HOXB13

心力衰竭（Heart Failure）是一种影响全球约3000万人的严重疾病，在成年人中发生的原因是心肌损伤后无法自我修复。虽然成人心脏中的心肌细胞更新正常，但其更新速率不足以在心肌细胞大量丢失后恢复心脏功能。然而，新生哺乳动物和某些低等脊椎动物具有强大的心脏再生能力，它们的心肌细胞在损伤后可快速增殖，以恢复正常心脏功能。但不幸的是，哺乳动物在出生后第7天（P7）失去了再生能力，这也标志着心肌细胞增殖的结束。哺乳动物出生后的血流和氧气水平发生显著变化，这触发了多个途径，促进心肌细胞生长模式从增生到肥大的转变，导致细胞周期永久停止。对小鼠的研究显示，在心肌梗死后，消除转录因子Meis1和Hoxb13可逆转成年心肌细胞周期阻滞并显著增强左心室功能。这提示了我们，通过抑制Meis1和Hoxb13的转录活性来刺激心肌细胞的生长，可能是一种有前途的心脏再生方法。2024年3月11日，德克萨斯大学西南医学中心的研究人员在 Nature Cardiovascular Research 期刊 发表了题为：Identification of FDA-approved drugs that induce heart regeneration in mammals 的研究论文。该研究结合生化实验和计算筛选，确定了两种FDA批准的常用抗生素——巴龙霉素（Paromomycin）和新霉素（Neomycin）可诱导心肌细胞增殖和心脏再生，二者联合使用，在心肌梗死小鼠模型和心脏缺血/再灌注损伤猪模型中成功诱导了心肌细胞增殖，改善了左心室收缩功能，并减少了瘢痕形成。在这项最新研究中，研究团队使用了从X射线晶体学到小型和大型动物研究等多个学科的筛选工具，从已获得FDA批准的药物中寻找可以阻断Meis1和Hoxb13活性并刺激活体生物心肌细胞生长和心脏再生的药物。筛选结果显示，巴龙霉素（Paromomycin）和新霉素（Neomycin）是其中最优的两个候选药物，它们能够诱导新生大鼠心室肌细胞（NRVM）有丝分裂，并能够抑制Meis1和Hoxb13的转录活性。X射线晶体结构分析证实，这两种抗生素都与Meis1的Hoxb13相互作用结构域附近结合，进而干扰这两种转录因子与DNA的结合。接下来，研究团队进一步证实了巴龙霉素和新霉素的联合使用可以刺激心肌细胞生长，并促进心脏再生。在两种心肌梗死小鼠模型中，巴龙霉素和新霉素的联合使用产生了最显著的左心室射血分数增强。最后，研究团队在大型哺乳动物（猪）中验证了巴龙霉素和新霉素的联合使用促进心脏再生潜力。结果显示，从缺血再灌注损伤一周后开始，每天静脉注射巴龙霉素和新霉素的混合物，使缺血再灌注损伤的猪模型的左心室短轴缩短率（评价左心室收缩率的指标）显著改善，此外，这种治疗还增加了心肌细胞有丝分裂的标志物，并减少了损伤后疤痕的大小。总的来说，该研究筛选到了两种已获FDA批准的常用抗生素——巴龙霉素（Paromomycin）和新霉素（Neomycin），它们通过阻断转录因子Meis1和Hoxb13的活性，在心肌梗死小鼠模型和心脏缺血/再灌注损伤猪模型中诱导心肌细胞增殖，改善左心室收缩功能，减少瘢痕形成。这些发现使研究人员更接近于在心力衰竭的临床试验中使用巴龙霉素和新霉素。论文链接：https://www.nature.com/articles/s44161-024-00450-y封面图来源：123rf版权声明/免责声明本文为授权转载文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢!药时代官方网站:www.drugtimes.cn联系方式:电话:13651980212微信:27674131邮箱:contact@drugtimes.cn全球首款端粒酶抑制剂能否获批？为什么这场ODAC会议值得关注默克终止BTK抑制剂开发！啃不动“自免”的骨头，肝损伤风险谁来验证……Ferring首席科学家杨翼博士：肥胖症疫苗离我们还有多远？点击这里，欣赏更多精彩内容！

Achieved FY2023 financial guidance FY2023 full year revenue grew 10% over prior year Webcast today, May 25, 2023 at 4:30 p.m. Eastern Time SOUTH SAN FRANCISCO, Calif., May 25, 2023 (GLOBE NEWSWIRE) -- 23andMe Holding Co. (Nasdaq: ME) (23andMe), a leading human genetics and biopharmaceutical company with a mission to help people access, understand, and benefit from the human genome, today reported its financial results for the fourth quarter (Q4) and full year of fiscal year 2023 (FY2023), which ended March 31, 2023. 23andMe is the only company with multiple U.S. Food and Drug Administration (FDA) authorizations for over-the-counter genetic health risk reports. The Company has also created the world’s largest, re-contactable crowdsourced platform of genotypic information paired with billions of phenotypic data points contributed by engaged customers. This unique platform enables the Company to discover new genetic insights, develop impactful risk prediction reports for common health conditions, and accelerate the identification of novel drug discovery programs rooted in human genetics across a spectrum of disease areas. “23andMe had a productive year with numerous consumer and therapeutics business milestones. We grew our customer base to over 14 million genotyped customers, and launched 11 new health reports for our 23andMe+ members, including the first and only direct-to-consumer FDA-authorized report on hereditary prostate cancer. As we continue to add value to our subscription product and integrate Lemonaid’s telehealth and pharmacy services, we believe we can truly help fulfill the promise of personalized care,” said Anne Wojcicki, Chief Executive Officer and Co-Founder of 23andMe. “Our Therapeutics group continues to advance a number of programs, including 23ME-00610, a wholly-owned immunotherapy currently in the Phase 2a portion of a Phase 1/2a study. We also remain well positioned to pursue collaborations with multiple pharma partners on a number of drug discovery and development and disease awareness efforts. By enhancing our efforts to provide a leading genetics-based health service and utilizing our discovery engine for new therapeutics, we have the opportunity to transform how we predict, prevent and treat diseases in the future.” Full Year FY2023 Financial Results Summary Delivered full year performance in FY23 that was within or better than guidance. $299 million revenue$312 million net loss$161 million Adjusted EBITDA deficit Solid balance sheet with cash of $387 million at year end. Recent Highlights ConsumerThe Company continued to add reports for 23andMe+ members, and launched a collaboration with Novartis for disease awareness. Launched three new reports for 23andMe+ members in the fourth quarter, and 11 total member-exclusive report launches in FY2023.The new reports released in the fourth quarter include: Preeclampsia PRS reportAttention deficit/hyperactivity disorder PRS reportHereditary prostate cancer (HOXB13-related) genetic health risk report Announced a collaboration with Novartis Pharmaceuticals Corporation to increase awareness for Lipoprotein(a) (Lp(a)). High levels of Lp(a) are associated with increased risk of heart attack, stroke and other life threatening conditions. The level of Lp(a) is almost entirely determined by genes and is unrelated to diet, exercise or obesity, creating the need for greater awareness. Therapeutics The Company continued to progress its wholly-owned 23ME-00610 program in the clinic. Presented results from the Phase 1 portion of the first-in-human Phase 1/2a study of 23ME-00610 in a poster at the 2023 American Association for Cancer Research (AACR) Annual Meeting. The results showed 23ME-00610 demonstrated an acceptable safety and tolerability profile, with favorable pharmacokinetics and peripheral CD200R1 saturation in patients with advanced solid malignancies.Dosed the first patient in the Phase 2a portion of its Phase 1/2a study evaluating the anti-tumor activity of the 23ME-00610 monotherapy in a number of previously disclosed expansion cohorts. Dosing will be at 1400 mg intravenously every 3 weeks based on Phase 1 data. The Phase 2a portion of the study will further characterize the safety, tolerability, pharmacokinetic and pharmacodynamic profile of 23ME-00610. CorporateThe Company added to its experienced leadership team and published its first ESG report. Announced the appointment of Reza Afkhami as Chief Corporate Development Officer overseeing corporate development efforts across the Company’s therapeutics, research services and consumer groups. Afkhami will lead the Company’s current efforts to pursue a wide range of collaborations, including leveraging the Company’s pipeline of genetically validated discovery and clinical programs, as well as patient recruitment and disease awareness campaigns.Published inaugural environmental social and governance (ESG) report that outlines the Company’s strategy and initiatives to ensure ethical management, promote a diverse and equitable culture, and implement sustainable business operations. The full report is available to view here. “Our 2023 fiscal year was important for 23andMe as we continued to prioritize the roll out of our next-generation genomic health services and advance our therapeutics efforts, while also remaining focused on growing our consumer business,” said Joe Selsavage, Interim Chief Financial and Accounting Officer of 23andMe. “We continue to use a disciplined approach in the advancement of our therapeutics portfolio and to focus our efforts on creating a new customer experience with our prevention-based genetic health services, further enabling our opportunities for growth.” FY2023 Fourth Quarter and Full Year Financial ResultsTotal revenue for the three and twelve months ended March 31, 2023, was $92 million and $299 million, respectively, compared to $101 million and $272 million, respectively, for the same periods in the prior year, representing a decrease of 8% and an increase of 10%, respectively. The decrease in fourth quarter revenue was primarily driven by a decrease in Research Services revenue from the GSK collaboration as the prior year included a cumulative revenue adjustment due to a change in estimate of total project resources, resulting in a higher percentage of completion to date, and a decrease in Consumer Services revenue from lower volumes on Personal Genome Service (PGS) kit sales as we focused on driving improved margins through higher average selling prices. Full year revenue growth was primarily driven by an increase in Consumer Services revenue attributable to a full year of telehealth services revenue from the Lemonaid Health Acquisition, whereas the prior year included only 5 months, and an increase in subscription services revenue, partially offset by a decrease in PGS kit revenue. Research Services revenue increased primarily due to an increase in GSK collaboration revenue related to GSK exercising their option to extend the exclusive target discovery period of our collaboration for a fifth year and an increase in revenue under research contracts with third parties. Revenue from Consumer Services, which includes PGS, telehealth and subscription services, represented approximately 88% and 83% of total revenue, respectively, for the three and twelve months ended March 31, 2023. Research Services revenue is primarily derived from the collaboration with GSK and accounted for approximately 12% and 17% of total revenue, respectively, for those same periods. Operating expenses for the three and twelve months ended March 31, 2023, were $109 million and $459 million, respectively, compared to $117 million and $387 million, respectively, for the same periods in the prior year. The decrease in operating expenses in the three-month period was primarily due to a one time net litigation settlement payment in fiscal year 2022 and timing differences in marketing campaigns and fewer promotional windows between the comparative periods. The increase in operating expenses in the twelve-month period was primarily attributable to increased personnel-related expenses driven by increased salaries and related taxes as a result of inflation and headcount growth, and a non-cash impairment charge of an intangible asset. These increases in operating expenses were primarily related to the previously acquired telehealth business. Net loss for the three and twelve months ended March 31, 2023, was $64 million and $312 million, respectively, compared to a net loss of $70 million and $217 million, respectively, for the same periods in the prior year. The improvement in the three-month period was primarily attributable to lower operating expenses (as noted above) and an increase in interest income from interest yields earned on cash held in money market funds. The increase in the twelve-month period was primarily attributable to the increase in operating expenses discussed above, as well as a benefit from change in fair value of warrant liabilities of $33 million and an income tax benefit of $3 million in the twelve months ended March 31, 2022. Total Adjusted EBITDA (as defined below) for the three and twelve months ended March 31, 2023, was a deficit of $39 million and $161 million, respectively, compared to a deficit of $30 million and $151 million, respectively, for the same periods in the prior year. The increase in the Adjusted EBITDA deficit for the three and twelve-month periods was primarily due to the increase in operating expenses noted above. Please refer to the tables below for a reconciliation of U.S. GAAP to Non-U.S. GAAP financial measures. Balance Sheet23andMe ended March 31, 2023 with cash and cash equivalents of $387 million, compared to $553 million as of March 31, 2022. FY2024 Financial GuidanceThe Company’s full year fiscal 2024 guidance is based on a conservative approach, recognizing the current uncertainties in the general economy and financial markets. Within the existing Consumer businesses of PGS and telehealth, the Company is prioritizing the minimization of cash burn over initiatives intended to create incremental top-line growth. For those areas of the business expected to drive future growth, which include the Company’s new genomic health services and Therapeutics, the Company plans to focus on the most strategically and financially valuable allocation of capital and invest appropriately. Given the Company’s shift in focus to higher margins rather than volume growth in PGS and telehealth, as well as the end of the target discovery term of the GSK collaboration, the Company does not foresee meaningful revenue contribution from these areas of Consumer in FY2024. Revenue guidance for FY2024, which will end on March 31, 2024, is projected to be in the range of $255 million to $280 million, with a net loss in the range of $340 million to $365 million. Full year adjusted EBITDA deficit is projected to be in the range of $170 to $195 million for fiscal year 2024. The Adjusted EBITDA guidance, assumes the following: We will continue to advance our current Therapeutic assetsNo additional revenue from new strategic partnershipsNo savings incurred from cost reduction initiatives, such as those related to the evaluation of opting-in or out of our GSK programs, out-licensing or partnering on our therapeutic programs or other internal operating cost reductions Adjusted EBITDA is our best proxy for cash burn and we do not assume the sale of any equity under our At-the-Market Sales program with Cowen and Company, LLC (the “ATM Program”). Conference Call Webcast Information23andMe will host a conference call at 4:30 p.m. Eastern Time on Thursday, May 25, 2023 to discuss the financial results for the full year and Q4 FY2023 and report on business progress. The webcast can be accessed on the day of the event at https://investors.23andme.com/news-events/events-presentations. A webcast replay will be available at the same address for a limited time within 24 hours after the event. About 23andMe23andMe is a genetics-led consumer healthcare and therapeutics company empowering a healthier future. For more information, please visit investors.23andme.com. Additional InformationThis press release shall not constitute an offer to sell or a solicitation of an offer to buy any of the securities, nor shall there be any sale of these securities, in any state or jurisdiction in which such an offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction. Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, including, without limitation, statements regarding the future performance of 23andMe’s Consumer and Research Services and Therapeutics businesses, the growth and potential of its proprietary research platform ,the development of the Company’s products and therapeutics programs, and access to and use of the ATM Program, including potential sales of shares pursuant thereto and the benefits thereof. All statements, other than statements of historical fact, included or incorporated in this press release, including statements regarding 23andMe’s expected future operating results, strategy, financial position, funding for continued operations, cash reserves, projected costs, plans, and objectives of management, are forward-looking statements. The words "believes," "anticipates," "estimates," "plans," "expects," "intends," "may," "could," "should," "potential," "likely," "projects," “predicts,” "continue," "will," “schedule,” and "would" or, in each case, their negative or other variations or comparable terminology, are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These forward-looking statements are predictions based on 23andMe’s current expectations and projections about future events and various assumptions. 23andMe cannot guarantee that it will actually achieve the plans, intentions, or expectations disclosed in its forward-looking statements and you should not place undue reliance on 23andMe’s forward-looking statements. These forward-looking statements involve a number of risks, uncertainties (many of which are beyond the control of 23andMe), or other assumptions that may cause actual results or performance to differ materially from those expressed or implied by these forward-looking statements. The forward-looking statements contained herein are also subject generally to other risks and uncertainties that are described from time to time in the Company’s filings with the Securities and Exchange Commission, including under Item 1A, “Risk Factors” in the Company’s most recent Annual Report on Form 10-K, as filed with the Securities and Exchange Commission, and as revised and updated by our Quarterly Reports on Form 10-Q and Current Reports on Form 8-K. The statements made herein are made as of the date of this press release and, except as may be required by law, 23andMe undertakes no obligation to update them, whether as a result of new information, developments, or otherwise. Use of Non-GAAP Financial MeasureTo supplement the 23andMe’s unaudited condensed consolidated statements of operations and unaudited condensed consolidated balance sheets, which are prepared in conformity with generally accepted accounting principles in the United States of America (GAAP), this press release also includes references to Adjusted EBITDA, which is a non-GAAP financial measure that 23andMe defines as net income (loss) before net interest income (expense), net other income (expense), income tax expenses (benefit), depreciation and amortization, impairment charges, stock-based compensation expense, acquisition-related costs, and other items that are considered unusual or not representative of underlying trends of our business, including but not limited to: changes in fair value of warrant liabilities, litigation settlement, and restructuring and other charges, if applicable for the periods presented. 23andMe has provided a reconciliation of net loss, the most directly comparable GAAP financial measure, to Adjusted EBITDA at the end of this press release. Adjusted EBITDA is a key measure used by 23andMe’s management and the board of directors to understand and evaluate operating performance and trends, to prepare and approve 23andMe’s annual budget and to develop short- and long-term operating plans. 23andMe provides Adjusted EBITDA because 23andMe believes it is frequently used by analysts, investors and other interested parties to evaluate companies in its industry and it facilitates comparisons on a consistent basis across reporting periods. Further, 23andMe believes it is helpful in highlighting trends in its operating results because it excludes items that are not indicative of 23andMe’s core operating performance. In particular, 23andMe believes that the exclusion of the items eliminated in calculating Adjusted EBITDA provides useful measures for period-to-period comparisons of 23andMe’s business. Accordingly, 23andMe believes that Adjusted EBITDA provides useful information in understanding and evaluating operating results in the same manner as 23andMe’s management and board of directors. In evaluating Adjusted EBITDA, you should be aware that in the future 23andMe will incur expenses similar to the adjustments in this presentation. 23andMe’s presentation of Adjusted EBITDA should not be construed as an inference that future results will be unaffected by these expenses or any unusual or non-recurring items. Adjusted EBITDA should not be considered in isolation of, or as an alternative to, measures prepared in accordance with GAAP. Other companies, including companies in the same industry, may calculate similarly-titled non-GAAP financial measures differently or may use other measures to evaluate their performance, all of which could reduce the usefulness of Adjusted EBITDA as a tool for comparison. There are a number of limitations related to the use of these non-GAAP financial measures rather than net loss, which is the most directly comparable financial measure calculated in accordance with GAAP. Some of the limitations of Adjusted EBITDA include (i) Adjusted EBITDA does not properly reflect capital commitments to be paid in the future, and (ii) although depreciation and amortization are non-cash charges, the underlying assets may need to be replaced and Adjusted EBITDA does not reflect these capital expenditures. When evaluating 23andMe’s performance, you should consider Adjusted EBITDA alongside other financial performance measures, including net loss and other GAAP results. ContactsInvestor Relations Contact: investors@23andMe.comMedia Contact: press@23andMe.com 23andMe Holding Co.Condensed Consolidated Statements of Operations and Comprehensive Loss(In thousands, except share and per share data)(Unaudited) Three Months EndedMarch 31, Year EndedMarch 31, 2023 2022 2023 2022 Revenue $92,377 $100,559 $299,489 $271,893 Cost of revenue 52,395 53,502 164,993 138,948 Gross profit 39,982 47,057 134,496 132,945 Operating expenses: Research and development 60,719 50,324 222,596 189,377 Sales and marketing 21,779 29,351 119,927 100,338 General and administrative 26,758 36,836 115,984 97,383 Total operating expenses 109,256 116,511 458,507 387,098 Loss from operations (69,274) (69,454) (324,011) (254,153)Other income (expense): Interest income, net 4,369 64 9,676 277 Change in fair value of warrant liabilities — — — 32,989 Other income (expense), net 174 (122) (93) (83)Loss before income taxes (64,731) (69,512) (314,428) (220,970)Benefit from income taxes (633) 32 (2,772) (3,480)Net loss (64,098) (69,544) (311,656) (217,490)Other comprehensive income (loss), net of tax (309) 215 (799) 179 Total comprehensive loss $(64,407) $(69,329) $(312,455) $(217,311)Net loss per share of Class A and Class B common stock attributable to common stockholders: Basic and diluted $(0.14) $(0.16) $(0.69) $(0.60)Weighted-average shares used to compute net loss per share: Basic and diluted 456,254,405 444,139,193 451,504,377 361,528,119 23andMe Holding Co.Condensed Consolidated Balance Sheets(In thousands, except share and per share amounts)(Unaudited) March 31, March 31, 2023 2022 ASSETS Current assets: Cash and cash equivalents $386,849 $553,182 Restricted cash 1,399 1,599 Accounts receivable, net 1,897 3,380 Inventories 10,247 10,789 Deferred cost of revenue 5,376 7,700 Prepaid expenses and other current assets 19,224 25,139 Total current assets 424,992 601,789 Property and equipment, net 38,608 49,851 Operating lease right-of-use assets 56,078 55,577 Restricted cash, noncurrent 6,974 6,974 Internal-use software, net 15,661 9,635 Intangible assets, net 45,520 73,905 Goodwill 351,744 351,744 Other assets 3,021 2,593 Total assets $942,598 $1,152,068 LIABILITIES AND STOCKHOLDERS’ EQUITY Current liabilities: Accounts payable $12,924 $37,930 Accrued expenses and other current liabilities 66,430 44,588 Deferred revenue 62,521 62,939 Operating lease liabilities 7,541 7,784 Total current liabilities 149,416 153,241 Operating lease liabilities, noncurrent 77,763 78,524 Other liabilities 1,480 4,647 Total liabilities 228,659 236,412 Stockholders' equity Preferred stock - par value $0.0001, 10,000,000 shares authorized as of March 31, 2023 and 2022; zero shares issued and outstanding as of March 31, 2023 and 2022 — — Common stock, par value $0.0001 - Class A shares, 1,140,000,000 shares authorized, 293,020,474 and 228,174,718 shares issued and outstanding as of March 31, 2023 and 2022, respectively; Class B shares, 350,000,000 shares authorized, 168,179,488 and 220,637,603 shares issued and outstanding as of March 31, 2023 and 2022, respectively 46 45 Additional paid-in capital 2,220,897 2,110,160 Accumulated other comprehensive income (loss) (620) 179 Accumulated deficit (1,506,384) (1,194,728)Total stockholders’ equity 713,939 915,656 Total liabilities and stockholders’ equity $942,598 $1,152,068 23andMe Holding Co.Condensed Consolidated Statements of Cash Flows(In thousands)(Unaudited) Year Ended March 31, 2023 2022 Cash flows from operating activities: Net loss $(311,656) $(217,490)Adjustments to reconcile net loss to net cash used in operating activities: Depreciation and amortization 32,071 23,699 Amortization and impairment of internal-use software 4,427 2,449 Stock-based compensation expense 116,017 57,933 Changes in fair value of warrant liabilities — (32,989)Impairment of long-lived assets 10,126 — Other 77 85 Changes in operating assets and liabilities: Accounts receivable, net 1,483 (899)Inventories 542 (4,262)Deferred cost of revenue 2,325 (2,219)Prepaid expenses and other current assets 6,653 (10,077)Operating right-of-use assets 7,393 7,078 Other assets (429) (1,820)Accounts payable (24,573) 22,856 Accrued expenses and other current liabilities 2,671 8,316 Deferred revenue (418) (8,799)Operating lease liabilities (8,934) (7,054)Other liabilities (3,165) (3,635)Net cash used in operating activities (165,390) (166,828)Cash flows from investing activities: Purchases of property and equipment (4,043) (3,967)Purchases of intangible assets — (5,500)Capitalized internal-use software costs (7,262) (4,505)Cash paid for acquisitions, net of cash acquired — (94,165)Net cash used in investing activities (11,305) (108,137)Cash flows from financing activities: Proceeds from exercise of stock options 4,203 16,998 Proceeds from issuance of common stock under employee stock purchase plan 6,464 — Payments for taxes related to net share settlement of equity awards (197) — Payments of deferred offering costs (693) (30,642)Proceeds from issuance of common stock upon merger — 309,720 Proceeds from PIPE — 250,000 Proceeds from exercise of merger warrants — 44 Payment for warrant redemptions — (116)Net cash provided by financing activities 9,777 546,004 Effect of exchange rates on cash and cash equivalents 385 (146)Net increase (decrease) in cash, cash equivalents and restricted cash (166,533) 270,893 Cash, cash equivalents and restricted cash—beginning of period 561,755 290,862 Cash, cash equivalents and restricted cash—end of period $395,222 $561,755 Reconciliation of cash, cash equivalents, and restricted cash within the consolidated balance sheets to the amounts shown in the consolidated statements of cash flows above: Cash and cash equivalents $386,849 $553,182 Restricted cash, current 1,399 1,599 Restricted cash, noncurrent 6,974 6,974 Total cash, cash equivalents and restricted cash $395,222 $561,755 23andMe Holding Co.Total Company and Segment Information and Reconciliation of Non-GAAP Financial Measures(In thousands)(Unaudited) The Company’s revenue and Adjusted EBITDA by segment and for the total Company is as follows: Three Months EndedMarch 31, Year EndedMarch 31, 2023 2022 2023 2022 Segment Revenue:(1) Consumer and Research Services $92,377 $100,559 $299,489 $271,893 Segment Adjusted EBITDA: Consumer and Research Services Adjusted EBITDA $4,989 $3,120 $(17,997) $(30,112)Therapeutics Adjusted EBITDA (29,904) (19,898) (88,503) (76,944)Unallocated Corporate (2) (13,744) (12,992) (54,801) (43,684)Total Adjusted EBITDA $(38,659) $(29,770) $(161,301) $(150,740)Reconciliation of net loss to Adjusted EBITDA: Net loss $(64,098) $(69,544) $(311,656) $(217,490)Adjustments: Interest income, net (4,369) (64) (9,676) (277)Other (income) expense, net (174) 122 93 83 Change in fair value of warrant liabilities — — — (32,989)Income tax expense (benefit) (633) 32 (2,772) (3,480)Depreciation and amortization 4,727 4,711 20,239 18,899 Amortization of acquired intangible assets 3,639 4,371 16,486 7,269 Impairment of acquired intangible asset — — 9,968 — Stock-based compensation expense 22,249 20,460 116,017 57,933 Acquisition-related costs (3) — 192 — 9,362 Litigation settlement (4) — 9,950 — 9,950 Total Adjusted EBITDA $(38,659) $(29,770) $(161,301) $(150,740) (1) There was no Therapeutics revenue for all periods presented.(2) Certain department expenses such as Finance, Legal, Regulatory and Supplier Quality, Corporate Communications, and CEO Office are not reported as part of the reporting segments as reviewed by the CODM. These amounts are included in Unallocated Corporate.(3) For the fiscal year ended March 31, 2022, acquisition-related costs primarily consisted of advisory, legal and consulting fees related to the Lemonaid Acquisition.(4) For the fiscal year ended March 31, 2022, litigation settlement is litigation cost net of insurance recoveries, which is not expected to occur on a recurring basis and not part of the Company's normal and continued business activity. 23andMe Holding Co.Reconciliation of GAAP Net Loss Outlook to non-GAAP Adjusted EBITDA Outlook(in thousands)(Unaudited) Outlook for the Year Ending March 31, 2024 as of March 31, 2023 Low High Reconciliation of estimated net loss to adjusted EBITDA: GAAP Net Loss outlook $(365,000) $(340,000)Adjustments Estimated interest (income) expense, net (11,000) (11,000)Estimated other (income) expenses, net — — Estimated depreciation and amortization 21,000 21,000 Estimated amortization of acquired intangible assets 11,000 11,000 Estimated stock-based compensation expense 149,000 149,000 Non-GAAP adjusted EBITDA outlook $(195,000) $(170,000)

研究者们鉴定了9个胃癌风险基因，其胚系致病性变异与胃癌易感性相关。其中，编码同源重组蛋白的基因发生胚系致病性变异，与幽门螺杆菌感染之间具有很强的相关性。 胃癌是全球第五大常见癌症，以及第四大癌症相关死亡原因。 环境暴露被认为是绝大多数胃癌病例的驱动因素，如不健康的饮食习惯、吸烟、慢性幽门螺杆菌感染等，这些因素与胃癌的发生密切相关。其中，幽门螺杆菌感染与胃癌风险之间的关系早在1991年就被首次报道，这导致幽门螺杆菌在1994年被世界卫生组织归类为I类致癌物。据统计，如今世界上有一半以上的人遭受幽门螺杆菌的困扰，在东亚地区因幽门螺杆菌感染导致的胃癌发生率已达十万分之17.6。 一项随机对照试验显示，幽门螺杆菌的根除可以降低胃癌的发病率，即使是在一级亲属中有胃癌的人群中也能看到效果。然而，家族通常共享遗传和环境因素，因此不清楚根除治疗是主要在基因易感人群中有效，或是在任何人群中都有效。 近日，一篇发表在《新英格兰医学杂志》期刊上的文章提出，部分基因的胚系致病性变异与幽门螺杆菌感染会形成两面包夹之势，极大加剧胃癌患病风险[1]。 论文首页截图 在这项研究中，研究者们纳入来自日本生物库（BBJ）的10426名胃癌患者、38153名非胃癌患者，以及来自爱知癌症中心医院流行病学研究项目（HERPACC）的1433名胃癌患者、5997名非胃癌患者进行分析。 所有参与者均受幽门螺杆菌感染。其中，来自BBJ或HERPACC的胃癌患者中位年龄为69或62岁，男性占比74.5%或74.6%；对照组参与者中位年龄为64岁或55岁，男性占比为53.1%或51.1%。 首先，研究者们基于BBJ队列对以下27个癌症易感基因的胚系致病性变异与胃癌风险之间的关系进行评估，包括编码同源重组蛋白的基因（HR基因）、编码错配修复蛋白的基因等：CDH1、ATM、BARD1、BRCA1、BRCA2、BRIP1、CHEK2、PALB2、RAD51C、RAD51D、MLH1、MSH2、MSH6、PMS2、APC、 BMPR1A、CDK4、CDKN2A、EPCAM、HOXB13、MUTYH、NBN、NF1、PTEN、SMAD4、STK11、TP53。 分析结果显示，BRCA1、BRCA2、APC、ATM、CDH1、MLH1、MSH2、MSH6、PALB2这九个基因发生胚系变异时会增加胃癌易感性，与胃癌风险显著相关。 九个胃癌易感基因 研究者们进一步调查了BBJ队列中基因变异携带者的年龄和临床诊断特征，结果发现，携带这些基因胚系致病性变异的人确诊胃癌时的年龄比非携带者更年轻。携带其中任何一个基因胚系致病性变异的患者，其诊断年龄中位数比非携带者年轻10岁以上，例如APC基因、CDH1基因、MLH1基因胚系致病性变异携带者的诊断中位数分别为18.0岁、20.5岁、11.5岁。 基因致病性变异携带者确诊时的年龄 随后，研究者们基于HERPACC队列鉴定出以上9个胃癌风险基因的74种胚系致病性变异。 另外还发现，与不携带HR基因胚系致病性变异且未感染幽门螺杆菌的人群相比，只感染幽门螺杆菌的人患胃癌风险增加476%（OR，5.76；95%CI，4.88-6.80）；只携带HR基因胚系致病性变异的人患胃癌风险增加68%（OR，1.68；95%CI，0.59-4.83）；而感染幽门螺杆菌+携带HR基因胚系致病性变异的人，患胃癌风险增加21倍多（OR，22.45；95%CI，12.09-41.70）。 分析结果提示，ATM、BRCA1、BRCA2、PALB2这4种HR基因发生任何一种胚系致病性变异，与幽门螺杆菌感染之间存在很强的相互作用，超额相对风险增加15.01（RERI，16.01；95%CI，2.22-29.81；P=0.02）。 HERPACC队列中，胃癌风险基因胚系致病性变异与幽门螺杆菌感染状态对胃癌风险的联合影响 相比之下，并未发现修复错配基因的胚系致病性变异和幽门螺杆菌感染之间存在强相互作用。 对于感染幽门螺杆菌的人来说，如果携带ATM、BRCA1、BRCA2和PALB2这4种HR基因的胚系致病性变异，在85岁之前发生胃癌的风险高达45.5%（95%CI，20.7-62.6），远高于非携带者的14.4%（95%CI，12.2-16.6）。而对于没有感染幽门螺杆菌的人群来说，是否携带HR基因胚系致病性变异，85岁之前发生胃癌的风险均低于5%。 不同人群到85岁时的累计患胃癌风险 研究者们对这背后的机制进行了推测。已有研究表明，幽门螺杆菌分泌的多功能效应蛋白CagA，会引起DNA双链断裂以及同源重组修复功能受损，导致基因组不稳定，有助于胃癌的发生。而对于HR基因胚系致病性变异的人来说，介导同源重组的蛋白无法正常表达，幽门螺杆菌感染所导致的胃癌相关 NA损伤作用则被放大。 推测HR基因致病性变异与幽门螺杆菌感染之间互作的机制[2] 总体来说，研究者们鉴定了9个胃癌风险基因，其胚系致病性变异与胃癌易感性相关。其中，编码同源重组蛋白的基因发生胚系致病性变异，与幽门螺杆菌感染之间具有很强的相关性。对于幽门螺杆菌感染者来说，ATM、BRCA1、BRCA2、PALB2基因发生胚系致病性变异大大提高其胃癌患病风险。 研究者们提出，在已知携带HR基因胚系致病性变异的人群中，检测和根除幽门螺杆菌感染可能尤为重要。 参考文献： [1]https://www.nejm.org/doi/full/10.1056/NEJMoa2211807 [2]https://www.nejm.org/doi/full/10.1056/NEJMe2215503