of once-daily ibrutinib 420 mg, either as a single agent (n = 104), or together with rituximab (375 mg/m2; n = 104), given weekly during cycle 1, then once per cycle until cycle 6. The primary end point was progression-free survival (PFS) in the intention-to-treat population. We enrolled 208 patients with CLL, 181 with relapsed CLL and 27 treatment-naive patients with high-risk disease (17p deletion or TP53 mutation). After a median follow-up of 36 months, the Kaplan-Meier estimates of PFS were 86% (95% confidence interval [CI], 76.6-91.9) for patients receiving ibrutinib, and 86.9% (95% CI, 77.3-92.6) for patients receiving ibrutinib plus rituximab. Similarly, response rates were the same in both arms (overall response rate, 92%). However, time to normalization of peripheral blood lymphocyte counts and time to complete remission were shorter, and residual disease levels in the bone marrow were lower, in patients receiving ibrutinib plus rituximab. We conclude that the addition of rituximab to ibrutinib in relapsed and treatment-naive high-risk patients with CLL failed to show improvement in PFS. However, patients treated with ibrutinib plus rituximab reached their remissions faster and achieved significantly lower residual disease levels. Given these results, ibrutinib as single-agent therapy remains current standard-of-care treatment in CLL. This trial was registered at www.clinicaltrials.gov as #NCT02007044.

Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependencies.

The identification of targetable vulnerabilities in the context of therapeutic resistance is a key challenge in cancer treatment. We detected pervasive aberrant splicing as a characteristic feature of chronic lymphocytic leukemia (CLL), irrespective of splicing factor mutation status, which was associated with sensitivity to the spliceosome modulator, E7107. Splicing modulation affected CLL survival pathways, including members of the B cell lymphoma-2 (BCL2) family of proteins, remodeling antiapoptotic dependencies of human and murine CLL cells. E7107 treatment decreased myeloid cell leukemia-1 (MCL1) dependence and increased BCL2 dependence, sensitizing primary human CLL cells and venetoclax-resistant CLL-like cells from an Eµ-TCL1-based adoptive transfer murine model to treatment with the BCL2 inhibitor venetoclax. Our data provide preclinical rationale to support the combination of venetoclax with splicing modulators to reprogram apoptotic dependencies in CLL for treating venetoclax-resistant CLL cases.