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Expressed strongly by myeloid cells, damage-associated molecular pattern (DAMP) proteins S100A8 and S100A9 are found in the serum of patients with infectious and autoimmune diseases. Compared to S100A9, the role of S100A8 is controversial. We investigated its biological activity in collagen-induced arthritis using the first known viable and fertile S100a8-deficient (S100a8-/-) mouse. Although comparable to the wild type (WT) in terms of lymphocyte distribution in blood and in the primary and secondary lymphoid organs, S100a8-/- mice had increased numbers of neutrophils, monocytes and dendritic cells in the blood and bone marrow, and these all expressed myeloid markers such as CD11b, Ly6G and CD86 more strongly. Granulocyte-macrophage common precursors were increased in S100a8-/- bone marrow and yielded greater numbers of macrophages and dendritic cells in culture. The animals also developed more severe arthritic disease leading to aggravated osteoclast activity and bone destruction. These findings were correlated with increased inflammatory cell infiltration and cytokine secretion in the paws. This study suggests that S100A8 is an anti-inflammatory DAMP that regulates myeloid cell differentiation, thereby mitigating the development of experimental arthritis.

Rpn13 is a novel mammalian proteasomal receptor that has recently been identified as an amplification target in ovarian cancer. It can interact with ubiquitin and activate the deubiquitinating enzyme Uch37 at the 26S proteasome. Since neither Rpn13 nor Uch37 is an integral proteasomal subunit, we explored whether either protein is essential for mammalian development and survival. Deletion of Uch37 resulted in prenatal lethality in mice associated with severe defect in embryonic brain development. In contrast, the majority of Rpn13-deficient mice survived to adulthood, although they were smaller at birth and fewer in number than wild-type littermates. Absence of Rpn13 produced tissue-specific effects on proteasomal function: increased proteasome activity in adrenal gland and lymphoid organs, and decreased activity in testes and brain. Adult Rpn13(-/-) mice reached normal body weight but had increased body fat content and were infertile due to defective gametogenesis. Additionally, Rpn13(-/-) mice showed increased T-cell numbers, resembling growth hormone-mediated effects. Indeed, serum growth hormone and follicular stimulating hormone levels were significantly increased in Rpn13(-/-) mice, while growth hormone receptor expression was reduced in the testes. In conclusion, this is the first report characterizing the physiological roles of Uch37 and Rpn13 in murine development and implicating a non-ATPase proteasomal protein, Rpn13, in the process of gametogenesis.

Mammalian sterile 20-like kinase 1 (Mst1) is a MAPK kinase kinase kinase which is involved in a wide range of cellular responses, including apoptosis, lymphocyte adhesion and trafficking. The contribution of Mst1 to Ag-specific immune responses and autoimmunity has not been well defined. In this study, we provide evidence for the essential role of Mst1 in T cell differentiation and autoimmunity, using both genetic and pharmacologic approaches. Absence of Mst1 in mice reduced T cell proliferation and IL-2 production in vitro, blocked cell cycle progression, and elevated activation-induced cell death in Th1 cells. Mst1 deficiency led to a CD4+ T cell development path that was biased toward Th2 and immunoregulatory cytokine production with suppressed Th1 responses. In addition, Mst1-/- B cells showed decreased stimulation to B cell mitogens in vitro and deficient Ag-specific Ig production in vivo. Consistent with altered lymphocyte function, deletion of Mst1 reduced the severity of experimental autoimmune encephalomyelitis (EAE) and protected against collagen-induced arthritis development. Mst1-/- CD4+ T cells displayed an intrinsic defect in their ability to respond to encephalitogenic antigens and deletion of Mst1 in the CD4+ T cell compartment was sufficient to alleviate CNS inflammation during EAE. These findings have prompted the discovery of novel compounds that are potent inhibitors of Mst1 and exhibit desirable pharmacokinetic properties. In conclusion, this report implicates Mst1 as a critical regulator of adaptive immune responses, Th1/Th2-dependent cytokine production, and as a potential therapeutic target for immune disorders.

Lung cancer metastasizing to the breast is rare. Only few published case reports can be found in the literature. Metastatic lung cancer to the breast and its ipsilateral axillary lymph node is extremely unusual. No awareness of any prior case reports of lung cancer with such a presentation is known. Herein, this study reports an unusual case of a middle aged Saudi female with non-small cell lung cancer that has metastasized, not only to the lungs and the breast, but also to the ipsilateral axillary lymph nodes. It is important for the oncologists to be mindful of rare presentations for such a common malignancy as lung cancer. سرطان الرئة المتفاقمة في الثدي أمر نادر الحدوث. يمكن العثور على عدد قليل من التقارير التي نشرت. سرطان الرئة المنتشر في الثدي و الغدد اللمفاوية في الإبط المماثل نادرة للغاية. نحن لسنا على علم بأي تقارير عن حالات الإصابة بسرطان الرئة مع هذا الانتشار من هذا القبيل. و نحن هنا نقرر حالة غير عادية لامرأة سعودية في منتصف العمر، مصابة بسرطان الرئة من الخلايا غير الصغيرة، الذي انتشار ليس فقط إلى الثدي، و لكن أيضا إلى العقد اللمفاوية في الجهة المماثلة. من المهم لأطباء الأورام أن يضعوا في اعتبارهم مثل هذا الورم.

Rpn13 is a novel mammalian proteasomal receptor that has recently been identified as an amplification target in ovarian cancer. It can interact with ubiquitin and activate the deubiquitinating enzyme Uch37 at the 26S proteasome. Since neither Rpn13 nor Uch37 is an integral proteasomal subunit, we explored whether either protein is essential for mammalian development and survival. Deletion of Uch37 resulted in prenatal lethality in mice associated with severe defect in embryonic brain development. In contrast, the majority of Rpn13-deficient mice survived to adulthood, although they were smaller at birth and fewer in number than wild-type littermates. Absence of Rpn13 produced tissue-specific effects on proteasomal function: increased proteasome activity in adrenal gland and lymphoid organs, and decreased activity in testes and brain. Adult Rpn13.sup.-/- mice reached normal body weight but had increased body fat content and were infertile due to defective gametogenesis. Additionally, Rpn13.sup.-/- mice showed increased T-cell numbers, resembling growth hormone-mediated effects. Indeed, serum growth hormone and follicular stimulating hormone levels were significantly increased in Rpn13.sup.-/- mice, while growth hormone receptor expression was reduced in the testes. In conclusion, this is the first report characterizing the physiological roles of Uch37 and Rpn13 in murine development and implicating a non-ATPase proteasomal protein, Rpn13, in the process of gametogenesis.

Patients harboring CRLF2-rearranged B-lineage acute lymphocytic leukemia (B-ALL) face a 5-year survival rate as low as 20%. While significant gains have been made to position targeted therapies for B-ALL treatment, continued efforts are needed to develop therapeutic options with improved duration of response. Here, first we have demonstrated that patients with CRLF2-rearranged Ph-like ALL harbor elevated thymic stromal lymphopoietin receptor (TSLPR) expression, which is comparable with CD19. Then we present and evaluate the anti-tumor characteristics of 1B7/CD3, a novel CD3-redirecting bispecific antibody (BsAb) that co-targets TSLPR. In vitro, 1B7/CD3 exhibits optimal binding to both human and cynomolgus CD3 and TSLPR. Further, 1B7/CD3 was shown to induce potent T cell activation and tumor lytic activity in both cell lines and primary B-ALL patient samples. Using humanized cell- or patient-derived xenograft models, 1B7/CD3 treatment was shown to trigger dose-dependent tumor remission or growth inhibition across donors as well as induce T cell activation and expansion. Pharmacokinetic studies in murine models revealed 1B7/CD3 to exhibit a prolonged half-life. Finally, toxicology studies using cynomolgus monkeys found that the maximum tolerated dose of 1B7/CD3 was ≤1 mg/kg. Overall, our preclinical data provide the framework for the clinical evaluation of 1B7/CD3 in patients with CRLF2-rearranged B-ALL.

Mammalian sterile 20-like kinase 1 (Mst1) is a MAPK kinase kinase kinase which is involved in a wide range of cellular responses, including apoptosis, lymphocyte adhesion and trafficking. The contribution of Mst1 to Ag-specific immune responses and autoimmunity has not been well defined. In this study, we provide evidence for the essential role of Mst1 in T cell differentiation and autoimmunity, using both genetic and pharmacologic approaches. Absence of Mst1 in mice reduced T cell proliferation and IL-2 production in vitro, blocked cell cycle progression, and elevated activation-induced cell death in Th1 cells. Mst1 deficiency led to a CD4+ T cell development path that was biased toward Th2 and immunoregulatory cytokine production with suppressed Th1 responses. In addition, Mst1-/- B cells showed decreased stimulation to B cell mitogens in vitro and deficient Ag-specific Ig production in vivo. Consistent with altered lymphocyte function, deletion of Mst1 reduced the severity of experimental autoimmune encephalomyelitis (EAE) and protected against collagen-induced arthritis development. Mst1-/- CD4+ T cells displayed an intrinsic defect in their ability to respond to encephalitogenic antigens and deletion of Mst1 in the CD4+ T cell compartment was sufficient to alleviate CNS inflammation during EAE. These findings have prompted the discovery of novel compounds that are potent inhibitors of Mst1 and exhibit desirable pharmacokinetic properties. In conclusion, this report implicates Mst1 as a critical regulator of adaptive immune responses, Th1/Th2-dependent cytokine production, and as a potential therapeutic target for immune disorders.

The emergence of highly immune invasive and transmissible variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has decreased the effectiveness of existing vaccines. It is, therefore, critical to develop effective and safe therapeutics for SARS-CoV-2 infections, especially for the most vulnerable and immunocompromised patients. Neutralizing antibodies have been shown to be successful at preventing severe disease from early SARS-CoV-2 strains, although their efficacy has diminished with the emergence of new variants. Here, we aim to develop fully human and broadly neutralizing monoclonal (mAb) and bispecific (BsAb) antibodies against SARS-CoV-2 and its variants. Specifically, we first identified two antibodies from human transgenic mice that bind to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein and are capable of neutralizing SARS-CoV-2 and variants of concern with high to moderate affinity. Two non-competing clones with the highest affinity and functional blocking of ACE2 binding were then selected to be engineered into two BsAbs, which were then demonstrated to have relatively improved affinity, ACE2 blocking ability, and pseudovirus inhibition against several variants, including Omicron (B.1.1.529). Our findings provide one mAb candidate and two bsAb candidates for consideration of further clinical development and suggest that the bispecific format may be more effective than mAbs for SARS-CoV-2 treatment.Competing Interest StatementThe authors have declared no competing interest.

Jordan has never conducted a nutrition survey to determine nutrient and energy intakes. The current study aimed to describe the energy and macronutrient consumed by the Jordanian population. A cross-sectional food consumption study was conducted, including a sample of Jordanians using two non-consecutive 24-h dietary recalls (24-h DR) between October 2021 and March 2022. A total of 2145 males and females aged 8 to 85 years old living in households were studied. The average of two 24-h DRs for each individual was converted into energy and nutrient intakes. After measuring weight, height, and waist circumference, the body mass index (BMI) and waist-to-height ratio (WHtR) were calculated. The percentage of under-reporters was higher in women than men (58.2% vs. 45.9%). Adults and older adult women had the highest prevalence of obesity (29.6%), while adults and older adult men had the highest prevalence of overweight (41.4%). There is a significant increase in energy intake in children, boys, and all adults, compared to the recommended calories. The mean energy percentage (E %) of total fat was 38%, exceeding the upper limit of the Acceptable Macronutrient Distribution Range (AMDR). At the same time, the mean daily dietary fiber intake fell below the recommended levels (ranging from 13.5 g in children to 19.5 g in older adults). The study population consumes more fat and less fiber than the recommended levels. Actions must be taken across all age groups to correct the deviation of energy and macronutrient intakes from the recommended dietary allowances.